^
1d
For patients with resectable disease at presentation (10%-15%), surgery followed by adjuvant chemotherapy with FOLFIRINOX (fluorouracil, irinotecan, leucovorin, oxaliplatin) represents a standard therapeutic approach with an anticipated median overall survival of 54.4 months, compared with 35 months for single-agent gemcitabine (stratified hazard ratio for death, 0.64 [95% CI, 0.48-0.86]; P = .003)...For patients with advanced (locally advanced and metastatic) PDAC, multiagent chemotherapy regimens, including FOLFIRINOX, gemcitabine/nab-paclitaxel, and nanoliposomal irinotecan/fluorouracil, all have a survival benefit of 2 to 6 months compared with a single-agent gemcitabine. For the 5% to 7% of patients with a BRCA pathogenic germline variant and metastatic PDAC, olaparib, a poly (adenosine diphosphate [ADB]-ribose) polymerase inhibitor, is a maintenance option that improves progression-free survival following initial platinum-based therapy...Currently available cytotoxic therapies for advanced disease are modestly effective. For all patients, multidisciplinary management, comprehensive germline testing, and integrated supportive care are recommended.
Review • Journal • BRCA Biomarker • PARP Biomarker
|
BRCA (Breast cancer early onset)
|
Lynparza (olaparib) • gemcitabine • 5-fluorouracil • oxaliplatin • Abraxane (albumin-bound paclitaxel) • leucovorin calcium • Onivyde (nanoliposomal irinotecan)
1d
We show miR-802 suppresses pancreatic cancer initiation by repressing oncogenic Kras-induced ADM. The role of miR-802 in ADM fills the gap in our understanding of oncogenic Kras-induced F-actin reorganization, acinar reprogramming and PDAC initiation. Modulation of the miR-802-RhoA-F-Actin network may be a new strategy to interfere with pancreatic carcinogenesis.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • RHOA (Ras homolog family member A) • SDC4 (Syndecan 4) • SOX9 (SRY-Box Transcription Factor 9)
|
KRAS mutation
2d
Furthermore, c-Myc bound with the promoter region of lactate dehydrogenase A (LDHA) to activate the transcription. Collectively, present findings reveal that circSLIT2/miR-510-5p/c-Myc/LDHA axis participates in the aerobic glycolysis and carcinogenesis of PDAC, and may act as a promising therapeutic target.
Journal
|
MYC (V-myc avian myelocytomatosis viral oncogene homolog) • LDHA (Lactate dehydrogenase A)
2d
Taken together, our findings confirm for the first time that circ-0005105 has critical functions by regulating the miR-20a-3p-COL11A1 axis. In the clinic, circ-0005105 can act as a potential prognostic marker and therapeutic target in PDAC.
Journal
|
COL1A1 (Collagen, type I, alpha 1) • MIR20A (MicroRNA 20a)
2d
The model constructed by XGBoost could predict PDAC TILs and may aid clinical decision making for immune therapy.
Clinical • Retrospective data • Journal • Tumor-Infiltrating Lymphocyte
|
CD20 (Membrane Spanning 4-Domains A1) • CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule)
|
CD8 expression • CD4 expression
2d
These findings indicate that activated PSCs play an important role in the development and progression of chronic pancreatitis into pancreatic cancer by regulating and promoting aerobic glycolysis. Our research provides a new theoretical basis for further understanding the mechanism of CP malignancy and the selection of targets for reversing CP malignancy.
Journal
|
LDHA (Lactate dehydrogenase A) • PKM (Pyruvate Kinase M1/2)
2d
Both IFN-γ and Batf3, which lack conventional dendritic cells, did not show a significant decrease in tumor volume when treated. These results indicate that IFN-γ and dendritic cells may play critical roles in the immune response necessary to treat pancreatic cancer.
Preclinical • Journal • IO biomarker
|
KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • CD4 (CD4 Molecule)
|
TP53 mutation • KRAS mutation • KRAS mutation + TP53 mutation
2d
Here, by utilizing exosomes secreted from hucMSCs, we systematically investigated the effects of hucMSCs-exo on PDAC growth in vitro and in vivo for the first time. Building on these results, we provided new insights into the role of hucMSCs-exo in the PDAC growth and revealed the attractive communication between hucMSCs and PDAC cells that occurs through MSCs-exosomes-miRNAs.
Journal
|
MIR21 (MicroRNA 21) • MIR100 (MicroRNA 100) • MIR92A1 (MicroRNA 92a-1) • MIR148A (MicroRNA 148a)
3d
Loss of ARID1A expression leads to an upregulation of inflammation, a trigger of carcinogenesis. A change in the transcription of cytokines resulted in increased secretion of inflammatory cytokines in the context of ARID1A-deficiency. Therefore, targeting inflammatory signaling pathways such as the NFκB or the JAK-STAT pathway could be a promising therapeutic option in ARID1A-deficient PDAC.
ARID1A (AT-rich interaction domain 1A)
|
ARID1A mutation
4d
Conclusions Collectively, our studies provide evidence for a novel role for P311 in M2 macrophage polarization and infiltration, uncovering the underlying oncogenic role of P311 in PDAC. Targeting P311 may serve as a novel potential therapeutic option to reset TAM polarization toward an antitumor state in PDAC.
CD163 (CD163 Molecule) • CSF1 (Colony stimulating factor 1) • IL10 (Interleukin 10) • CD68 (CD68 Molecule)
5d
The 5 MSI cases were PD-L1-. The distinct PD-1/PD-L1-associated immunoarchitectural patterns underpin the heterogeneity of the immunological responses and might be used to inform patient outcomes and therapeutic decisions in pancreatic cancer.
Clinical • Journal • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • CD8 (cluster of differentiation 8) • PD-1 (Programmed cell death 1) • CD68 (CD68 Molecule) • MRC1 (Mannose Receptor C-Type 1)
|
PD-L1 expression
5d
In resected human pancreatic neoplasms, we find that foci of phospho-ERK-positive acinar cells are common and frequently contain activating KRAS mutations, suggesting that these acinar regions represent an early cancer precursor lesion. These data support a model in which rare TERT acinar cells may sustain KRAS mutations, driving acinar cell expansion and creating a field of aberrant cells initiating pancreatic tumorigenesis.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • TERT (Telomerase Reverse Transcriptase)
|
KRAS mutation • ER positive • KRAS expression • TERT mutation
5d
USP21 promotes KRAS*-independent tumor growth via its regulation of MARK3-induced macropinocytosis, which serves to maintain intracellular amino acid levels for anabolic growth. The USP21-mediated KRAS* bypass, coupled with the frequent amplification of USP21 in human PDAC tumors, encourages the assessment of USP21 as a novel drug target as well as a potential parameter that may affect responsiveness to emergent anti-KRAS* therapy.
Journal
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
5d
In conclusion, patients with cholestasis seem to have a lower risk for POPF, and an increase in collagen I. A degenerated matrix with lower content of structural ECM components correlates with increased risk of POPF. However, ex vivo uniaxial compression testing failed to clearly explain the link of ECM properties and POPF.
Journal
|
FN1 (Fibronectin 1)
6d
Lynch syndrome tends to be associated with poorly differentiated carcinoma, including signet ring cell carcinoma in colon, but has not been reported in pancreas. It imposes a diagnostic challenge for FNA cytology and frozen section if not aware of this rare variant.
Clinical
|
MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2)
|
MSH2 mutation
6d
This case provides a unique synchronous presentation of 2 distinct neoplasms within the pancreaticobiliary system. Although this presentation is rare, it should be considered when assessing multiple pancreaticobiliary lesions.
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation • KRAS G12V • KRAS G12
6d
FXYD2 shows higher sensitivity and specificity for identifying intrahepatic cholangiocarcinoma compared with albumin ISH in a limited cohort. The combination of DPC4 and FXYD2 may represent a diagnostically useful panel in differentiating adenocarcinomas of upper GI and pancreatobiliary origin.
BAP1 (BRCA1 Associated Protein 1) • MUC5AC (Mucin 5AC) • S100P (S100 calcium binding protein P)
7d
There was a significant immunohistochemically positive correlation between KIAA1199 and HIF1α. These findings suggest that hypoxia-induced KIAA1199 expression may contribute to enhanced motility in PDAC.
Journal
|
HIF1A (Hypoxia inducible factor 1, alpha subunit) • HAS3 (Hyaluronan Synthase 3)
|
HAS3 expression
7d
Then PDGL-GEM was co-precipitated with the autophagy inhibitor chloroquine phosphate (CQ) and calcium phosphate to formulate PDGL-GEM@CAP/CQ. More importantly, mechanistic studies in vitro and in vivo suggested that the nanobomb inhibits metastasis by downregulating MMP-2 and paxillin, as well as reducing fibrosis. The pH-sensitive PDGL-GEM@CAP/CQ shows potential for inhibiting proliferation and metastasis of pancreatic cancer through an autophagy-dependent pathway.
Journal
|
MMP2 (Matrix metallopeptidase 2) • PXN (Paxillin)
|
gemcitabine • chloroquine phosphate
7d
Finally, in vivo assays demonstrated that miR-374b-5p overexpression suppressed tumor growth and lung metastasis in PANC-1 cells. Thus, our findings indicate that miR-374b-5p could be a potential prognostic biomarker and therapeutic target for KDM5B-induced EMT in PC.
Journal
|
CDH1 (Cadherin 1) • VIM (Vimentin)
|
CDH1 expression • VIM expression
7d
Finally, we determined that CCIs involving 33 poor-prognostic LR pairs were associated with tumor grade. Although the clinical implication of the set of LR pairs must be determined, our results may provide potential therapeutic targets in PDAC.
Journal
|
ANXA1 (Annexin A1)
7d
Our study indicates that PDAC cells produced CCL2, which promoted localized M-MDSC recruitment and immune suppression, thereby promoting tumor progression.
Journal
|
CD8 (cluster of differentiation 8) • CCL2 (Chemokine (C-C motif) ligand 2) • CD14 • CD33 (CD33 Molecule)
|
CCL2-H
8d
The activation of receptors has been reported to be aberrant to cell cycle regulation, and signal transduction pathways, such as growth-factor induced proliferation, and can also influence the apoptotic sensitivity of tumor cells. In this article, the regulation of RTKs/TGFβR between pancreatic ductal adenocarcinoma (PDAC) and CAFs, as well as the RTKs/TGFβR inhibitor-based clinical trials on pancreatic cancer are reviewed.
Review • Journal
|
TGFB1 (Transforming Growth Factor Beta 1)
8d
Additionally, the combination of anakinra with cytotoxic chemotherapy significantly extends overall survival compared with vehicle treatment or anakinra monotherapy in this aggressive genetic mouse model of PDAC. These data highlight the importance of IL-1 in mediating tumor-stromal IL-6/STAT3 crosstalk in the TME and provide preclinical rationale for targeting IL-1 signaling as a therapeutic strategy in PDAC.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • IL6 (Interleukin 6)
|
KRAS G12D • KRAS G12
|
Kineret (anakinra)
8d
Despite the inherent biases of this retrospective study, the addition of Sintilimab significantly improved salvage resection rates and OS compared with the NPS regimen and had a favorable safety profile in treatment naïve mPDAC patients.
Retrospective data • Journal
|
Cancer antigen 19-9
|
Abraxane (albumin-bound paclitaxel) • Tyvyt (sintilimab) • Teysuno (gimeracil/oteracil/tegafur)
9d
CAFs are a key element of intra-tumoral migration and should be further investigated as a potential therapeutic target.
Journal
|
IL6 (Interleukin 6)
9d
The CEUS enhancement patterns of PDAC in the arterial phase include iso-enhancement and hypo-enhancement. Enhancement pattern was not significantly correlated with the degree of differentiation of tumour tissue, but patient survival time differed significantly between the two enhancement patterns, with longer survival for patients with iso-enhancement.
Journal
|
Cancer antigen 19-9
9d
ApoE mediates immune suppression in pancreatic ductal adenocarcinoma.
Journal
|
APOE (Apolipoprotein E)
10d
P3, N=378, Recruiting, Erasmus Medical Center | Not yet recruiting --> Recruiting
Clinical • Enrollment open
|
CEACAM5 (CEA Cell Adhesion Molecule 5)
|
5-fluorouracil • oxaliplatin • irinotecan • leucovorin calcium
11d
Clinical • Late-breaking abstract
|
CDKN2A (Cyclin-dependent kinase inhibitor 2A)
|
CDKN2A mutation
11d
Clinical • Late-breaking abstract
|
CDKN2A (Cyclin-dependent kinase inhibitor 2A)
|
CDKN2A mutation
11d
However, PHGDH knockdown efficiently suppressed PDAC cell growth and tumor growth under serine starvation. These findings provide evidence that targeting the serine biosynthesis pathway by inhibiting PHGDH is a potent therapeutic approach to eliminate PDAC cells in nutrient-deprived microenvironments.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • PHGDH (Phosphoglycerate Dehydrogenase)
|
KRAS mutation • PHGDH-L
12d
To conclude, CDK1 inhibition induces G2/M cell cycle arrest, stimulates apoptosis, and specifically targets CSCs, which makes it a promising treatment for PDAC. Screening of patients for CDK1 overexpression and further research into combination treatments is essential for optimizing this novel targeted therapy.
Review • Journal
|
CDK1 (Cyclin-dependent kinase 1)
|
CDK1 overexpression
12d
Here, we discuss the significance of targeting PI3K signaling and the biological impact of PI3K inhibition in modulating the tumor-stromal immune crosstalk within the microenvironment of pancreatic cancer. Furthermore, this review updates on the current challenges involving the therapeutic implications of targeting this pathway in PDAC.
Review • Journal
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
12d
PV in homologous recombination genes were associated with improved overall survival (HR = 0.51; 95% CI 0.34-0.77). (4) Our analysis emphasizes the value of multigene panel testing in PDAC patients, especially in individuals with a positive family cancer history, and underlines the importance of population-matched controls for risk assessment.
Clinical • Journal • BRCA Biomarker
|
BRCA2 (Breast cancer 2, early onset) • BRCA1 (Breast cancer 1, early onset) • CHEK2 (Checkpoint kinase 2)
12d
Integration of genomic data for classification of PDAC into clinically defined entities-i.e., classical vs. squamous subtypes of PDAC-leading to different treatment approaches has the potential for significantly improving patient outcomes. In this review, we summarize current knowledge about the most relevant genomic subtypes of PDAC including the impact of distinct patterns of intra-tumoral genomic heterogeneity on the classification and clinical and therapeutic management of PDAC.
Clinical • Review • Journal
|
KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • SMAD4 (SMAD family member 4)
13d
Moreover, high-risk groups were associated with significantly higher levels of plasma B cells and resting NK cells infiltration, and lower levels of infiltrating resting memory CD4 T cells, monocytes, and resting mast cells. Our study proposed a robust m6A-related prognostic signature of lncRNAs for predicting OS in PDAC, which provides some clues for further studies focusing on the mechanism process underlying m6A modification of lncRNAs.
Journal
|
CD4 (CD4 Molecule)
13d
We discuss the various efforts for therapeutic targeting of KRAS. Further, we explore the reasons behind these obstacles, novel successful approaches to target mutant KRAS including G12C mutation as well as the mechanisms of resistance.
Review • Journal
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation • KRAS G12C • KRAS G12
16d
Our study clearly shows that β1 integrins are robust targets for overcoming radioresistance in PDAC. This seems to apply equally to therapy-sensitive and radioresistant cells. Concerning tumor heterogeneity, this dual therapy-sensitizing potential might be exploitable for a significant improvement of patient survival.
Preclinical • Journal
|
RET (Ret Proto-Oncogene) • PDPK1 (3-Phosphoinositide dependent protein kinase 1)
16d
Univariate and multivariate Cox regression analyses revealed that the risk score was also an important predictor of pancreatic cancer. In conclusion, 6-mRNA expression is a potentially valuable method for predicting pancreatic cancer metastasis, assessing clinical outcomes, and facilitating future personalized treatment for patients with ductal adenocarcinoma of the pancreas (PDAC).
Journal
|
LAMC2 (Laminin subunit gamma 2)
18d
Additionally, small molecule STING agonists trigger IFN signaling-dependent TYMP expression in PDAC cells and increase tumor [F]FLT uptake in vivo following systemic treatment. These findings indicate that [F]FLT accumulation in tumors is sensitive to IFN signaling and that [F]FLT PET may serve as a pharmacodynamic biomarker for STING agonist-based therapies in PDAC and possibly other malignancies characterized by elevated STING expression.
Journal • IO biomarker
|
STING (stimulator of interferon response cGAMP interactor 1)
19d
In addition, the Human Protein Atlas was used to investigate the protein expression of five hub CRGs. In brief, we utilized scRNA-seq to reveal the invasive trajectory of ductal cells and identified crucial CRGs in PDAC, which may help predict patient survival and provide potential clinical therapeutic targets against CSCs.
