Pancreatic Ductal Adenocarcinoma

Background : First-line therapy’s (tx) choice between the two most efficacious approved regimens (FOLFIRINOX and Gemcitabine plus Nab-Paclitaxel - GemNab) in mPDAC is usually based on patients’ (pts) baseline characteristics... HR-DDR somatic alterations emerged as possible predictor of lower benefit from platinum-free regimens. Thus, platinum-based regimens should be preferred in this setting. Validation in wider cohorts and correlation with HR-DDR germline mutations are warranted.

Our study suggests an important prognostic role of p53 signaling muts in mPDAC pts; wt pts resulted in a longer OS than mutated pts, although some muts, in particular tp53 exon4 mut, seem to be associated with longer survival. Further studies are needed to investigate these findings, including an in-depth analysis of structural proteomics.

Furthermore, in vivo studies indicated that 177Lu-DOTA-amatuximab exhibited limited side effects. The development of 89Zr/177Lu-labeled amatuximab may provide novel insights into the formulation of precision diagnostic and therapeutic strategies for MSLN- overexpressing tumors, including PDAC.

The cytotoxicity of trametinib (MEK inhibitor), DT2216 (BCL-xL degrader) and afatinib (pan-EGFR inhibitor) and their combination was tested in patient-derived, primary PDAC cells using a live cell imaging system. Pathway analysis revealed the addition of afatinib in triplet regimen further inhibited PI3K/AKT effectors of p90RSK, p70S6K, and GSK3α/β along with a secondary pathway of P38 MAPK. Our study identifies an important contribution of EGFR inhibition to elevate the response of PDAC, supporting a clinical assessment of this triplet combination in patients.

In contrast, C57BL/6 and FcγR-humanized C57BL/6 mice both have endogenous IgG that occupy their FcγR (murine for the former and human for the latter), precluding interactions with radioimmunoconjugates. Ultimately, these data suggest that understanding the interplay between radiolabeled antibodies and FcγR is critical during the preclinical evaluation of radioimmunoconjugates.

Mechanistically, phospho‑kinase array profiles showed that the enhanced anticancer efficacy of the combination treatment could be attributed to the inhibition of STAT3 signaling, which led to a significant reduction in tumor growth in a pancreatic cancer animal model. The results showed that the repositioning of aripiprazole inhibits cancer cell growth by blocking the STAT3 signaling pathway and effectively enhancing cisplatin‑induced apoptosis, thereby suggesting that the combination of aripiprazole and cisplatin may be a potent chemotherapeutic strategy for the treatment of pancreatic cancer.

Importantly, the level of shed AXL has a potential correlation with lymph node metastasis, and inhibition of AXL shedding and its kinase activity showed a substantial synergistic effect in inhibiting cancer cell growth. In summary, we provide TMEPro, a generically applicable clinical functional proteomic strategy, and a comprehensive resource for better understanding the PDAC TME and facilitating the discovery of new diagnostic and therapeutic targets.

Tissue mobilization increases ctDNA levels. Intraoperative detection of ctDNA is associated with a worse prognosis.

Our findings support the concept that, in the context of obesity, ω-3 FA have protective effects during early-stage pancreatic carcinogenesis through the regulation of intestinal permeability and endotoxemia.

We also highlight the advent of KRAS targeted therapy, a milestone advance that has transformed treatment paradigms and offers a platform for combined immunotherapy and targeted strategies. This review provides a perspective summarizing current scientific and therapeutic challenges as well as practice-changing opportunities for the PDAC field at this major inflection point.

This review underscores the intricate interplay between cell-intrinsic molecular drivers and cell-extrinsic microenvironmental factors, shaping PanIN predisposition, initiation, and progression. Future research aims to unravel these interactions to develop targeted therapeutic strategies and early detection techniques, aiming to alleviate the severe impact of pancreatic cancer by addressing both genetic predispositions and environmental influences.

Furthermore, PDAC cells were arrested in G2/M and underwent apoptosis or senescence with the treatment of LIB3S0280. These findings suggest that TBK1 inhibitor LIB3S0280 has great potential as a lead compound in the further development of a novel treatment for PDAC.

CHC enumeration and phenotyping display promise as a real-time indicator of disease burden, recurrence risk, and treatment response in PDAC. CHCs have great potential as tumor-derived biomarkers to optimize therapeutic strategies and improve survival in patients with PDAC.

The genes found to be critical for the viability of metastatic cells form a basis for further investigations of the processes responsible for triggering and driving metastasis. As shown for MYBL2, unexpected processes of regulating metastasis might also be involved.

We conclude that TGF-β is only one of the players that mediates the communication between PDAC cells and fibroblasts and controls the acquisition of aggressive phenotypes. Hence, these advanced in vitro models may be exploited to further investigate these events and to design innovative anti-PDAC therapies.

Furthermore, we demonstrate its clinical diagnostic potential by detecting KRAS mutations from a pancreatic ductal adenocarcinoma patient using only 60 μL of plasma. This paves the way for