Journal • Tumor Mutational Burden
|
TMB (Tumor Mutational Burden)
19d
To surmount the pathological obstacle, we developed a size switchable nanosystem based on PEG-PLGA nanospheres encapsulated within liposomes for the combined delivery of vactosertib (VAC), a TGF-β1 receptor kinase inhibitor, and the cytotoxic drug paclitaxel (TAX). The inhibition of ECM hyperplasia by VAC allows TAX more ready access to the cancer cells in addition to its small size, thereby shrinking pancreatic tumor xenografts more effectively than a combination of the free drugs. This size switchable nanosystem enables sequential delivery of drugs at a fixed dose combination with simplified administration and provides an encouraging cascade approach of drug penetration for enhanced chemotherapy in cancers with a dense desmoplastic stroma.
Journal
|
FN1 (Fibronectin 1) • TGFB1 (Transforming Growth Factor Beta 1)
|
paclitaxel • vactosertib (TEW-7197)
20d
Disulfiram (DSF), an old anti-alcoholism drug, has emerged as a candidate for drug repurposing in oncology. DSF exhibited a synergistic effect, as analyzed by drug coefficient interactions, with either PP2, or dasatinib, or SRC depletion in suppressing PDAC cells in vitro and/or in vivo. The present results indicate DSF is a potential therapeutic drug, particularly when it is combined with SRC inhibitors, and warrant further studies on the pharmacological utility of DSF as a promising adjunct therapy for the treatment of PDAC.
Preclinical • Journal • PARP Biomarker • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • STAT3 (Signal Transducer And Activator Of Transcription 3) • AFAP1 (Actin Filament Associated Protein 1)
|
STAT3 expression
|
dasatinib • disulfiram
20d
We identified potential prognostic biomarkers and therapeutic targets of patients with PDAC. Understanding these molecular aberrations that determine patient outcomes after surgery and chemotherapy has the potential to improve the treatment outcomes of PDAC patients.
Clinical • Clinical data • Journal
|
KRAS (KRAS proto-oncogene GTPase) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • MSI (Microsatellite instability) • LRP1B (LDL Receptor Related Protein 1B) • SMAD4 (SMAD family member 4) • RNF43 (Ring Finger Protein 43)
|
TP53 mutation • KRAS mutation
22d
This not only defined the genetics of tumor entities, but also identified the prognosis and biology of tumor groups on the basis of RNA expression patterns. The range of treatment could be expanded by targeted molecular therapies (especially for patients with BRCA1/2 germline mutations, NTRK- or NRG1-fusions, or oncogenic BRAF and PIK3CA mutations as well as tumors with microsatellite instability (MSI)), even if targeted therapies are currently only available for a minority of patients (<10%).
Review • Journal • BRCA Biomarker
|
BRAF (B-raf proto-oncogene) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • BRCA2 (Breast cancer 2, early onset) • BRCA1 (Breast cancer 1, early onset) • MSI (Microsatellite instability) • NRG1 (Neuregulin 1) • NTRK (Neurotrophic receptor tyrosine kinase)
|
BRAF mutation • PIK3CA mutation • NRG1 fusion • NRG1 fusion
22d
This study showed that the PS may be useful for predicting the prognosis of BRPC patients treated with NAT.
Clinical • Journal
|
Cancer antigen 19-9
24d
P1, N=15, Terminated, BioNTech Research & Development, Inc. | Active, not recruiting --> Terminated; Sponsor decision
Clinical • Trial termination
|
Cancer antigen 19-9
|
BNT321
25d
pCR or near-pCR to preoperative CRT contributed to achieving a high rate of R0 resection and improving survival for localized PDAC. The use of gemcitabine plus S-1 as a radiosensitizer, lower serum CA19-9 level after CRT, and longer preoperative treatment duration were significantly associated with pCR or near-pCR.
Clinical • Journal
|
Cancer antigen 19-9
|
gemcitabine • Teysuno (gimeracil/oteracil/tegafur)
25d
To our knowledge, this is the first report of the synchronous occurrence of PDAC and PGL. This case emphasizes the importance of thorough macroscopic examination of pancreatic resection specimens, as coexisting neoplasms may otherwise be missed.
Journal • BRCA Biomarker
|
KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • BRCA2 (Breast cancer 2, early onset) • NCOR1 (Nuclear Receptor Corepressor 1) • SPTA1 (Spectrin Alpha)
|
TP53 mutation • KRAS mutation
26d
Immunohistochemistry was useful to rule out a STIC and help identify the primary tumour. Lack of PAX-8 expression, along with immunoreactivity for CK7, CK20, and CDX-2 provided support for a nongynecologic origin. The normal endoscopy and the presence of a mass in the tail of the pancreas made this the most probable origin of the tumour.
TP53 (Tumor protein P53) • CDX-2 • PAX8 (Paired box 8) • Cancer antigen 19-9
|
CDX-2 expression
26d
UPCOC is very rare. It often occurs around the sixth decade. Histological study reveals two distinct cell populations.
Clinical
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
26d
Both epithelial and stromal STIM1 may have a role in the early development of PDAC. Targeting STIM1 may be effective in pri- mary and metastatic PDAC patients. The significant epithelial STIM1 expression and its association with presence of desmoplastic stroma may indicate epithelial mesenchymal transition.
STIM1 (Stromal Interaction Molecule 1)
26d
KLK6 inhibition reduced KLK6 mRNA expression, cell metabolic activity and KLK6 secretion and increased the secretion of other serine and aspartic lysosomal proteases. The association of high KLK levels and poor prognosis suggests that inhibiting KLKs may be a therapeutic strategy for precision medicine.
Journal
|
CD68 (CD68 Molecule) • KRT19 (Keratin 19)
26d
Additionally, we demonstrate that PLEXIND1-mediated interactions can be selectively disrupted using a peptide based on its C-terminal sequence (a PDZ domain-binding motif), an outcome that may possess significant therapeutic implications. To our knowledge, this is the first report showing that (1) PLEXIND1 acts as a TGFβ coreceptor and mediates SMAD3 signaling, and (2) differential roles of PLEXIND1 in PDAC cell lines correlate with KRAS and KRAS status.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • TGFB1 (Transforming Growth Factor Beta 1) • SMAD3 (SMAD Family Member 3)
|
KRAS mutation
26d
Tumor cell extravasation was dependent on the platelet-activating factor receptor (PAFR) as a PAFR antagonist inhibited tumor cell extravasation in wildtype mice but not in C/EBPδ mice. Overall, we show that systemic C/EBPδ facilitates pancreatic cancer metastasis, and we suggest this is due to C/EBPδ-PAFR-dependent tumor cell extravasation.
Journal
|
CEBPD (CCAAT Enhancer Binding Protein Delta)
26d
It is, therefore, important to push for a broader molecular approach in PDAC research. Here, we provide a selected summary of emerging strategy options for targeting PDAC using CDK4/6 inhibitors, RAS inhibitors, and new drug combinations with immune checkpoint agents.
Review • Journal • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • PD-1 (Programmed cell death 1)
|
KRAS mutation
26d
We identified a panel of miRNAs that could represent putative therapeutic targets for the development of new miRNA-based therapies for PDAC.
Journal
|
MIR100 (MicroRNA 100) • MIR7 (MicroRNA 7) • MIR195 (MicroRNA 195) • MIR29A (MicroRNA 29a)
26d
The monoclonal antibody inhibiting the IL-6 receptor, Tocilizumab, inhibited this signaling. In conclusion, we show an important mechanism between PSC-cancer cell interaction involving ATP and IL-6, activating P2X7 and IL-6 receptors, respectively, both potential therapeutic targets in PDAC.
Journal
|
IL6 (Interleukin 6) • STAT3 (Signal Transducer And Activator Of Transcription 3)
|
Actemra IV (tocilizumab)
26d
The sensitivity of histological analysis combined with that of IMP3 staining was 91.9%, which was significantly greater than that of histology alone (80.6%). The use of IMP3 and p53 immunohistochemical staining did not significantly improve the sensitivity of cytohistological analysis; however, IMP3 staining may be helpful for the histological analysis of malignant pancreatic tumors.
Journal
|
TP53 (Tumor protein P53) • IGF2 (Insulin-like growth factor 2)
|
TP53 expression
26d
Thus, REG3β is a promising therapeutic target to treat PDAC with an original rationale. In conclusion, we demonstrated that the far microenvironment is essential for PDAC progression by producing active secretory factors, and some of them could be used as therapeutic targets.
Journal
|
CTGF (Connective tissue growth factor)
27d
The combination of miRNAs-21, -210 tissue expression and serum CA19-9 showed 100% accuracy in the diagnosis of PA, as well as miR-181c expression in the plasma (PApxPCp). The expression of microRNAs in plasma proved to be a promising tool for a noninvasive detection test for PA, as well as further studies will evaluate the utility of microRNAs expression as biomarkers for prognostic and response to therapy in PA.
Journal
|
Cancer antigen 19-9
27d
SMAD3 and SMAD4 regulate the radiosensitivity of PDAC, at least in part, by P21 and FOXO3a, respectively. These results indicate that mutations of SMAD3 and SMAD4 likely cause the difference of response to radiotherapy in PDAC, which might be considered as the biomarkers and potential targets for the radiotherapy of pancreatic cancer.
Journal
|
SMAD4 (SMAD family member 4) • FOXO3 (Forkhead box O3) • SMAD3 (SMAD Family Member 3) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
|
SMAD4 mutation
28d
Clinical • New P2 trial
|
PIAS4 (Protein Inhibitor Of Activated STAT 4) • Cancer antigen 19-9
|
cisplatin • gemcitabine • 5-fluorouracil • capecitabine • Abraxane (albumin-bound paclitaxel) • irinotecan
28d
Our study showed that GRP78 expression in NAT cohort is lower than that in SF cohort. GRP78 expression correlated with shorter survival in both SF and NAT patients. Our findings suggest that targeting GRP78 may help to improve the prognosis in PDAC patients.
Clinical • Journal
|
HSPA5 (Heat Shock Protein Family A (Hsp70) Member 5)
29d
P1, N=15, Recruiting, Fred Hutchinson Cancer Research Center | Not yet recruiting --> Recruiting
Clinical • Enrollment open
|
MSLN (Mesothelin) • HLA-A (Major Histocompatibility Complex, Class I, A)
|
MSLN expression
|
fludarabine IV • cyclophosphamide intravenous
29d
Our large cohort study showed that PNI and CA19-9 were associated with poor clinical outcomes in PDAC patients following surgical resection. Additionally, combining PNI with CA19-9 enabled further classification of patients according to their clinical outcomes.
Clinical • Retrospective data • Journal
|
CRP (C-reactive protein) • Cancer antigen 19-9
1m
CircEYA3 promotes the progression of PDAC through the miR-1294/c-Myc signalling axis, and circEYA3 may be an efficient molecular therapeutic target in PDAC.
Journal
|
MYC (V-myc avian myelocytomatosis viral oncogene homolog)
|
MYC expression
1m
Interestingly, truncated O-GalNAc glycans could facilitate an mTORC1 inhibitor resistance using AZD8055...Finally, we found that the expression of epithelial-mesenchymal-transition markers, key features of aggressive PDACs cells, are enhanced and truncated O-GalNAc glycans enhance pancreatic cancer cell growth in a xenograft mouse model. Our study demonstrates that truncated O-GalNAc glycans have a strong impact on AKT/mTOR and RAS/MAPK signaling pathways, are modulated by EGF or IGF-1 signaling and should be considered for targeted therapy of these pathways in PDAC.
Journal
|
IGF1 (Insulin-like growth factor 1) • EGF (Epidermal growth factor)
|
AZD8055
1m
The combination of a TP53 ctDNA mutation before start of FOLFIRINOX and a homozygous TP53 Pro72Arg variant is a promising biomarker, associated with early tumor progression during FOLFIRINOX and poor OS. The results of this exploratory study need to be validated in an independent cohort.
Clinical • Journal
|
TP53 (Tumor protein P53)
|
TP53 mutation
|
5-fluorouracil • leucovorin calcium
1m
P=N/A, N=2000, Active, not recruiting, Immunovia, Inc. | Trial completion date: Jun 2022 --> Sep 2021 | Trial primary completion date: Apr 2021 --> Sep 2021
Clinical • Trial completion date • Trial primary completion date • Diagnostic assay
|
BRCA2 (Breast cancer 2, early onset) • BRCA1 (Breast cancer 1, early onset) • ATM (ATM serine/threonine kinase) • STK11 (Serine/threonine kinase 11) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • EPCAM (Epithelial cell adhesion molecule) • PRSS1 (Serine Protease 1)
|
ATM mutation • STK11 mutation • PALB2 mutation
|
IMMray™ PanCan-d
1m
FUS-mediated circRHOBTB3 functions as a tumor activator to promote PDAC cell proliferation by modulating miR-600/NACC1/Akt/mTOR axis regulated autophagy.
Journal
|
FUS (FUS RNA Binding Protein) • NACC1 (Nucleus Accumbens Associated 1)
1m
Nuclear BCL10 translocation activates NF-κB signaling and contributes to tumor progression and poor prognosis of advanced/metastatic PDAC.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • CDK4 (Cyclin-dependent kinase 4) • CDK2 (Cyclin-dependent kinase 2) • BCL3 (BCL3 Transcription Coactivator) • CDK1 (Cyclin-dependent kinase 1) • RELA (RELA Proto-Oncogene) • CCNB1 (Cyclin B1) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • GNRP (Ras-Specific Guanine Nucleotide-Releasing Factor 1)
|
KRAS mutation • CDKN1B expression
|
gemcitabine • oxaliplatin
1m
Overall, the results of our study indicate that DOG1 may represent a potential biomarker for pancreatic cancer diagnosis and a putative therapeutic target in pancreatic cancer. However, DOG1 expression is unrelated to pancreatic cancer aggressiveness.
Journal
|
CD8 (cluster of differentiation 8)
|
CD8 positive
1m
Since therapeutic resistance of melanoma brain metastasis (MBM) limits patient survival, we demonstrate that sequencing anti-PD-1/L1 therapy before MAPKi combination suppresses MBM and improves mouse survival with robust T cell clonal expansion in both intracranial and extracranial metastatic sites. We propose clinically testing brief anti-PD-1/L1 (± anti-CTLA-4) dosing before MAPKi co-treatment to suppress therapeutic resistance.
Clinical • Journal • PD(L)-1 Biomarker • IO biomarker
|
BRAF (B-raf proto-oncogene) • KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NF1 (Neurofibromin 1) • CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • CD4 (CD4 Molecule)
|
KRAS mutation • BRAF mutation • NRAS mutation • NF1 mutation
1m
He was treated with pembrolizumab, but his disease rapidly progressed...Through this case and a review of the literature, we highlight the low penetrance of PMS2 germline mutations in PDAC and discuss pitfalls in ascertaining MMRd and MSI based on IHC testing alone. An orthogonal confirmatory assay is warranted in the presence of uncommon immunophenotypes, such as isolated PMS2 loss, to optimize selection of patients with PDAC for immunotherapy.
Clinical • Journal • Tumor Mutational Burden • PD(L)-1 Biomarker • IO biomarker
|
TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • CD8 (cluster of differentiation 8) • PMS2 (PMS1 protein homolog 2)
|
TMB-L • PMS2 mutation
|
Keytruda (pembrolizumab)
1m
From the perspective of tumor immunobiology, we identify multiple inflammatory states (proposed as types I-III) and see that systemic chronic dysregulation, independent of tumor microenvironment, can be measured and is a possible tool for stratification. Thus, direct correlation of local cytokine levels to peripheral blood levels needs to be regarded with caution.
Journal
|
IL2 (Interleukin 2) • CD163 (CD163 Molecule) • MIF (Macrophage Migration Inhibitory Factor)
|
IL2 expression • IL2-L
1m
Finally, both were associated with the patients' clinicopathological features and worse overall survival. Conclusively, our findings enrich the role of ELK3 in PDAC, and provide potential avenues for exploring more effective biomarkers and therapeutic strategies for the treatment of PDAC.
Journal
|
ZEB1 (Zinc Finger E-box Binding Homeobox 1)
1m
Journal
|
Cancer antigen 19-9
1m
Moreover, ectopic overexpression of miR-607 could inhibit cell migration and invasion of BxPc-3 and PANC-1 cells by decreasing EMT ability. Low serum miR-607 level may serve as a potential diagnostic and prognostic biomarker through regulation of tumor metastasis in PDAC patients.
Clinical • Journal
|
Cancer antigen 19-9
1m
Taken together, our data support PRMT1 as a compelling target in PDAC and informs a mechanism-based translational strategy for future therapeutic development.Statement of significancePDAC is a highly lethal cancer with limited therapeutic options. This study identified and characterized PRMT1-dependent regulation of RNA metabolism and coordination of key cellular processes required for PDAC tumor growth, defining a mechanism-based translational hypothesis for PRMT1 inhibitors.
Journal
|
PRMT1 (Protein Arginine Methyltransferase 1)
|
PRMT1 inhibitor
1m
Germline pathogenic variants associated with PDAC were seen in 29.1% of our high-risk cohort (55/189 kindreds; 82/285 participants). Importantly, 10.4% of kindreds offered genetic testing were newly identified as having germline pathogenic variants, with majority being BRCA2. As genetic testing standards evolve rapidly in PDAC, 5-yearly reassessment of high-risk individuals by Familial Cancer Services is warranted.
Journal • BRCA Biomarker
|
BRCA2 (Breast cancer 2, early onset) • STK11 (Serine/threonine kinase 11) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • PALB2 (Partner and localizer of BRCA2) • MLH1 (MutL homolog 1) • PRSS1 (Serine Protease 1)
1m
Our findings support EUS-FNA biopsies as a feasible tissue source for integrated genomic and transcriptomic analysis of PDAC across all tumour stages, including cases with non-diagnostic cytology. Our transcriptome-derived genetic signature in combination with tissue KRAS mutation analysis significantly improves upon the diagnostic accuracy of current standard procedures, and has potential clinical utility in improving the speed and accuracy of diagnosis for patients presenting with PDAC.
Journal
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
1m
In contrast, APOE promotes antitumor immunity in other cancer types including melanoma, highlighting the context dependency of APOE signaling and its impact on the tumor microenvironment. As new immunotherapy approaches increasingly aim to modulate both the myeloid and lymphoid compartments of the PDAC immune milieu, identification of specific mechanisms that foster macrophage-mediated immune suppression may facilitate the development of effective strategies that enable the immune system to tackle these tumors.See related article by Kemp et al., p. 4305.
Journal • IO biomarker
|
APOE (Apolipoprotein E)
1m
There are several targeted therapies approved by the Food and Drug administration (FDA) in PDAC: EGFR inhibitor erlotinib (combined with gemcitabine) in unselected patients, TRK inhibitors larotrectinib and entrectinib for patients with NTRK fusion mutation, the PD-1 inhibitor pembrolizumab for mismatch repair-deficient patients, and the poly-ADP-ribose polymerase (PARP) inhibitor olaparib in patients with germline BRCA mutation as a maintenance therapy. This was the first phase 3 randomized trial to establish a biomarker-driven approach in the treatment of PDAC and establishes a precedent for maintenance therapy in PDAC. The review herein aims to outline the current treatment landscape for PDAC patients with DDR gene-mutated tumors, highlight novel therapeutic approaches focused on surmounting tumor resistance, and explore new strategies which may lead to an expansion in the number of patients who benefit from these targeted treatments.
Review • Journal • BRCA Biomarker • PARP Biomarker • PD(L)-1 Biomarker • IO biomarker
|
BRCA2 (Breast cancer 2, early onset) • BRCA1 (Breast cancer 1, early onset) • BRCA (Breast cancer early onset) • NTRK (Neurotrophic receptor tyrosine kinase)
|
BRCA1 mutation • BRCA2 mutation • MSI-H/dMMR • BRCA mutation • NTRK fusion
|
Keytruda (pembrolizumab) • Lynparza (olaparib) • erlotinib • Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • gemcitabine
1m
P1, N=60, Recruiting, M.D. Anderson Cancer Center | Trial completion date: May 2021 --> May 2022 | Trial primary completion date: May 2021 --> May 2022
Clinical • Trial completion date • Trial primary completion date
|
CEACAM5 (CEA Cell Adhesion Molecule 5) • Cancer antigen 19-9
|
Keytruda (pembrolizumab) • Zyclara (imiquimod)
1m
Dual EPS8 and ALDH7A1 knockdown had a synergistic effect on suppressing PADC cell proliferation in vitro and in vivo. In conclusion, this study revealed that EPS8 supports PADC growth by interacting with ALDH7A1 and inhibiting BMI1 mediated proteasomal degradation of ALDH7A1.
Journal
|
EGFR (Epidermal growth factor receptor) • BMI1 (BMI1 proto-oncogene, polycomb ring finger) • ALDH7A1 (Aldehyde Dehydrogenase 7 Family Member A1)
1m
Our data, as opposed to figures expected from the literature, highlighted that platinum-based regimens provoked an increased toxicity on proliferating cells, when dose intensity was maintained, or an as-expected toxicity, when dose intensity was reduced, while no change in toxicity and dose intensity was evident with AG. Furthermore, an apparently improved outcome of platinum-based triplets or quadruplets over other regimens was observed.
Clinical • Journal • BRCA Biomarker
|
BRCA2 (Breast cancer 2, early onset) • BRCA1 (Breast cancer 1, early onset) • Cancer antigen 19-9
|
cisplatin • gemcitabine • 5-fluorouracil • capecitabine • oxaliplatin • Abraxane (albumin-bound paclitaxel) • irinotecan • leucovorin calcium
1m
The genomic concordance rate between tissue DNA and ctDNA analyses was 65.22%. Our study demonstrates the feasibility of an NGS-based approach for ctDNA analysis and underlines the importance of using a disease-specific panel with a sufficiently high coverage.
Clinical • Journal • Next-generation sequencing • Circulating tumor DNA
|
KRAS (KRAS proto-oncogene GTPase) • TROP2 (Trophoblast Cell Surface Antigen 2)
|
KRAS mutation
1m
YAP/TAZ have become extensively studied in PDAC and their biological importance during the development and progression of PDAC has been uncovered. In this review, we summarize the biological significance of a dysregulated Hippo signaling pathway or activated YAP/TAZ in PDAC and propose a role for YAP/TAZ as a therapeutic target.
Review • Journal
|
KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • SMAD4 (SMAD family member 4)
|
KRAS mutation
1m
In addition, new strategies are being investigated, which are designed to overcome the resistance to checkpoint inhibitors, targeting DNA repair pathways including mismatch repair, increasing antigen presentation through the use of vaccines, targeting various signaling pathways, and reprogramming the tumor microenvironment. Here, we review the landscape of PDAC treatment strategies and some of these new agents.
Journal
|
KRAS (KRAS proto-oncogene GTPase)
1m
According to The Cancer Genome Atlas dataset, these genes are all prognostic factors for pancreatic cancer. Thus, the feasibility of using our deep learning-based method for the selection of genes associated with pancreatic cancer development and prognosis was confirmed.
Journal
|
NCAM1 (Neural cell adhesion molecule 1)
1m
Clinical • P2 data
|
GSK3B (Glycogen Synthase Kinase 3 Beta)
|
gemcitabine • Abraxane (albumin-bound paclitaxel) • 9-ING-41
1m
In vitro experiments demonstrated that the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) and the de novo purine synthesis inhibitor L-alanosine synergized to kill MTAP-deficient pancreatic cancer cells. Collectively, these results reveal that MTAP deficiency drives pancreatic cancer progression by inducing metabolic reprogramming, providing a novel target and therapeutic strategy for treating MTAP-deficient disease.
Journal
|
HIF1A (Hypoxia inducible factor 1, alpha subunit) • MTAP (Methylthioadenosine Phosphorylase)
|
MTAP deletion
|
deoxyglucose
1m
We evaluated the impact of MUC1 expression on outcome in a cohort of 158 patients with resected pancreatic ductal adenocarcinomas (PDAC) in the CONKO-001 study (adjuvant gemcitabine [gem] vs. observation [obs])...In the study arms, prognostic effects of MUC1 were also evident in the observation group (HR for DFS: 0.55; 95% CI 0.29 to 1.04, p = .062; HR for OS: 0.34, 95% CI 0.17 to 0.67, p = .001) and trending in the gem group (HR for DFS: 0.48, 95% CI 0.24 to 0.95, p = .041; HR for OS: 0.56, 95% CI 0.28 to1.11, p = .093). Our data suggest that MUC1 expression is a powerful prognostic marker in patients with PDAC after curatively intended resection.
Journal
|
MUC1 (Mucin 1)
|
MUC1 expression
|
gemcitabine
1m
Targeting Pin1 using clinically available drugs induces complete elimination or sustained remissions of aggressive PDAC by synergizing with anti-PD-1 and gemcitabine in diverse model systems. Mechanistically, Pin1 drives the desmoplastic and immunosuppressive TME by acting on CAFs and induces lysosomal degradation of the PD-1 ligand PD-L1 and the gemcitabine transporter ENT1 in cancer cells, besides activating multiple cancer pathways. Thus, Pin1 inhibition simultaneously blocks multiple cancer pathways, disrupts the desmoplastic and immunosuppressive TME, and upregulates PD-L1 and ENT1, rendering PDAC eradicable by immunochemotherapy.
Journal
|
SLC29A1 (Solute Carrier Family 29 Member 1)
|
gemcitabine • anti-PD-1 antibody
1m
The combination of SBRT plus pembrolizumab and trametinib could be a novel treatment option for patients with locally recurrent pancreatic cancer after surgery. Phase 3 trials are needed to confirm our findings.
Clinical • P2 data • Journal • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
|
Keytruda (pembrolizumab) • Mekinist (trametinib) • gemcitabine • 5-fluorouracil
1m
Enrollment open
|
IL6 (Interleukin 6) • CRP (C-reactive protein)
|
5-fluorouracil • leucovorin calcium • nidanilimab (CAN04)
1m
PSCs stimulated PDAC cells to secrete S100A9, which acts as a chemoattractant to attract circulatory monocytes into cancer microenvironment and induces expression of PD-L1 on macrophages. High expression of S100A9 and PD-L1 was associated with worse overall survival in a cohort of patients with PDAC.
Journal • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • S100A9 (S100 Calcium Binding Protein A9)
|
PD-L1 expression • S100A9 expression
1m
Subsequently, inhibition of PKCι in PDAC alleviates the immune suppression and enhances the cytotoxicity of NK92 towards PDAC through restraining PDL1 overexpression. Combined with PD1/PDL1 blocker, PKCι inhibitor remarkably elevates the cytotoxicity of NK92 against PDAC cells in vitro, establishing PKCι inhibitor as a promising candidate for boosting the immunotherapy of PDAC.
Journal • PD(L)-1 Biomarker • IO biomarker
|
KRAS (KRAS proto-oncogene GTPase) • STAT3 (Signal Transducer And Activator Of Transcription 3) • YAP1 (Yes associated protein 1)
|
PD-L1 expression • PD-L1 overexpression
1m
The tumor pH-sensitive polymer is synthesized by conjugating N,N-dipentylethyl moieties and monomethoxylpoly(ethylene glycol) onto PAMAM dendrimer, into whose cavity a hydrophobic gemcitabine (Gem) prodrug is accommodated...This collectively facilitates the infiltration of cytotoxic T cells into the tumors and renders checkpoint inhibitors more effective in previously unresponsive PDAC models. This study reveals a promising strategy for improving the chemoimmunotherapy of pancreatic cancer.
Journal • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1)
|
PD-L1 expression
|
gemcitabine
1m
These differences were more pronounced in BxPC-3, which contains a loss-of-function mutation in the tumor-suppressing gene SMAD4. These findings suggest a proto-oncogenic role of DNAJA1 in PDAC progression and suggest DNAJA1 may function synergistically with other proteins with altered activities in pancreatic cancer cell lines.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • SMAD4 (SMAD family member 4)
|
BCL2 expression • SMAD4 mutation
1m
We constructed a novel four-gene signature to predict the prognosis of Stages III and IV PDAC patients by applying WGCNA and CIBERSORT algorithm scoring to transcriptome data different from traditional methods of filtrating for differential genes in cancer and healthy tissues. The findings may provide reference to predict survival and was beneficial to individualized management for advanced PDAC patients.
Journal • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • PD-1 (Programmed cell death 1) • CXCL9 (Chemokine (C-X-C motif) ligand 9) • CD4 (CD4 Molecule)
1m
Multivariate Cox regression analysis showed that 7 variables, namely, pTNM stage (P=0.002), PDL1 expression (P=0.001), CDX2 expression (P=0.008), DPC4 expression (P=0.004), CD4 expression in LSH (P<0.001), CD8 expression in LSH (P=0.010) and CD15 expression in LSH (P=0.031), were significantly correlated with the prognosis of PDAC patients. The findings of this study indicate that LSH is an effective tool for a panoramic assessment of the immune microenvironment in pancreatic cancer patients.
Journal • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • CD20 (Membrane Spanning 4-Domains A1) • CD8 (cluster of differentiation 8) • CDX-2 • NCAM1 (Neural cell adhesion molecule 1) • CD4 (CD4 Molecule) • FUT4 (Fucosyltransferase 4)
|
PD-L1 expression • CD4 expression • CDX-2 expression
1m
The relationship between genetic alterations and clinicopathological factors as well as prognosis demonstrated important genomic impact on tumor biology. This study will help to optimize clinical treatment of Oriental PDAC patients and improve their survival.
Clinical • Journal
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation • KRAS G12D • KRAS G12
1m
ADAM8-dependent co-variates, miR-451 and miR-720 were also diagnostic, as patients with PDAC had significantly higher serum levels of miR-451 and lower serum levels of miR-720 than healthy controls and reached high sensitivity and specificity (AUC = 0.93 and 1.00, respectively) to discriminate PDAC from healthy control. Thus, detection of ADAM8-positive EVs and related cargo miR-720 and miR-451 may constitute a specific biomarker set for screening individuals at risk for PDAC.
Journal
|
ADAM8 (ADAM Metallopeptidase Domain 8)
2ms
Treatment with recombinant CXCL13, IL-21 and Tfh cells alleviated tumor growth and enhanced the infiltration of CD8 T cells and B cells, as well as B cell maturation in a PDAC mouse model. Our results revealed the important role of Tfh cells in mediating anti-tumor cellular immunity and humoral immunity in PDAC via secreting CXCL13 and IL-21 and determined a novel mechanism of immunosuppression in PDAC.
Journal
|
PD-L1 (Programmed death ligand 1) • CD8 (cluster of differentiation 8) • CXCL13 (Chemokine (C-X-C motif) ligand 13) • IL21 (Interleukin 21)
2ms
This study investigates the effect of 5-fluorouracil (5-FU), irinotecan, and oxaliplatin (FOLFIRINOX), and gemcitabine plus nab-paclitaxel (GEMnPAC) regimens on PD-L1 mRNA expression in plasma-derived microvesicles (MVs) in 50 PDAC patients...The increase in PD-L1 mRNA expression in MVs was not related to tumor response (PR + SD: p = 0.08; PD: p = 0.28). Our findings demonstrate that GEMnPAC can increase PD-L1 mRNA expression in patient-derived circulating MVs, providing a rationale for testing the efficacy of this regimen in sequential or simultaneous combinations with immunotherapy in PDAC patients.
Journal • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1)
|
PD-L1 expression
|
gemcitabine • 5-fluorouracil • oxaliplatin • Abraxane (albumin-bound paclitaxel) • irinotecan • leucovorin calcium
2ms
The primary objective of this study is to assess the safety of the combination of IRE with IMO-2125 (a toll-like receptor 9 ligand) and/or nivolumab in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Consequently, there is an urgent need for innovative and radically different treatment approaches. Should electroimmunotherapy establish an effective and durable anti-tumor response, it may ultimately improve PDAC's dismal prognosis.
P1 data • Preclinical • Journal
|
PD-L1 (Programmed death ligand 1) • TLR9 (Toll Like Receptor 9)
|
Opdivo (nivolumab) • tilsotolimod (IMO-2125)
2ms
Decreasing WTAPP1 RNA significantly suppressed the in vivo growth and metastasis of PDAC cell lines and patient-derived xenografts. These results indicate that m6A-mediated increases in WTAPP1 expression promotes PDAC progression and thus may serve as a therapeutic target.
Journal
|
WT1 (WT1 Transcription Factor)
2ms
Taken together, our findings indicate that doxycycline enhances the effects of gemcitabine on cell cycle progression, thus rendering pancreatic cancer cells more sensitive to gemcitabine. However, additional studies are required to assess the mechanisms of doxycycline and gemcitabine synergism, which might lead to novel treatment options for pancreatic cancer.
Journal
|
CCND1 (Cyclin D1) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
|
gemcitabine • doxycycline
2ms
This study developed a noncontrast MRI-based radiomics model that can preoperatively determine CD8 T-cell expression in patients with PDAC and potentially immunotherapy planning. 5 TECHNICAL EFFICACY: Stage 2.
Clinical • Journal • IO biomarker
|
CD8 (cluster of differentiation 8)
|
CD8 expression • CD8-H
2ms
Small molecule inhibitors of glycogen synthase kinase-3 beta have demonstrated therapeutic potential in pre-clinical models and are currently being evaluated in early phase clinical trials involving pancreatic cancer patients with interim results showing favorable results. Moreover, recent studies support a rationale for the combination of glycogen synthase kinase-3 beta inhibitors with chemotherapy and immunotherapy, warranting the evaluation of novel combination regimens in the future.
Review • Journal • IO biomarker
|
GSK3B (Glycogen Synthase Kinase 3 Beta)
|
9-ING-41
2ms
The mechanisms regulating its dual roles in tumorigenesis remain to be elucidated. Further understanding of the activin signaling pathway may identify potential therapeutic targets for human cancers and other diseases.
Review • Journal
|
TGFB1 (Transforming Growth Factor Beta 1)
2ms
Notably, affected PDAC patients within a family carried identical germline mutations in up to three different genes, e.g., DAB1, POLQ and FGFBP3. These results support the hypothesis that FPC is a highly heterogeneous polygenetic disease caused by low-frequency or rare variants.
Journal • BRCA Biomarker
|
BRCA2 (Breast cancer 2, early onset) • BRCA1 (Breast cancer 1, early onset) • ATM (ATM serine/threonine kinase) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • PALB2 (Partner and localizer of BRCA2)
|
BRCA1 mutation • BRCA2 mutation • PALB2 mutation • CDKN2A mutation
2ms
An Integrated Budding Immune Signature (IBIS) stratified PDAC-patients into prognostic subgroups more efficiently than each bio- marker alone, improving the prognostic power and risk stratification in- dependently of other known prognostic factors, including tumour grade or tumour stage.
Clinical • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • CD8 (cluster of differentiation 8) • PD-1 (Programmed cell death 1) • CD4 (CD4 Molecule) • CD68 (CD68 Molecule) • MRC1 (Mannose Receptor C-Type 1) • FOXP3 (Forkhead Box P3)
2ms
In this retrospective study, we showed the role of germline and somatic DDR mutation in predicting the efficacy of olaparib and platinum-based chemotherapy in Chinese patients. However, the value of DDR mutation in the prediction of hypermutation status and the sensitivity to the PD-1 blockade needed further investigation.
Clinical • Retrospective data • Journal • Tumor Mutational Burden • BRCA Biomarker • PARP Biomarker • PD(L)-1 Biomarker • IO biomarker
|
KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • BRCA2 (Breast cancer 2, early onset) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • SMAD4 (SMAD family member 4) • RAD50 (RAD50 Double Strand Break Repair Protein)
|
KRAS mutation • RAD50 mutation
|
Lynparza (olaparib)
2ms
Altered PLS3 expression was useful in diagnosis and prognosis of PDA as well as to distinguish PDA from DLBCL.
Journal
|
SPP1 (Secreted Phosphoprotein 1) • KRT7 (Keratin-7)
2ms
Furthermore, immunohistochemical analysis indicates that the survival benefit may be CD8+ T-cell mediated. The therapeutic and molecular imaging tool kit developed could be exploited to better structure clinical trials and address the therapeutic gaps in challenging malignancies such as PDAC.
Preclinical • Journal • Checkpoint inhibition • PD(L)-1 Biomarker • IO biomarker
|
CD8 (cluster of differentiation 8)
|
PD-L1 expression
2ms
CBC and blood chemistry analyses showed no systemic toxicity in Fraction B treated Panc-1 tumor bearing mice compared to that of control group. Our data support that Fraction B is a potential candidate for PDAC treatment.
Journal
|
CD44
|
CD44 expression
2ms
g/sBRCA1/2 mutations did not appear to have different actionable utility. Platinum and PARPi therapies offer therapeutic benefit, and very durable outcomes are observed in a subset of patients who have g/sBRCA1/2 mutations with biallelic status.
Clinical • Journal • BRCA Biomarker • PARP Biomarker
|
BRCA2 (Breast cancer 2, early onset) • BRCA1 (Breast cancer 1, early onset) • BRCA (Breast cancer early onset)
|
BRCA1 mutation • BRCA2 mutation
2ms
These results revealed that FGFBP1-mediated interaction between CAFs and PCCs via FGF22/FGFR2 facilitates the migration and invasion of PCCs. FGFR2 could act as a prognostic marker for patients with PDAC.
Journal
|
FGFR2 (Fibroblast growth factor receptor 2) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • FBXW7 (F-Box And WD Repeat Domain Containing 7)
|
MYC expression
2ms
Patients older than 74 years of age, with tumors larger than 3 cm in diameter, poorly differentiated, less than 7 regional lymph node dissected, positive uncinate margin, and preoperative CA19-9 higher than 1.5×10 U/L were independent risk factors in patients with pancreatic head cancer. Old age, tumor lager than 3 cm, poor differentiation, low examined lymph nodes, direct uncinate margin involvement and (or) with preoperative CA19-9 higher than 1.5×10 U/L are related to poor prognosis of head pancreatic cancer.
Clinical • Retrospective data • Journal
|
Cancer antigen 19-9
2ms
Therapeutic potential of ULK1/2 inhibitor and 2-deoxyglucose (2-DG) or 3-bromopyruvate (3-BP) was evaluated in cell-derived xenograft (CDX) and the patient-derived xenograft (PDX) models of nude mice...Pharmacological deactivation of ULK1/2 potentiates the antineoplastic efficacy of 2-DG and 3-BP in CDX and PDX models. Our findings underscore the Ser227 autophosphorylation-dependent nuclear YAP stabilization as a central node that couples ULK1/2-initiated autophagy to hypoxic glycolysis during PDAC development and propose that targeting ULK1/2 combined with 2-DG or 3-BP might be a feasible therapeutic strategy against PDAC.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • PKM (Pyruvate Kinase M1/2)
|
deoxyglucose
2ms
We developed a novel ICI score that could independently predict the response to immunotherapy and survival of patients with PC. Evaluation of the ICI landscape in a larger cohort could clarify the interactions between these infiltrating cells, the tumor microenvironment and response to immunotherapy.
Journal • Tumor Mutational Burden • IO biomarker
|
KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • SMAD4 (SMAD family member 4)
|
TP53 mutation • KRAS mutation • TP53 mutation + KRAS mutation • KRAS mutation + TP53 mutation
2ms
The method identified Trametinib (MEKi) as a strong CRT sensitizer in KRAS-mutant NSCLC and PDAC cell lines. To increase the accessibility of our screening method and accelerate the pace at which novel combinations with CRT are identified and incorporated into standard practices for treatments, we report details on screening method optimization, data generation, and downstream data analysis.
Journal
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
|
Mekinist (trametinib)
2ms
Enrollment closed
|
PD-L1 (Programmed death ligand 1)
|
Avastin (bevacizumab) • Tecentriq (atezolizumab) • gemcitabine • 5-fluorouracil • Cotellic (cobimetinib) • oxaliplatin • Abraxane (albumin-bound paclitaxel) • leucovorin calcium • tiragolumab (MTIG7192A) • etrumadenant (AB928) • pegvorhyaluronidase alfa (PEGPH20) • Actemra IV (tocilizumab) • motixafortide (BL-8040) • selicrelumab (RG7876) • simlukafusp alfa (RG7461)
2ms
Eight percent developed a new pancreatic mass or cyst during surveillance, two individuals developed PDAC, and no serious complications resulted from surveillance. After discussion of the risks, limitations, and potential benefits, PDAC surveillance can be considered in BRCA1/BRCA2/ATM/PALB2 carriers without a family history of PDAC, however the effectiveness of PDAC surveillance in this population requires further study.
Journal
|
BRCA2 (Breast cancer 2, early onset) • BRCA1 (Breast cancer 1, early onset) • PALB2 (Partner and localizer of BRCA2)
2ms
New P1 trial
|
IL6 (Interleukin 6) • CRP (C-reactive protein)
|
5-fluorouracil • leucovorin calcium • nidanilimab (CAN04)
2ms
By capturing immune-related signals in the PDAC tumor microenvironment, we reveal a novel molecular subtype, Immune Class. Immune Class serves as an independent favorable prognostic factor for overall survival in PDAC patients.
Journal • Tumor Mutational Burden • PD(L)-1 Biomarker • IO biomarker
|
TMB (Tumor Mutational Burden)
2ms
Therefore, N2E4 has the potential for targeting therapy of PDAC. This study lays a foundation for the future development of NRP2-based targeted therapy for PDAC.
Journal
|
HIF1A (Hypoxia inducible factor 1, alpha subunit)
2ms
With the deepening of related studies, some meaningful positive and negative results have surfaced, and CAFs may be the key to unlocking the door to pancreatic cancer treatment. Our review summarizes recent advances in the heterogeneity, function, and markers of CAFs in pancreatic cancer, as well as research and treatment targeting CAFs in pancreatic cancer.
Review • Journal
|
IL6 (Interleukin 6)
2ms
Here, we review recent advances in genetic analysis of PDACs and describe future perspectives in precision medicine according to molecular subtypes or actionable gene mutations for patients with PDAC. We believe the breakthroughs will soon emerge to fight this deadly disease.
Review • Journal • BRCA Biomarker • PARP Biomarker
|
KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • SMAD4 (SMAD family member 4) • BRCA (Breast cancer early onset)
|
TP53 mutation • KRAS mutation • CDKN2A mutation • SMAD4 mutation • BRCA mutation
2ms
In larger human pancreatic ducts, basal cells exist. ΔNp63 suppresses duct cell identity. These cells may play an important role in pancreatic disease, including PDAC ontogeny, but are not present in mouse models.
Journal
|
SOX9 (SRY-Box Transcription Factor 9) • KRT19 (Keratin 19)
|
SOX9 expression
2ms
This unique longitudinal analysis provides insights into networks underlying human PDAC progression and pathogenesis. Implications: Manipulation of HBP1, BACH1, and RUN3 networks during PDAC progression can be harnessed to develop new targets for treating PDAC.
Journal
|
BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • IL2RA (Interleukin 2 receptor, alpha) • BACH1 (BTB Domain And CNC Homolog 1)
2ms
Loss of UGP2 leads to decreased intracellular glycogen levels and defects in N-glycosylation targets that are important for the survival of PDACs, including the epidermal growth factor receptor (EGFR). These critical roles of UGP2 in cancer maintenance, metabolism, and protein glycosylation may offer insights into therapeutic options for otherwise intractable PDACs.
Journal
|
EGFR (Epidermal growth factor receptor) • YAP1 (Yes associated protein 1)
2ms
A growing body of preclinical and clinical studies document significant correlations between mutations (for example, in KRAS and TP53), stress responses (such as hypoxia and autophagy), metabolic reprogramming and chemotherapeutic responses. Here, we describe the molecular machinery of cell death, discuss the complexity and multifaceted nature of lethal signalling in PDAC cells, and highlight the challenges and opportunities for activating cell death pathways through precision oncology treatments.
Review • Journal
|
KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53)
|
TP53 mutation • KRAS mutation
2ms
Infiltrative appearance is associated with PBST; whereas, nodular appearance more likely predicts IST. The potential role of CT lesion morphology on guiding appropriate chemotherapy in cases with no chance for surgery or biopsy requires addressing. Key Words: Intestinal differentiation, Pancreatobiliary differentiation, Periampullary adenocarcinoma.
Journal
|
CDX-2
|
CDX-2 expression
2ms
We then demonstrate that GLS1 inhibition reduced fructose-2,6-bisphosphate levels, the product of PFKFB3, whereas PFKFB3 inhibition increased glutamine consumption, and these effects were augmented by the co-inhibition of GLS1 and PFKFB3, suggesting a reciprocal regulation between PFKFB3 and GLS1. In conclusion, this study identifies a novel mutant KRAS-induced metabolic vulnerability that may be targeted via combinatorial inhibition of GLS1 and PFKFB3 to suppress PDAC cell growth.
Journal
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
|
telaglenastat (CB-839)
2ms
In sum, our findings support the premise that EVI1 is a crucial driver of oncogenic transcription programs in PDA cells. Further, we emphasize the instructive role of epigenetic aberrancy in establishing PDA tumorigenesis.
Journal
|
MECOM (MDS1 And EVI1 Complex Locus)
2ms
Combined tumor epithelial and stromal histopathology with keratin 81 expression is suggested to be useful to predict prognosis of PDAC.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • MET (MET proto-oncogene, receptor tyrosine kinase) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • SMAD4 (SMAD family member 4) • HNF1A (HNF1 Homeobox A)
|
CDKN2A mutation • SMAD4 mutation
2ms
Serum thrombospondin-2 in combination with CA 19-9 has potential as a biomarker for distal cholangiocarcinoma and pancreatic cancer.
Journal
|
THBS2 (Thrombospondin 2)
2ms
As a result, fraxetin hindered hypoxia-induced angiogenesis by decreasing HIF-1α and VEGFA expression, controlled glucose metabolism by reducing GLUT1 expression, inhibited the EMT by blocking the Slug-E-cadherin axis, and drove ROS-mediated apoptosis by regulating the STAT3-Ref1 axis. In conclusion, fraxetin enhances the anti-tumor activity of gemcitabine and suppresses pancreatic cancer development by antagonizing STAT3 activation.
Clinical • Journal
|
KRAS (KRAS proto-oncogene GTPase) • HIF1A (Hypoxia inducible factor 1, alpha subunit) • CDH1 (Cadherin 1) • STAT3 (Signal Transducer And Activator Of Transcription 3) • SNAI2 (Snail Family Transcriptional Repressor 2)
|
CDH1 expression • HIF1A expression • VEGFA expression
|
gemcitabine
2ms
Upon inhibition of autophagy, SLC7A11 is localized to lysosomes in an MTORC2-dependent manner. Our findings reveal a novel connection between autophagy and cysteine metabolism in pancreatic cancer.
Journal
|
SLC7A11 (Solute Carrier Family 7 Member 11)
2ms
Combination chemotherapy, either modified FOLFIRINOX (mFFX) or gemcitabine-nabpaclitaxel, are used in the treatment of most patients with advanced pancreatic ductal adenocarcinoma (PDAC), yet robust biomarkers of outcome are currently lacking to guide regimen selection...Our results provide strong evidence that GATA6 IHC can be used as a single biomarker in the clinic to predict clinical outcome in advanced PDAC, warranting further investigation in prospective clinical trials. These results provide the basis for an improved classification of PDAC and future biomarker design using digital pathology workflow.
Clinical • Clinical data • Journal
|
GATA6 (GATA Binding Protein 6)
|
GATA6 expression
|
gemcitabine • 5-fluorouracil • Abraxane (albumin-bound paclitaxel) • leucovorin calcium
2ms
In conclusion, FDRs of FPC patients carry rare germline variants related to cancer pathogenesis that may contribute to increased susceptibility to PDAC. The identified variants may potentially be useful for risk prediction of high-risk individuals in predisposed families.
Clinical • Journal
|
LRP1B (LDL Receptor Related Protein 1B)
2ms
Tumor-infiltrating CD8 T cells had an increased proportion of cells expressing an exhausted expression profile that included upregulation of the immune checkpoint TIGIT, a finding that we validated at the protein level. Our findings point to a profound alteration of the immune landscape of tumors, and to patient-specific immune changes that should be taken into account as combination immunotherapy becomes available for pancreatic cancer.
Journal • IO biomarker
|
CD8 (cluster of differentiation 8) • TIGIT (T Cell Immunoreceptor With Ig And ITIM Domains 2)
2ms
This restrictive effect is entirely dependent on functional adaptive immunity. Collectively, these results reveal two functionally distinct pancreatic fibroblast lineages and highlight the importance of mesenchymal and immune cell interactions in restricting tumor growth.
Journal
|
ENG (Endoglin)
2ms
Detection of ctDNA in the post-operative ccfDNA with or without tumor-informed guidance was not associated with outcomes. Therefore, the detection of PDAC-derived ctDNA during a broad and untargeted survey of ccfDNA with NGS may be a valuable, non-invasive, prognostic biomarker to integrate into the clinical assessment and management of patients prior to surgery.
Journal • Next-generation sequencing • Circulating tumor DNA
|
KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • SMAD4 (SMAD family member 4)
|
TP53 mutation • KRAS mutation
2ms
The assessment of KRAS mutation by liquid biopsy can be considered as an additional tool for the estimation of the disease course and outcome in PDAC patients.
Retrospective data • Review • Journal
|
KRAS (KRAS proto-oncogene GTPase)
2ms
Immunohistochemistry-based validation using tissue microarrays from 346 patients with PDAC showed significant expression of EphB4 in >70% of patients. In summary, we present a comprehensive landscape of tyrosine phosphoproteome with EphB4 as a promising therapeutic target in pancreatic ductal adenocarcinoma.
Clinical • Journal
|
EPHB4 (EPH receptor B4)
|
EPHB4 expression
2ms
BET inhibitors (JQ1 or I-BET762) + gemcitabine were synergistic in vitro, in Panc1, MiaPaCa2 and Su86 PC cell lines. These proteins contribute to cholesterol biosynthesis and lipid metabolism, and their overexpression supports tumor cell proliferation. IPA data indicated that JQ1 + gemcitabine selectively inhibited the LXR/RXR activation pathway, suggesting the hypothesis that this inhibition may contribute to the observed in vivo efficacy of JQ1 + gemcitabine.
Preclinical • Journal
|
RAD51 (RAD51 Homolog A) • CASP3 (Caspase 3)
|
gemcitabine • JQ-1 • molibresib (GSK525762)
2ms
Histological and genetic analyses of this massive thymus enabled us (1) to characterize it as a highly proliferative thymic lymphoma and (2) to detect the unexpected recombination of the Lox-STOP-Lox cassette upstream Kras allele and subsequent KRAS protein expression in all cells composing thymic masses. Finally, we highlighted that development of such thymic tumor was associated with accelerated pancreatic carcinogenesis, immune compartment disorganization, and in some cases, lung malignancies.
Preclinical • Journal • Adverse events
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
2ms
HMGA2 is a prognostic marker in PDAC. Firstly, we found a positive correlation for cytoplasmic HMGA2 expression with lympho-vascular invasion and, secondly, we found a significantly stronger nuclear expression of HMGA2 in cancer-positive lymph node nuclei compared to primary tumor cell nuclei. So far, the role of cytoplasmic HMGA2 is nearly unknown, however, our data lend support to the hypothesis that cytoplasmic HMGA2 expression is involved in nodal spread.
Journal
|
HMGA2 (High mobility group AT-hook 2)
2ms
The administration of TGZ markedly enhances sensitivity to GEM via downregulating CD73 in PDAC. Our findings support that CD73 could be targeted to overcome chemoresistance in PDAC.
Journal
|
CD73 (5'-Nucleotidase Ecto) • NT5E (5'-Nucleotidase Ecto)
|
CD73 expression
|
gemcitabine
2ms
Agr2 is identified as a novel adaptor protein for nuclear import of RNAPII in mammalian cells. Also, we provide genetic evidence defining Agr2-dependent nuclear import of RNAPII as a pharmaceutically accessible target for prevention and treatment in PDAC in the context of wild-type p53.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • AGR2 (Anterior gradient 2)
2ms
These results demonstrate that ANGPTL4 is critical for ADM/PanIN initiation and PDAC progression through the regulation of periostin. Thus, the ANGPTL4/periostin axis is considered a potential target for ADM-derived PDAC.
Journal
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
2ms
Furthermore, we showed that TRIM15 might promote PDAC metastasis by regulating lipid metabolism via the APOA1-LDLR axis. Consequently, targeting the TRIM15-APOA1-LDLR axis may be a strategy to inhibit PDAC metastasis by blocking triglyceride synthesis.
Journal
|
APOA1 (Apolipoprotein A-I)
2ms
Elevated GNA15 mRNA correlates with poor prognosis. In addition, ectopic Gα15 signaling provides an unprecedented mechanism in the early steps of pancreas carcinogenesis distinct from classical G protein oncogenic mutations described previously in GNAS and GNAQ/GNA11.
Journal
|
GNAQ (G Protein Subunit Alpha Q) • GNA11 (G Protein Subunit Alpha 11) • GNAS (GNAS Complex Locus)
2ms
We also summarize therapeutic approaches to target the stroma. With a better understanding of the complex cellular and molecular networks in PDA, strategies aimed at sensitizing PDA to chemotherapy or immunotherapy through re-programing the tumor microenvironment can be designed, and in turn lead to improved clinical treatment for pancreatic cancer patients.
Review • Journal
|
CD4 (CD4 Molecule)
2ms
The identified biomarker panels have shown the potential to diagnose PDAC patients and stratify patients based on their prognostic outcomes. If independently validated, this may lead to the development of a diagnostic and prognosticating blood test for PDAC.
Journal
|
MSLN (Mesothelin) • S100A4 (S100 calcium binding protein A4)
2ms
A population-based prediction model for OS was developed for patients with metastatic PDAC and showed good performance. The predictors that were included in the model comprised both baseline patient and tumor characteristics and type of treatment. SOURCE-PANC will be incorporated in an electronic decision support tool to support shared decision-making in clinical practice.
Clinical • Journal
|
Cancer antigen 19-9
|
gemcitabine • 5-fluorouracil • Abraxane (albumin-bound paclitaxel) • leucovorin calcium
2ms
Major breakthroughs have been achieved in the management of metastatic pancreatic ductal adenocarcinoma (PDAC) with FOLFIRINOX (5-fluorouracil + irinotecan + oxaliplatin) and gemcitabine plus nab-paclitaxel approved as a first-line therapy, although the prognosis is still poor...Although not confirmed in large, prospective trials, gemcitabine alone as a maintenance therapy following induction treatment with gemcitabine plus nab-paclitaxel could be an option, while a small subset of patients with a germline mutation of breast cancer gene (BRCA) can benefit from the polyadenosine diphosphate-ribose polymerase (PARP) inhibitor olaparib...The Food and Drug Administration (FDA) recently approved larotrectinib for patients with any tumors harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, and pembrolizumab for patients with a mismatch repair deficiency in a second-line setting, including PDAC. Research focused on targeted therapy and immunotherapy is active and could improve patients' outcomes in the near future.
Review • Journal • BRCA Biomarker • PARP Biomarker • PD(L)-1 Biomarker • IO biomarker
|
BRCA (Breast cancer early onset) • NTRK (Neurotrophic receptor tyrosine kinase)
|
BRCA mutation
|
Keytruda (pembrolizumab) • Lynparza (olaparib) • Vitrakvi (larotrectinib) • gemcitabine • 5-fluorouracil • oxaliplatin • Abraxane (albumin-bound paclitaxel) • irinotecan • leucovorin calcium
2ms
Journal
|
FGFR3 (Fibroblast growth factor receptor 3) • AQP1 (Aquaporin 1)
2ms
Despite the perceived benefit of UFS, only 1-in-5 UFS patients actually realize maximal survival when known factors highly associated with outcomes are assessed. Patients are proportionally more likely to do worst, rather than best after UFS treatment. Similarly staged patients undergoing ITT-neoadjuvant therapy achieve survival superior to the majority of UFS patients. Patients and providers should be aware of the false perception of 'optimal' survival benefit with UFS in anatomically resectable PDAC.
Journal
|
Cancer antigen 19-9
2ms
P1, N=108, Recruiting, I-Mab Biopharma Co. Ltd. | Not yet recruiting --> Recruiting
Clinical • Enrollment open
|
CLDN18 (Claudin 18)
|
TJ-CD4B
2ms
Keeping in mind the small sample size of our series, gBRCA1pv and > 65 years pts yielded limited benefit from 2LT. Platinum-based 2LT obtained longer PFS2 and OS2 as opposed to platinum-free 2LT. Pts with PFS1 ≤ 6 months had longer PFS2 and OS2, but shorter OStot if compared to pts with PFS1 > 6 months.
Clinical • BRCA Biomarker • PARP Biomarker
|
BRCA2 (Breast cancer 2, early onset) • BRCA1 (Breast cancer 1, early onset)
2ms
Real-time and prospective genomic profiling of pts with advanced cancer using ctDNA is feasible, fast and helps to identify therapeutic targets approved or evaluated in clinical trials.
Clinical • MSi-H Biomarker • Circulating tumor DNA
|
MSI (Microsatellite instability)
|
MSI-H/dMMR
|
Guardant360® CDx
2ms
PDAC studies were done in RAS-mutant (7 KRAS, 1 NRAS) patient derived xenograft (PDX) models, and Panc-1 (KRAS-G12D) cells and xenografts +/- gemcitabine (Gem). NSCLC studies were done in A549 (KRAS G12S) cells and xenografts, and ST2972 (KRAS G12C) PDX tumors +/- docetaxel (Doc). In RAS-mutant PDAC PDX models derived from previously treated patients, SA SY-5609 (6mpk QD x28) induced regressions in 50% (4/8) of models and was well-tolerated (average body weight change [avg-BWC] 0%); regressions were sustained ≥2 weeks (wks) after drug discontinuation... SY-5609 shows robust antitumor activity in RAS-mutant PDAC and NSCLC preclinical models. support clinical evaluation of SY-5609 in combination with Gem in PDAC and Doc in NSCLC.
Preclinical • Combination therapy
|
KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)
|
KRAS mutation • NRAS mutation • KRAS G12C • KRAS G12D • KRAS G12 • KRAS G12S • NRAS G12D • NRAS G12S
|
gemcitabine • docetaxel • SY-5609
2ms
Subsequent treatment of PDAC cells in vitro with paclitaxel-loaded MSNs indeed showed high cytotoxicity, whereas no cell death was observed in white blood cell-derived cell lines, confirming efficacy of the nanoparticle-mediated drug delivery system. Taken together, this research introduces a novel ADAM9-responsive, protease-dependent, drug delivery system for PDAC as a promising tool to reduce the cytotoxicity of systemic chemotherapy.
Journal
|
ADAM9 (ADAM Metallopeptidase Domain 9)
|
paclitaxel
2ms
Decreasing LINC00842 level and inhibiting fatty acid synthase activity significantly repress PDAC growth and invasiveness in mouse pancreatic xenograft or patient-derived xenograft models. These results demonstrate that LINC00842 plays a role in promoting PDAC malignancy and thus might serve as a druggable target.
Journal
|
FASN (Fatty acid synthase)
2ms
Subsequent treatment with gemcitabine plus nab-paclitaxel failed to control the disease...Overall, amplification of oncogenic KRAS was not only associated with an aggressive phenotype, but also supported cancer resistance to chemotherapy. Importantly, this case suggests that plasma detection of KRAS amplification is feasible in the clinical routine and constitutes a powerful tool for assessing tumor aggressiveness.
Clinical • Journal • Liquid biopsy
|
KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53)
|
TP53 mutation • KRAS mutation • KRAS amplification
|
gemcitabine • 5-fluorouracil • Abraxane (albumin-bound paclitaxel) • leucovorin calcium
2ms
TP53 is a well-characterized tumor suppressor gene, and a critical regulatory component of the executive CCNG1/CDK/Myc/Mdm2/p53 axis, which regulates proliferative cell competence, DNA fidelity and survival. Studies are underway to determine whether TP53 mutations in pancreatic cancer can help identify a subset of patients with advanced metastatic cancer with an otherwise poor prognosis who would respond favorably to DeltaRex-G, which would broaden the treatment options for patients with otherwise lethal PDAC.
Clinical • Review • Journal
|
TP53 (Tumor protein P53) • MDM2 (E3 ubiquitin protein ligase)
|
TP53 mutation
|
DeltaRex-G (retroviral expression vectors bearing inhibitory genes)
2ms
Additionally, association of epidemiologically established risk factors for CP and PDAC, like alcohol intake, tobacco exposure, and metabolic factors with PMF activation, is discussed to comprehend the role of lifestyle factors on pancreatic pathologies. Overall, this analysis provides insight into the biology of PMF activation and highlights salient features of this process, which offer promising therapeutic targets.
Review • Journal
|
TGFB1 (Transforming Growth Factor Beta 1)
2ms
28 treatment-naïve patients who underwent EUS-FNB and had a final diagnosis of pancreatic ductal adenocarcinoma (PDAC) were included in the study. All the EUS-FNB samples were adequate for the evaluation of MMR and PD-L1 expression. None of the patients with PDAC included in the study had a dMMR tumor.
Clinical • MSi-H Biomarker • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2)
|
PD-L1 expression • MSI-H/dMMR
2ms
Based on our calculation, we defined BX-795, GSK503, JIB-04, Sapanisertib and Erastin as hits and further evaluated the relevance of Erastin. Based on our data, HDAC inhibitors like Entinostat are synergistic with the ferroptosis-inducer Erastin and should be further advanced in preclinical models.
Preclinical • Combination therapy
|
HDAC2 (Histone deacetylase 2)
|
sapanisertib (TAK-228) • erastin • entinostat (SNDX-275)
2ms
We provide evidence that AMPK can be inhibited with PF-3758309, allowing to target a central metabolic regulator and underscoring the relevance of drug repurposing.
PAK4 (P21 (RAC1) Activated Kinase 4) • AMPK (Protein Kinase AMP-Activated Catalytic Subunit Alpha 1)
|
PF-3758309
2ms
Together, these results reveal that ROBO1 regulates actin cytoskeletal organization at pancreatic tumor cell peripheries. This is a first step in unravelling the role of ROBO1 in pancreatic cancer.
RHOA (Ras homolog family member A) • ANLN (Anillin Actin Binding Protein)
2ms
We provide evidence that AMPK can be inhibited with PF-3758309, allowing to target a central metabolic regulator and underscoring the relevance of drug repurposing.
PAK4 (P21 (RAC1) Activated Kinase 4) • AMPK (Protein Kinase AMP-Activated Catalytic Subunit Alpha 1)
|
PF-3758309
2ms
Based on our calculation, we defined BX-795, GSK503, JIB-04, Sapanisertib and Erastin as hits and further evaluated the relevance of Erastin. Based on our data, HDAC inhibitors like Entinostat are synergistic with the ferroptosis-inducer Erastin and should be further advanced in preclinical models.
Preclinical • Combination therapy
|
HDAC2 (Histone deacetylase 2)
|
sapanisertib (TAK-228) • erastin • entinostat (SNDX-275)
2ms
28 treatment-naïve patients who underwent EUS-FNB and had a final diagnosis of pancreatic ductal adenocarcinoma (PDAC) were included in the study. All the EUS-FNB samples were adequate for the evaluation of MMR and PD-L1 expression. None of the patients with PDAC included in the study had a dMMR tumor.
Clinical • MSi-H Biomarker • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2)
|
PD-L1 expression • MSI-H/dMMR
2ms
Overall, our preliminary findings demonstrate that ATM and/or P53-depleted tumor cells are differentially able to mediate specific CAF differentiation, which in turn could dramatically promote tumor aggressiveness.
KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • ATM (ATM serine/threonine kinase) • TNFA (Tumor Necrosis Factor-Alpha) • ACTA2 (Actin Alpha 2 Smooth Muscle) • IL1A (Interleukin 1, alpha)
|
TP53 mutation • KRAS G12D • KRAS G12 • ATM overexpression • ATM expression
2ms
Based on our calculation, we defined BX-795, GSK503, JIB-04, Sapanisertib and Erastin as hits and further evaluated the relevance of Erastin. Based on our data, HDAC inhibitors like Entinostat are synergistic with the ferroptosis-inducer Erastin and should be further advanced in preclinical models.
Preclinical • Combination therapy
|
HDAC2 (Histone deacetylase 2)
|
sapanisertib (TAK-228) • erastin • entinostat (SNDX-275)
2ms
We provide evidence that AMPK can be inhibited with PF-3758309, allowing to target a central metabolic regulator and underscoring the relevance of drug repurposing.
PAK4 (P21 (RAC1) Activated Kinase 4) • AMPK (Protein Kinase AMP-Activated Catalytic Subunit Alpha 1)
|
PF-3758309
2ms
28 treatment-naïve patients who underwent EUS-FNB and had a final diagnosis of pancreatic ductal adenocarcinoma (PDAC) were included in the study. All the EUS-FNB samples were adequate for the evaluation of MMR and PD-L1 expression. None of the patients with PDAC included in the study had a dMMR tumor.
Clinical • MSi-H Biomarker • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • MSI (Microsatellite instability) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2)
|
PD-L1 expression • MSI-H/dMMR
2ms
We also describe known genomic hallmarks of these lesions and summarize the latest data about molecular processes involved in IPMNs initiation and progression to IPMCs. Finally, potential implications for clinical practice and future research strategies are discussed.
Clinical • Review • Journal
|
GNAS (GNAS Complex Locus)
2ms
Furthermore, mimi-surv was shown to identify more PDAC related miRNAs than other methods because it used the known structure for miRNA-mRNA regularization. An implementation of mimi-surv is available at http://statgen.snu.ac.kr/software/mimi-surv.
Journal
|
MIR96 (MicroRNA 96)
2ms
Furthermore, experimental manipulation of the anti-metastasis splicing isoform TAF8L revealed that splice isoform switching of TAF8 is crucial for PDAC metastasis. In conclusion, our findings demonstrate the essentiality of HNRNPC-mediated alternative splicing events that impinges on metastatic PDAC.
Journal
|
HNRNPC (Heterogeneous Nuclear Ribonucleoprotein C)
2ms
However, data regarding BRCA1/2-mutant PDAC are lacking. In this review, we aim to outline the specific landscape of BRCA-mutant PDAC, focusing on heritability, clinical features, differences between BRCA1 and 2 mutations and between germline and sporadic alterations, as well as established therapeutic strategies and those that are still under evaluation.
Review • Journal • BRCA Biomarker
|
BRCA2 (Breast cancer 2, early onset) • BRCA1 (Breast cancer 1, early onset) • BRCA (Breast cancer early onset)
|
BRCA1 mutation • BRCA2 mutation • BRCA1 mutation + BRCA2 mutation • BRCA mutation
2ms
Administration of mice with a GLUT1-specific inhibitor reduced tumor burden, comparable with gemcitabine, the current standard-of-care. In addition, we observe that intra-tumoral macrophages from human PDAC patients exhibit a pronounced glycolytic signature, which reliably predicts poor survival. Our data support a key role for macrophage metabolism in tumor immunity, which could be exploited to improve patient outcomes.
Journal
|
IL1B (Interleukin 1, beta)
|
gemcitabine
2ms
We did not identify any histomorphological features associated with either types of CCA or metastatic PDAC. As a conclusion of novel finding, FOXF1 immunohistochemistry may be regarded as a specific but insensitive marker of hilar/extrahepatic CCA and metastatic PDAC and it may help distinguish them from peripheral CCA.
Clinical • Journal
|
CRP (C-reactive protein)
2ms
Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.
Journal
|
FTL (Ferritin Light Chain) • TFRC
2ms
More than one-quarter of patients who underwent upfront surgery for PDAC were alive after 5 years, although only 11% of the initial cohort were cancer-free. Long-term survival can also be achieved in tumors with more favorable biology in an upfront setting followed by adjuvant chemotherapy.
Journal
|
Cancer antigen 19-9
2ms
TGF-β is important in PDAC anti-tumor immunity, demonstrating context-dependent impact on immune cells. TGF-β has an overall immunosuppressive effect mediated by TAM PD-L1 expression and decreased presence of DCs. Future investigations will focus on enhancing anti-cancer immune effects of TGF-β receptor inhibition.
Journal • PD(L)-1 Biomarker • IO biomarker
|
TGFB1 (Transforming Growth Factor Beta 1)
|
PD-L1 expression • PD-L1 overexpression
|
galunisertib (LY2157299)
2ms
Triple combination of motixafortide, pembrolizumab and chemotherapy was safe, well tolerated and showed signs of efficacy in a population with poor prognosis and aggressive disease.
Journal
|
CXCL12 (C-X-C Motif Chemokine Ligand 12)
|
Keytruda (pembrolizumab) • gemcitabine • 5-fluorouracil • leucovorin calcium • Onivyde (nanoliposomal irinotecan) • motixafortide (BL-8040)
2ms
Furthermore, tiny PNI and LNM lesions in xenograft models were detected by NIRF imaging, with TBRs measuring 2.59 ± 0.19 and 2.88 ± 0.72, respectively. Therefore, the clinical translation of this probe might shed new light on NIRF-guided pancreatectomy and improve the surgical prognosis of PDAC patients.
Preclinical • Journal
|
MET (MET proto-oncogene, receptor tyrosine kinase)
|
MET positive • MET expression
2ms
Several genes with the highest prevalence of PVs are involved in breast and ovarian cancer suggesting strong overlap with underlying genetics in these disorders but no single gene was predominant. More research is needed to further understand the risk of PDAC associated with these many diverse genes.
Clinical • Review • Journal • BRCA Biomarker
|
BRCA2 (Breast cancer 2, early onset) • CDKN2A (Cyclin-dependent kinase inhibitor 2A)
2ms
https://github.com/GiantSpaceRobot/tsRNAsearch. Supplementary data are available at Bioinformatics online.
Journal
|
MIR135B (MicroRNA 135b)
2ms
The combination of alisertib and nab-paclitaxel has manageable side-effect profile and showed promising preliminary efficacy in high-grade NETs, warranting further testing.
Clinical • P1 data • Journal
|
AURKA (Aurora kinase A)
|
Abraxane (albumin-bound paclitaxel) • alisertib (MLN8237)
2ms
Similarly, these cells mediated enhanced in vivo antitumor efficacy in xenograft models of HER2 pancreatic ductal adenocarcinoma, exhibiting elevated expression of granzymes and reduced expression of exhaustion markers. These data suggest that this T cell subset presents an opportunity to improve CAR T cell therapy for the treatment of solid tumors.
Clinical • Journal • CAR T-Cell Therapy • IO biomarker
|
HER-2 (Human epidermal growth factor receptor 2) • CD8 (cluster of differentiation 8)
|
CD8 expression
2ms
These results support the hypothesis that AVA, although reducing radiotherapy damage to normal tissues, acts synergistically only with high dose per fraction radiation regimens analogous to stereotactic ablative body radiotherapy against tumors by a hydrogen peroxide-dependent mechanism. This tumoricidal synergy is now being tested in a phase I-II clinical trial in humans (NCT03340974).
Journal
|
TNFA (Tumor Necrosis Factor-Alpha) • CAT (Catalase)
|
avasopasem manganese (GC4419)
2ms
Gene aggregation analysis showed that DEGs highly expressed in high-risk group were mainly concentrated in the glycolysis level, immune status, and tumor cell proliferation, etc. In addition, the samples in high-risk group showed immunosuppressed status and infiltrated by relatively more macrophages and less CD8+T cell. These findings suggested that the gene signature based on glycolysis-related genes had potential diagnostic, therapeutic, and prognostic value for PDAC.
Journal
|
CD8 (cluster of differentiation 8)
2ms
An RFS of 9 months is the best threshold to distinguish ER and LR. The model can accurately predict the risk of ER in PDAC after radical resection, and risk grouping can predict the patients who could benefit from upfront surgery.
Retrospective data • Journal
|
Cancer antigen 19-9
2ms
D and f values derived from the IVIM model had higher sensitivity and diagnostic performance for grading fibrosis in PDAC compared to the conventional DWI model. IVIM-DWI may have the potential as an imaging biomarker for predicting the fibrosis grade of PDAC.
Journal
|
CD34 (CD34 molecule) • KRT19 (Keratin 19)
2ms
Sorting for CD133 identified a cell population in the LUAD microniche that produced organoids with a high percentage of PORCN + and proliferating cells and an elevated EV secretion, which may explain that CD133 marks LUAD cells with malignant behavior. Collectively, we show here that high cell proliferation rate, induced by Wnt pathway activation, is coupled to a higher EV release, a critical finding that may be considered when developing EV-based diagnostic tools.
Journal
|
CD133
2ms
The inhibitory effect on Kras -induced growth is maintained in the pancreatitis-accelerated model, while simultaneously modifying immunoregulatory gene networks that also contribute to carcinogenesis. This study outlines the existence of a novel KRAS-EHMT2 pathway that is critical for mediating the growth-promoting and immunoregulatory effects of this oncogene in vivo, extending human observations to support a pathophysiological role for the H3K9me pathway in PDAC.
Journal • Epigenetic controller
|
KRAS (KRAS proto-oncogene GTPase) • CHEK2 (Checkpoint kinase 2) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
|
KRAS deletion
2ms
In low score group, the programmed cell death 1 ligand 1(PD-L1) (+) cases showed worse prognosis but higher T cell infiltration than PD-L1(-) cases. Our immunity-related 18-gene signature could effectively predict PDAC prognosis, and it might be a practical predictive tool to identify PDAC subtype benefitting from gemcitabine-based adjuvant chemotherapy or potentially responding to PD1/PD-L1 blockade therapy.
Clinical • Journal • Gene Signature • PD(L)-1 Biomarker • IO biomarker
|
PCNA (Proliferating cell nuclear antigen)
|
gemcitabine
2ms
This study provides supportive evidence that TLS induction may potentiate the anti-tumor activity of chemotherapy in a murine model of PDAC. A detailed understanding of TLS kinetics and their induction, due to multiple host and tumor factors may help design personalized therapies harnessing the potential of immuno-oncology.
Preclinical • Journal
|
KRAS (KRAS proto-oncogene GTPase) • CXCL13 (Chemokine (C-X-C motif) ligand 13)
|
gemcitabine
2ms
Here we review convergent and disparate metabolic networks regulated by oncogenic mutant KRAS in colon, lung and pancreas tumours, with an emphasis on co-occurring mutations and the role of the tumour microenvironment. Furthermore, we explore how these networks can be exploited for therapeutic gain.
Review • Journal
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
2ms
Targeted NGS can reliably detect KRAS mutations from EUS-FNA samples and exhibits high KRAS mutational concordance with primary tumor and ctDNA. This suggests targeted NGS of EUS-FNA samples may enable preoperative ctDNA prognostication using digital droplet PCR and supplement diagnoses in patients with inconclusive EUS-FNA.
Clinical • Journal • Next-generation sequencing
|
KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53)
|
TP53 mutation
2ms
Collectively, we identify SIRT5 as a key tumor suppressor in PDAC, whose loss promotes tumorigenesis through increased non-canonical utilization of glutamine via GOT1, and that SIRT5 activation is a novel therapeutic strategy to target PDAC.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • SIRT5 (Sirtuin 5)
|
gemcitabine
3ms
Here, we summarize established and new strategies in autophagy-related drug discovery and indicate a path toward establishing a more efficient discovery of autophagy-selective pharmacological agents. With this knowledge at hand, modern concepts for therapeutic exploitation of autophagy might become more plausible.Abbreviations: ALS: amyotrophic lateral sclerosis; AMPK: AMP-activated protein kinase; ATG: autophagy-related gene; AUTAC: autophagy-targeting chimera; CNS: central nervous system; CQ: chloroquine; GABARAP: gamma-aminobutyric acid type A receptor-associated protein; HCQ: hydroxychloroquine; LYTAC: lysosome targeting chimera; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NDD: neurodegenerative disease; PDAC: pancreatic ductal adenocarcinoma; PE: phosphatidylethanolamine; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol 3-phosphate; PROTAC: proteolysis-targeting chimera; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like autophagy activating kinase 1.
Journal
|
mTOR (Mechanistic target of rapamycin kinase) • SQSTM1 (Sequestosome 1) • GABARAP (GABA Type A Receptor-Associated Protein) • PIK3C3 (Phosphatidylinositol 3-Kinase Catalytic Subunit Type 3) • AMPK (Protein Kinase AMP-Activated Catalytic Subunit Alpha 1)
|
hydroxychloroquine • chloroquine phosphate
3ms
NACRT for PDAC decreased overall immune cell counts, but these changes were heterogeneous within the cancer cell nests and cancer stroma. The CD204+ macrophage count in the cancer cell nest is an independent predictor of early disease recurrence in PDAC patients after NACRT.
Journal
|
CD20 (Membrane Spanning 4-Domains A1) • CD4 (CD4 Molecule) • FOXP3 (Forkhead Box P3)
3ms
Ablation of HSP47 promotes gemcitabine-induced suppression of tumor growth in PDAC cell-bearing mice. Overall, these results indicated that HSP47 confers chemoresistance on PDAC cells and suggested that disruption of HSP47 may improve the efficacy of chemotherapy for patients with PDAC.
Journal
|
CALR (Calreticulin)
|
gemcitabine
3ms
However, over-expressing CDON suppresses cholesterol-mediated Shh release in some PDAC contexts, which may be relative to the mutational burden of the cells. Identifying mechanisms that either sequester or stimulate Shh release from the tumor cell membrane may provide new avenues to reduce signaling between the tumor and its surrounding environment, which may restrain tumor development.
Journal • Tumor Mutational Burden
|
TMB (Tumor Mutational Burden) • SHH (Sonic Hedgehog Signaling Molecule)
3ms
Moreover, we have identified that collagen-induced CXCL5 production was mediated by a DDR1-PKCθ-SYK-NFkB signaling cascade. Together, these results highlight the critical contribution of collagen I-DDR1 interaction in the formation of an immune microenvironment that promotes PDAC metastasis.
Journal
|
SYK (Spleen tyrosine kinase) • CXCL5 (Chemokine (C-X-C motif) ligand 5)
3ms
P1, N=12, Not yet recruiting, CHU de Quebec-Universite Laval | Initiation date: Jun 2021 --> Sep 2021
Clinical • Trial initiation date • Combination therapy
|
PD-L1 (Programmed death ligand 1) • LRP1 (LDL Receptor Related Protein 1)
|
5-fluorouracil • leucovorin calcium • Repatha (evolocumab) • atorvastatin
3ms
Therefore, new biomarkers for PDAC are critically needed. This review aims at recent advancements in the identification and characterization of new biomarkers, microRNAs, which might prove useful in the early detection of PDAC.
Journal
|
CEACAM5 (CEA Cell Adhesion Molecule 5) • Cancer antigen 19-9
3ms
Journal
|
CXCR4 (Chemokine (C-X-C motif) receptor 4)
3ms
Changes in DNA methylation status and/or histone modification, such as acetylation, methylation or phosphorylation, among others, are the most important targets for epigenetic cancer therapy. Therefore, the present review aims to compile the basic information of epigenetic modifications, pathways and factors, and provide a rationale for the research and treatment of highly aggressive tumors with epigenetic drugs.
Review • Journal
|
CTNNB1 (Catenin (cadherin-associated protein), beta 1)
3ms
First-line treatment based on a combined chemotherapy (FOLFIRINOX or gemcitabine plus nab-paclitaxel) provides limited benefits. Olaparib, a PARP inhibitor, has been approved as maintenance for PDAC patients harboring germline BRCA1/2 pathogenic mutations and previously treated with a platinum-based chemotherapy...Failed samples were all from tissue macrosections, which had higher fragmented DNA than standard sections, biopsies and fine-needle aspirations, likely due to fixation procedures. BRCA1/2 testing on pancreatic tumor tissues can also be feasible on small biopsies, but more cases must be analyzed to define its role and value in the PDAC diagnostic algorithm.
Clinical • Journal • BRCA Biomarker • PARP Biomarker
|
BRCA2 (Breast cancer 2, early onset) • BRCA1 (Breast cancer 1, early onset)
|
BRCA2 mutation
|
Lynparza (olaparib) • gemcitabine • 5-fluorouracil • Abraxane (albumin-bound paclitaxel) • leucovorin calcium
3ms
The suppression of CD8+ cell proliferation by insulin-pretreated PDAC cells was reversed by PD-1 blockade with Pembrolizumab or by PD-L1 siRNA...Our findings provide a novel insight into the protumorigenic role of insulin in PDAC. Recognizing the impact of insulin on PD-L1 expression as part of the immune privilege, strategies to interfere with this mechanism could pave the way towards a more efficient immunotherapy of PDAC.
Journal • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • CD8 (cluster of differentiation 8) • EGF (Epidermal growth factor) • IR (Insulin receptor)
|
PD-L1 expression
|
Keytruda (pembrolizumab)
3ms
On the other hand, nucleolin overexpression increased β-catenin stabilization. In conclusion, in this study, we identified β-catenin as a new nucleolin interactor and suggest that the Wnt/β-catenin pathway could be a new target of the nucleolin antagonist N6L in PDAC.
Journal
|
NCL (Nucleolin)
|
NCL overexpression
3ms
Finally, a clinico-genomic model was developed to estimate the prognosis of patients with PDAC based on clinical parameters and genetic alterations affecting survival in patients; 20 single nucleotide variants and three copy number variations were selected. Targeted deep sequencing on minimal specimens of PDACs was performed, and it was applied to establish a clinico-genomic model for prognosis prediction.
Journal • BRCA Biomarker
|
KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • BRCA2 (Breast cancer 2, early onset) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • NF1 (Neurofibromin 1) • SMAD4 (SMAD family member 4) • Cancer antigen 19-9
|
TP53 mutation • KRAS mutation • NF1 mutation
3ms
NPC-1C and PAM4 antibody reactive epitopes on MUC5AC are immunogenic and could represent specific changes on the native MUC5AC glycoprotein linked to carcinogenesis. It was never studied to predict treatment response.
Clinical • Review • Journal
|
MUC5AC (Mucin 5AC)
|
MUC5AC expression
|
ensituximab (NEO-102)
3ms
Mutational signature pattern analysis reveals a predominance of an age-related pattern. Our findings highlight that biliary ITPN and classical cholangiocarcinoma display commonalities, in particular mutations in genes of the chromatin remodeling pathway, and appear, therefore, more closely related than pancreatic ITPN and classical pancreatic ductal adenocarcinoma.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • FGFR2 (Fibroblast growth factor receptor 2) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • SMAD4 (SMAD family member 4) • GNAS (GNAS Complex Locus)
|
FGFR2 mutation
3ms
Syndecan-1 was found to be downregulated during cholangiocarcinogenesis, yet we could not show significant effects on prognosis on protein level. Further analyses are needed to further depict its specific role.
Clinical • Journal
|
SDC1 (Syndecan 1)
3ms
Immunotherapy has shown promising results in high-TMB PDAC, but the sample size of high-TMB PDAC treated so far is quite small. This study highlights interesting peculiarities of PDAC harboring high-TMB and may represent a reliable starting point for the assessment of TMB in the clinical management of patients affected by pancreatic cancer.
Review • Journal • Tumor Mutational Burden • IO biomarker
|
TMB (Tumor Mutational Burden) • MSI (Microsatellite instability)
|
TMB-H
3ms
In vivo, B390 not only suppressed tumor growth by increasing tumor cell death, it also inhibited lymphangiogenesis and lymphovascular invasion. Taken together, our data demonstrate that B390 was able to alleviate loss-of-DUSP2-mediated pathological processes, which provides the proof-of-concept evidence to demonstrate the potential of using selective HDAC1/2 inhibitors in PDAC treatment and suggests reinstating DUSP2 expression may be a strategy to subside PDAC progression.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • VEGFC (Vascular Endothelial Growth Factor C)
|
KRAS mutation
3ms
Importantly, our nomogram displayed higher C-index for OS than previous reported models, indicating a better predictive value of our model. A simple and practical nomogram for patient prognosis in PDAC of pancreatic head following pancreaticoduodenectomy was established, which shows satisfactory predictive efficacy and deserves further evaluation in the future.
Clinical • Journal
|
Cancer antigen 19-9
3ms
Other smart strategies, such as nanomedicines, sonic Hedgehog inhibitor, or smoothened inhibitor, are discussed to enhance chemotherapeutic agents' efficiency by disrupting the PDAC stroma. This review highlights the current challenges and various preclinical and clinical strategies to overcome current PDAC therapy difficulties, thus significantly advancing PDAC research knowledge.
Clinical • Journal • Tumor Mutational Burden • IO biomarker
|
TMB (Tumor Mutational Burden)
|
TMB-L
3ms
CD58 expression is upregulated in PDAC tissues and its high expression is notably related to poor survival of PDAC. Therefore, CD58 may serve as a novel and effective marker for predicting the prognosis of PDAC patients.
Clinical • Journal
|
CD8 (cluster of differentiation 8) • CD58 (CD58 Molecule)
3ms
Further studies showed that the effect of IL‑28RA on PDAC cells was exerted by regulating the phosphorylation levels of STAT1 and AKT. In conclusion, lower IL‑28RA expression may contribute to the pathogenesis of PDAC, where results from the present may provide further insights into the progression of PDAC, in addition to highlighting potentially novel therapeutic targets for this disease.
Journal
|
STAT1 (Signal Transducer And Activator Of Transcription 1) • CCNB1 (Cyclin B1)
|
IL2RA expression
3ms
Surrogate readouts of HRD identify a greater proportion of patients with HRD than analyses limited to gene-level approaches. There is a clear need to harmonize HRD definitions and to validate the optimal biomarker for treatment selection. Universal HRD screening including integrated somatic and germline analysis should be offered to all patients with PDAC.
Retrospective data • Review • Journal • BRCA Biomarker
|
BRCA2 (Breast cancer 2, early onset) • BRCA1 (Breast cancer 1, early onset) • HRD (Homologous Recombination Deficiency) • PALB2 (Partner and localizer of BRCA2) • CHEK2 (Checkpoint kinase 2) • RAD51 (RAD51 Homolog A)
|
BRCA1 mutation • BRCA2 mutation • ATM mutation • HRD • PALB2 mutation • CHEK2 mutation • HRD + BRCA1 mutation • RAD51 mutation
3ms
However, in STARPAC clinical trial (NCT03307148), stromal modulation by ATRA even at first dose is accompanied with serum PTX3 response in patients who later go on to demonstrate disease control but not those in whom the disease progresses. PTX3 is a putative stromally-derived biomarker for PDAC which warrants further testing in prospective, larger, multi-center cohorts and within clinical trials targeting stroma.
Journal
|
TNFA (Tumor Necrosis Factor-Alpha) • Cancer antigen 19-9
3ms
These findings demonstrate that the combination of GnP therapy with C4BPA inhibits PDAC progression by promoting antitumor T cell accumulation in the tumor microenvironment.
Journal • Tumor-Infiltrating Lymphocyte • IO biomarker
|
CD8 (cluster of differentiation 8) • CD40 (CD40 Molecule)
|
CD40 expression
|
gemcitabine • Abraxane (albumin-bound paclitaxel)
3ms
Moreover, lipidomics showed the induction in PCSCs of molecular species of cardiolipin with mixed incorporation of 16:0, 18:1, and 18:2 acyl chains. Our data indicate a crucial role of FA elongation and alteration in cardiolipin acyl chain composition in PCSCs, representing attractive therapeutic targets in PDAC.
Journal
|
LDHA (Lactate dehydrogenase A)
3ms
ADM/PanINs and IPMNs show specific stemness signatures with unique metabolisms. Inhibition of PGC1α using SR18292 diminishes the specific stemness by targeting FAO-independent and FAO-dependent OXPhos of ADM/PanINs and IPMNs, respectively.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • SMAD4 (SMAD family member 4) • NRF1 (Nuclear Respiratory Factor 1) • GNAS (GNAS Complex Locus) • PPARG (Peroxisome Proliferator Activated Receptor Gamma)
|
doxycycline
3ms
Combined depletion of ITGAV in PDA cells and E- and P-selectins in host mice massively suppresses intraperitoneal carcinomatosis of PDA cells xenografted into immunodeficient mice, confirming the hypothesis of a partly redundant adhesion cascade of metastasizing cancer cells. Our data strongly encourage developing novel therapeutic approaches for the combined targeting of E- and P-selectins and ITGAV in PDA.
Journal
|
TGFB1 (Transforming Growth Factor Beta 1)
3ms
Highly stabilized mutp53 is degradable by the Hsp90 inhibitors Onalespib and Ganetespib, and correlates with growth suppression, possibly suggesting therapeutic vulnerabilities to target GOF mutp53 proteins in PDAC. The selective mutp53 GOF signals through enhancing the STAT3 axis, which was confirmed since targeting STAT3 by knockdown or pharmacological inhibition phenocopied mutp53 depletion and reduced cell viability and migration preferentially in mutp53-containing PDAC cells. Our results confirm that mutp53 GOF activities are allele specific and can span across tumor entities.
Journal
|
STAT3 (Signal Transducer And Activator Of Transcription 3)
|
TP53 mutation
|
ganetespib (ADX-1612) • onalespib (AT13387)
3ms
In contrast, transplanted PDLOs with mutant GNAS lead to intraductal papillary mucinous neoplasia-like structures. Conclusively, PDLOs enable in vitro and in vivo studies of pancreatic plasticity, dysplasia, and cancer formation from a genetically defined background.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • GNAS (GNAS Complex Locus)
|
KRAS expression
3ms
KRAS, but not GNAS, induces acinar-to-ductal metaplasia-like changes in culture and in vivo. We develop a renewable source of ductal and acinar organoids for modeling exocrine development and diseases and demonstrate lineage tropism and plasticity for oncogene action in the human pancreas.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • GNAS (GNAS Complex Locus)
3ms
High expression of SOX9 and TSPAN8 has been associated with tumor stage, poor prognosis and poor patient survival in PDAC. In conclusion, this study highlights the importance of the EGF-SOX9-TSPAN8 signaling cascade in the control of PDAC invasion and implies that TSPAN8 may be a promising novel therapeutic target for the treatment of PDAC.
Journal
|
EGFR (Epidermal growth factor receptor) • SOX9 (SRY-Box Transcription Factor 9)
|
SOX9 overexpression • SOX9 expression
3ms
Despite such morphological similarities with IPMNs, the prognosis of large-duct PDA is equivalent to that of classic PDA. Differential diagnosis is therefore essential.
Review • Journal
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
3ms
IL1R1 and LAMA2 were identified as the site- and immune-related genes in pancreatic ductal adenocarcinoma, and their high expression in pancreatic head cancer exhibited high immune scores and predicted unfavorable prognosis. The authors identified IL1R1 and LAMA2 as immune- and locus-associated genes, and their high expression predicted a poor prognosis.
Journal
|
IL1R1 (Interleukin 1 receptor, type I)
3ms
We have identified a novel molecule AS-10, a selenazolidine-bis-aspirinyl derivative, that was two to three orders of magnitude more potent than aspirin and at least one to two orders of magnitude more potent than gemcitabine in inhibiting PDAC cancer cell growth/viability against three PDAC cell lines while sparing mouse embryonic fibroblasts in the same exposure range. As NF-κB activation in PDAC cells confers resistance to gemcitabine, the AS-10 combination with gemcitabine increased the in vitro cytotoxicity more than the additivity of both compounds. Overall, our results suggest AS-10 may be a promising drug lead for PDAC, both as a single agent and in combination therapy.
Journal
|
CCND1 (Cyclin D1) • TNFA (Tumor Necrosis Factor-Alpha) • CASP3 (Caspase 3) • CASP7 (Caspase 7) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
|
gemcitabine • aspirin
3ms
The identified proteins could be informative for developing treatment strategies for patients with PDAC and peritoneal dissemination.
Clinical • Journal
|
LYVE1 (Lymphatic vessel endothelial hyaluronan receptor 1)
3ms
Together, our data show that increased NADK activity is an important adaptation driven by oncogenic signaling. Our findings indicate that NADK could serve as a much-needed therapeutic target for PDAC.
Journal
|
KRAS (KRAS proto-oncogene GTPase)
3ms
The net reclassification index (NRI), integrated discrimination improvement (IDI) and decision curve analysis showed improvement of accuracy of the nomogram in predicting OS and better net benefit in guiding clinical decisions in comparison with CONUT and PNI. The nomogram incorporating four preoperative nutritional and tumor markers including serum albumin concentration, lymphocyte count, CA19-9 and diabetes mellitus could predict the prognosis more accurately than CONUT and PNI and may serve as a clinical decision support tool to determine what treatment options to choose.
Journal
|
Cancer antigen 19-9
3ms
MYC suppressed loading of dsRNA onto TLR3 and its subsequent degradation via association with MIZ1. Collectively, these findings suggest that MYC and MIZ1 suppress a surveillance pathway that signals perturbances in mRNA processing to the immune system, which facilitates immune evasion in pancreatic ductal adenocarcinoma.
Journal • IO biomarker
|
KRAS (KRAS proto-oncogene GTPase) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • TLR3 (Toll Like Receptor 3)
|
KRAS G12D • KRAS G12 • MYC expression • KRAS deletion
3ms
Clinical • Enrollment open • Combination therapy
|
BRAF (B-raf proto-oncogene) • KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)
|
BRAF V600E • KRAS mutation • NRAS mutation • BRAF V600 • BRAF V600K
|
Mekinist (trametinib) • DCC-3116
3ms
P=N/A, N=1000, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Jan 2022 --> Jun 2023 | Trial primary completion date: May 2021 --> Aug 2022
Trial completion date • Trial primary completion date
|
TP53 (Tumor protein P53) • BRCA2 (Breast cancer 2, early onset) • BRCA1 (Breast cancer 1, early onset) • STK11 (Serine/threonine kinase 11) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • APC (APC Regulator Of WNT Signaling Pathway) • EPCAM (Epithelial cell adhesion molecule)
|
TP53 mutation • BRCA1 mutation • ATM mutation • PALB2 mutation • APC mutation • MSH2 mutation • PMS2 mutation
3ms
Clinical • New P3 trial
|
CEACAM5 (CEA Cell Adhesion Molecule 5)
|
5-fluorouracil • oxaliplatin • irinotecan • leucovorin calcium
3ms
Here we report tumor-cell-intrinsic chromatin accessibility patterns of treatment-naïve surgically resected PDAC tumors that were subsequently treated with (Gem)/Abraxane adjuvant chemotherapy...Applying this methodology to the original ATAC-seq libraries as well as independent libraries generated from patient-derived organoids, we validate ATAC-array technology in both the original ATAC-seq cohort as well as in an independent validation cohort. We conclude that PDAC prognosis can be predicted by ATAC-array, which represents a low-cost, clinically feasible technology for assessing chromatin accessibility profiles.
Journal
|
EPCAM (Epithelial cell adhesion molecule) • ZKSCAN1 (Zinc Finger With KRAB And SCAN Domains 1)
|
Abraxane (albumin-bound paclitaxel)
3ms
Molecular markers can also provide an insight to the prognosis. For instance, the loss of SMAD4 is associated with a poor outcome whereas mutations in MLL, MLL2, MLL3, and ARID1A are associated with improved survival.
Review • Journal
|
KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • ARID1A (AT-rich interaction domain 1A) • KMT2D (Lysine Methyltransferase 2D) • KMT2C (Lysine Methyltransferase 2C) • SMAD4 (SMAD family member 4) • MUC1 (Mucin 1) • MLL2 (Myeloid/lymphoid or mixed-lineage leukemia 2) • MUC4 (Mucin 4, Cell Surface Associated) • KRT19 (Keratin 19) • MUC5AC (Mucin 5AC)
|
TP53 mutation • KRAS mutation • ARID1A mutation • KMT2D mutation • MLL2 mutation • MUC4 expression • MLL mutation
3ms
Ca 19.9, at the cut-off >78 U/ml, indicated a significant trend to predict the need for VR (sensitivity 67%, specificity 53%; p = 0.059). In R-PDAC with normal serum albumin levels, Ca 19.9 predicts pN+ and R+, thus suggesting a crucial role in deciding on NAT.
Retrospective data • Journal
|
Cancer antigen 19-9
3ms
Increased activity of p38 in normal cells was associated with metastatic disease and poor prognosis in human melanoma patients whereas inactivation of p38 suppressed lung metastases. We discuss the p38α-driven mechanisms stimulating the metastatic processes and potential use of p38 inhibitors in adjuvant therapy of metastatic cancers.
Journal
|
FAP (Fibroblast activation protein, alpha)
3ms
Clinical • New P2 trial
|
IL6 (Interleukin 6) • IL1A (Interleukin 1, alpha) • IL1B (Interleukin 1, beta) • Cancer antigen 19-9
|
oxaliplatin • Abraxane (albumin-bound paclitaxel) • irinotecan • Kineret (anakinra)
3ms
Inhibition of glucose metabolism with low dose 2-deoxyglucose in combination with a MEK inhibitor induced apoptosis in KrasG12D-driven PDAC cells in vitro...Molecular and metabolic analyses indicated that co-targeting glycolysis and MAPK signaling results in apoptosis via induction of lethal ER stress. Together, our work suggests that combined inhibition of glycolysis and the MAPK pathway may serve as an effective approach to target KRAS-driven PDAC.
Journal
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation • KRAS G12D
|
deoxyglucose
3ms
Although it has been reported that FOXM1 enhances Wnt signaling, FOXM1 induced DKK1 expression independently of Wnt signaling in PDAC and ESCC cells. These results suggest that DKK1 and FOXM1 create a positive feedback loop to promote cancer cell proliferation.
Journal
|
DKK1 (dickkopf WNT signaling pathway inhibitor 1) • FOXM1 (Forkhead Box M1)
|
DKK1 overexpression
3ms
Zenocutuzumab, an investigational bispecific antibody, has shown early efficacy in an ongoing phase I/II study of patients with tumors harboring NRG1 fusions. The data so far appear particularly promising in NRG1 fusion-positive pancreatic ductal adenocarcinoma, which tends to occur in younger patients.
Journal
|
NRG1 (Neuregulin 1)
|
NRG1 fusion • NRG1 fusion
|
zenocutuzumab (MCLA-128)
3ms
This unparalleled examination of CD40 therapeutic mechanisms in patients provides insights for design of subsequent clinical trials targeting this pathway.
Clinical • Journal
|
CXCL10 (Chemokine (C-X-C motif) ligand 10) • CCL2 (Chemokine (C-C motif) ligand 2) • CCL22 (C-C Motif Chemokine Ligand 22) • CD40 (CD40 Molecule)
|
selicrelumab (RG7876)
3ms
Furthermore, rBC2LCN-precipitated fractions were blotted with an anti-CEA polyclonal antibody (pAb), and CEA pAb-precipitated fractions were blotted with rBC2LCN lectin. The results demonstrate that CEA is in fact a ligand of rBC2LCN lectin.
Journal
|
CEACAM5 (CEA Cell Adhesion Molecule 5)
4ms
Separately, the identification of ideal targets for the targeted therapy of PDAC is also reviewed exhaustively. Additionally, the review also addresses the applications of targeted immunotherapeutics like checkpoint inhibitors, adoptive T-cell therapy etc.
Review • Journal • IO biomarker
|
CD8 (cluster of differentiation 8)
|
CD8 expression
4ms
An elevated preoperative plasma D-dimer level was a reliable independent prognostic factor for OS in patients with PDAC undergoing resection. Combination of D-dimer, CA19-9, and NLR can enhance the prognostic accuracy before operation.
Clinical • Journal
|
Cancer antigen 19-9
4ms
Moreover, high-level stromal HA expression was associated with low ICS (p = 0.017). In conclusion, stromal HA accumulation is associated with poor survival and low immune response in PDAC.
Journal • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • CD8 (cluster of differentiation 8) • CD73 (5'-Nucleotidase Ecto)
|
PD-L1 expression • CD73 expression
4ms
Following coculture of activated T cells and BxPC-3 with CF33-hNIS-antiPDL1, the cell surface PD-L1 blockade on BxPC-3 cells by virus-delivered anti-PD-L1 antibody increased granzyme B release and prevented virus-induced decrease of perforin release from activated CD8+ T cells. Our results suggest that CF33-IOVs can prime immune checkpoint inhibition of PDAC and enhance antitumor immune killing.
Journal • PD(L)-1 Biomarker • IO biomarker
|
CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • GZMB (Granzyme B)
|
PD-L1 expression
|
CHECKvacc (CF33-hNIS-antiPDL1)
4ms
Kaplan-Meier analysis showed that overall survival of patients in the predicted stage I-II PDAC group was longer than patients in stage III-IV PDAC group (p<0.0001). We propose a combined model with excellent performance for the preoperative, individualized, noninvasive discrimination of stage I-II and III-IV PDAC and prediction of overall survival.
Journal
|
CEACAM5 (CEA Cell Adhesion Molecule 5)
4ms
Moreover, they significantly compromised the effectiveness of the conventional chemotherapy drug paclitaxel, as well as a novel therapy that combines an ERK inhibitor with chloroquine, which is currently in clinical trials for PDAC. The survival benefits provided by oncogenic KRAS-derived exosomes were markedly reduced when depleted of Survivin using siRNA or upon treatment with the Survivin inhibitor YM155. Taken together, these findings demonstrate how KRAS mutations give rise to exosomes that provide a unique form of intercellular communication to promote cancer cell survival and therapy resistance, as well as raise interesting possibilities regarding their potential for serving as therapeutic targets and diagnostic markers for KRAS-dependent cancers.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • BIRC5 (Baculoviral IAP repeat containing 5)
|
KRAS mutation
|
paclitaxel • chloroquine phosphate • sepantronium bromide (YM155)
4ms
While blocking IL-6 activity by tocilizumab only partially reverted the EMT phenotype in H6c7-kras cells, neutralization of TNF-α by etanercept was able to clearly impair EMT-associated properties in premalignant PDEC. Altogether, the current study attributes a role to a T2DM-related hyperglycemic, inflammatory micromilieu in the acquisition of malignancy-associated alterations in premalignant PDEC, thus providing new insights on how metabolic diseases might promote PDAC initiation.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • CDH1 (Cadherin 1)
|
IL6 expression
|
Actemra IV (tocilizumab) • Enbrel (etanercept)
4ms
Univariate and multivariate analysis showed that history of diabetes &lsqb;HR 2.656 (1.194-5.908), P = 0.017], numbers of positive lymph nodes &lsqb;HR 1.871 (1.388-2.522), P < 0.001], preoperative numbers of CD44+ CTECs &lsqb;HR 1.216 (1.064-1.390), P = 0.004], and POM1 CA19-9 level &lsqb;HR 1.002 (1.001-1.002), P < 0.001] were independent prognostic factors for DFS. The detection of CD44+CTECs in patients with resectable PDAC preoperatively could be an independent predictor of shorter DFS after radical surgery.
Clinical • Journal
|
CD44 • VIM (Vimentin) • Cancer antigen 19-9
|
CD44 expression • VIM expression
4ms
Clinical • Enrollment open
|
CTLA4 (Cytotoxic T-Lymphocyte Associated Protein 4) • TNFRSF9 (TNF Receptor Superfamily Member 9)
|
Keytruda (pembrolizumab) • lenvatinib
4ms
Inhibition of VCP either by genetic depletion or the pharmacological inhibitor CB-5083 increased ubiquitination and degradation of p53-R273H, leading to cell death. Consistently, ablation of VCP markedly retarded growth of cultured PDAC cells and xenograft PDAC tumors. Together, these results unveil VCP as a novel partner of p53-R273H in promoting PDAC growth and as a potential target for developing anti-PDAC therapy.
Journal
|
TP53 (Tumor protein P53) • MDM2 (E3 ubiquitin protein ligase)
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TP53 mutation • TP53 R273H
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CB-5083
4ms
The combination of zinc with TSQ, but not with TPEN, also induced cell death in PANC-1, a human pancreatic cancer cell line. These results suggest that a TSQ-zinc complex formed in pancreatic tumors induces cell death if zinc is overloaded.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • EPCAM (Epithelial cell adhesion molecule)
|
KRAS mutation • KRAS expression
4ms
P=N/A, N=1000, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting
Enrollment closed
|
TP53 (Tumor protein P53) • BRCA2 (Breast cancer 2, early onset) • BRCA1 (Breast cancer 1, early onset) • STK11 (Serine/threonine kinase 11) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • APC (APC Regulator Of WNT Signaling Pathway) • EPCAM (Epithelial cell adhesion molecule)
|
TP53 mutation • BRCA1 mutation • ATM mutation • PALB2 mutation • APC mutation • MSH2 mutation • PMS2 mutation
4ms
We were able to affinity-select EpCAM expressing CTCs with high purity (0-3 white blood cells/mL of blood), enumerate the selected cells, determine their viability, and immunophenotype the cells. The assay could be completed in 8 h.
Journal • Liquid biopsy
|
EPCAM (Epithelial cell adhesion molecule)
|
EPCAM expression
4ms
As an independent predictor of overall survival of PDAC patients, preoperative serum CA19-9 is defective in survival stratification when TBIL≥102.6 μmol/L but a positive survival prognosis could be achieved with the application of combined preoperative CA19-9/AST and CA19-9/γ-GGT.
Clinical • Journal
|
Cancer antigen 19-9
4ms
Under-expression of onco-miRs (miR-21, miR-155, and miR-221), over-expression of several apoptotic potential targets of oncomiRs (Bax, Casp-9, and P53), over-expression of tumor suppressive-miRs (let-7b, miR-34a, and miR-126), and under-expression of Bcl-2 was found in SPNs-treated cells. We suggest that silybin encapsulated in polymersomes (SPNs) may be useful as a complementary agent for destroying both pancreatic cancer cells and pancreatic CSCs along with chemotherapeutic agents.
Journal • IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MIR155 (MicroRNA 155) • CD133 • MIR21 (MicroRNA 21) • CD24 (CD24 Molecule) • CD44 • MIR34A (MicroRNA 34a-5p) • CASP9 (Caspase 9) • MIR126 (MicroRNA 126) • MIR221 (MicroRNA 221)
|
BCL2 expression • TP53 overexpression • miR-155 expression • miR-21 overexpression • BCL2 underexpression • CD133 expression • CD44 expression
4ms
Accordingly, we review several methods that have been used to target SETDB1, such as using Mithramycin A, Mithralog EC-8042, 3'-deazaneplanocin A (DZNep), and paclitaxel. Finally, we conclude by highlighting remaining gaps in knowledge and challenges surrounding SETDB1. Ultimately, our review captures the wide scope of findings on SETDB1's history, function, its implications in cancer, and provides suggestions for future research in the field.
Review • Journal
|
AR (Androgen receptor) • SETDB1 (SET Domain Bifurcated Histone Lysine Methyltransferase 1)
|
SETDB1 overexpression
|
paclitaxel • mithramycin analogue (EC-8042)
4ms
Our results showed that both YAP1-1 and YAP1-2 isoforms are important mediators in the EMT process of pancreatic cancer. However, YAP1-2 is more important in mediating TGF-β-induced EMT, which requires AKT signaling.
Journal
|
YAP1 (Yes associated protein 1) • TGFB1 (Transforming Growth Factor Beta 1) • EGF (Epidermal growth factor)
4ms
We developed a CT-based XGBoost classifier to extrapolate the infiltration levels of CD8 T-cells in patients with PDAC. This method could be useful in identifying potential patients who can benefit from immunotherapies.
Clinical • Journal • IO biomarker
|
CD8 (cluster of differentiation 8)
4ms
The status of CA19-9 was significantly associated with the incidence of distant recurrence whereas the status of FDG-PET was significantly associated with the incidence of local recurrence, and only patients with a favorable response in both CA19-9 and PET statuses showed a significantly better survival than the others (5-year survival: 56% vs 24%, P < .001), and those with unfavorable response in either of CA19-9 or PET status showed similar poor survival to those with unfavorable in both (P = .164). CA19-9 and PET evaluation provided oncologically different risk assessments in terms of tumor recurrence profile, and favorable response in both CA19-9 and FDG-PET were necessary to achieve prognostic benefit from NACRT.
Clinical • Journal
|
Cancer antigen 19-9
4ms
Tumor-specific targeted delivery of 5FU using EGFR-aptamers as carrier achieved high target specificity, overcame 5FU resistance, proved to be effective in a syngeneic orthotopic transplantation model, in KPC mice, in a CDX model as well as PDOs and therefore represents a promising backbone for pancreatic cancer chemotherapy in patients. Furthermore, our approach has the potential to target virtually any cancer entity sensitive to 5FU treatment by incorporating 5FU into a cancer-cell-targeting aptamers as delivery platform.
Journal
|
EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53)
|
5-fluorouracil
4ms
Consistently, the co-culture experiments showed that overexpression of miR-194-5p in tumor cell enhanced IFN-γ production by CD8 T cells. In conclusion, miR-194-5p may serve as a novel immunotherapeutic target for pancreatic ductal adenocarcinoma (PDAC) by inhibiting the expression of PD-L1, and play important roles in inhibiting the progression of pancreatic cancer and boosting the anti-tumor effect of CD8 T cells.
Journal • PD(L)-1 Biomarker • IO biomarker
|
CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma)
|
PD-L1 expression • PD-L1 negative
4ms
Clinical • New trial • IO biomarker
|
PD-L1 (Programmed death ligand 1) • CD8 (cluster of differentiation 8) • CEACAM5 (CEA Cell Adhesion Molecule 5)
|
PD-L1 expression • CD8 expression • CEACAM5 expression
4ms
Moreover, the tumors generated by mutp53-silenced KPC cells were markedly smaller than those elicited by mutp53-proficient control KPC cells. Altogether, our findings suggest that missense p53 mutations may contribute to worse PDAC prognosis by promoting a more vigorous fibrotic tumor microenvironment and impeding the ability of the immune system to eliminate the cancer cells.
Journal
|
KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • CD8 (cluster of differentiation 8)
|
TP53 mutation • KRAS mutation
4ms
This study is the first to describe hypoxic microenvironment-induced spatial transcriptome changes in PDAC, and to identify potential treatment targets for PDAC. These data will provide the basis for further investigations of the prognoses and treatments of hypoxic tumors.
Journal
|
LDHA (Lactate dehydrogenase A) • ENO1 (Enolase 1)
4ms
P2, N=10, Active, not recruiting, HonorHealth Research Institute | Recruiting --> Active, not recruiting | Trial completion date: Jun 2021 --> Jun 2022 | Trial primary completion date: Dec 2020 --> Dec 2021
Clinical • Enrollment closed • Trial completion date • Trial primary completion date • Combination therapy
|
MUC16 (Mucin 16, Cell Surface Associated)
|
Opdivo (nivolumab) • cisplatin • gemcitabine • Abraxane (albumin-bound paclitaxel) • paricalcitol
4ms
The decision curve analysis indicated that the radiomics model had clinical utility. A non-invasive and quantitative mpMRI-based radiomics model can accurately predict TP53 mutation status in pancreatic cancer patients and contribute to the precision treatment.
Journal
|
TP53 (Tumor protein P53)
|
TP53 mutation
4ms
Several combination strategies are currently under evaluation in clinical trials, in order to bypass the resistance mechanisms responsible for the intrinsic resistance of mutated KRAS to the main therapeutic strategies adopted to date. Results suggest that the therapeutic scenario of KRAS has started to change, and further research will bring therapeutic results in this field.
Review • Journal
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation • KRAS G12C • KRAS G12
|
Lumakras (sotorasib)
4ms
Preoperative and postoperative risk factors for an ER included a tumor size >3.0 cm (odds ratio (OR): 3.11, 95% confidence interval (CI): 1.35-7.14) and preoperative carbohydrate antigen 19-9 (CA19-9) levels >52 U/mL (OR: 3.25, 95% CI: 1.67-6.30) and a pathological tumor size >3.0 cm (OR: 2.00, 95% CI: 1.03-3.90) and postoperative carbohydrate antigen 19-9 levels >37 U/mL (OR: 2.11, 95% CI: 1.02-4.36), respectively. Preoperatively (>52 U/mL) and postoperatively (>37 U/mL) elevated CA19-9 and a tumor size >3.0 cm were independent predictors for an ER after a pancreatectomy for a PDAC.
Journal
|
Cancer antigen 19-9
4ms
In parallel, HO-1 inhibition abrogated the influx of macrophages and FoxP3+ cells, while increasing the proportion of CD8+ infiltration in the pancreatic tumors. These effects were mediated primarily by reducing expression of the immunosuppressive cytokine IL-10.
Journal
|
CD8 (cluster of differentiation 8) • HMOX1 (Heme Oxygenase 1) • IL10 (Interleukin 10) • FOXP3 (Forkhead Box P3)
|
gemcitabine • Abraxane (albumin-bound paclitaxel)
4ms
In situ hybridization of miR-181a and immunohistochemistry of EPB41L4B and SEL1L in pancreatic tissues (n = 4 Healthy; n = 3 IPMN; n = 4 PDAC) were also carried out. In this study, we offer insights on the potential implication of miRNA alteration in the regulation of structural and metabolic changes that pancreatic cells experience during IPMN establishment and that are maintained in PDAC.
Journal
|
MIR181A1 (MicroRNA 181a-1)
4ms
Recently, a breakthrough in improving their survival has been achieved by using first-line chemotherapy, such as gemcitabine plus nab-paclitaxel or oxaliplatin plus irinotecan plus 5-fluorouracil plus calcium folinate. Overall, the KRAS mutation can drive an immunosuppression in pancreatic ductal adenocarcinomas or in colorectal carcinomas, but this mechanism is not true in KRAS-mutant lung adenocarcinomas, especially in the presence of TP53 inactivation. As a result, the response of these adenocarcinomas to checkpoint inhibitors will vary.
Review • Journal • IO biomarker
|
KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53)
|
TP53 mutation • KRAS mutation
|
gemcitabine • 5-fluorouracil • oxaliplatin • Abraxane (albumin-bound paclitaxel) • irinotecan • leucovorin calcium
4ms
We identified p110 CUX1 as major driver of pancreatic cancer formation in the context of mutant KRAS. These results provide the first in vivo evidence for the importance of CUX1 in the development of pancreatic cancer, and highlight the importance of CUX1-dependent signaling pathways as potential therapeutic targets.
Journal
|
EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • CUX1 (cut like homeobox 1) • ADAM17 (ADAM Metallopeptidase Domain 17)
|
KRAS mutation • KRAS G12D • KRAS G12
4ms
Although IDO generally inhibits T-cell proliferation, a high expression of IDO was associated with improved survival. We expect immune checkpoint inhibitors against VISTA, LAG3, and TIM3 to be inefficient in a clinical application.
Journal • IO biomarker
|
LAG3 (Lymphocyte Activating 3) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2)
|
HAVCR2 expression • IDO1 expression • LAG3 expression
4ms
Overall, reviewed biomarker studies should aim to improve methodological and reporting quality, and novel candidate biomarkers should be investigated further in order to demonstrate their clinical usefulness. However, challenges and complexities in the path of translating the discovered biomarkers from the research laboratory to the clinical setting remain and would have to be addressed before a more realistic breakthrough in earlier detection of PDAC is achieved.
Review • Journal
|
Cancer antigen 19-9
4ms
Our data indicate that CFB, a key secreted protein, promotes proliferation by preventing cellular senescence and is associated with immunological tumor promotion in PDAC. These findings suggest that CFB may be a potential target for the treatment of PDAC.
Journal
|
CCND1 (Cyclin D1) • CD8 (cluster of differentiation 8) • CFB (Complement Factor B) • FOXP3 (Forkhead Box P3) • PCNA (Proliferating cell nuclear antigen) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
|
CCND1 expression • CD8-H • FOXP3 expression
4ms
K17 has been identified as a robust and independent prognostic biomarker that stratifies clinical outcomes for cases that are diagnosed by NAB. Testing for K17 also has the potential to inform clinical decisions for optimization of chemotherapeutic interventions.
Journal
|
KRT17 (Keratin 17)
4ms
FGF14 may define a distinct subset of PDAC patients with better prognosis. Moreover, FGF14-based sub-classification of PDAC suggests that FMN2 and PGR can be employed as good prognostic markers in PDAC and this classification may lead to new therapeutic approaches.
Journal
|
FGFR1 (Fibroblast growth factor receptor 1) • FGFR4 (Fibroblast growth factor receptor 4) • IGF2BP2 (Insulin Like Growth Factor 2 MRNA Binding Protein 2)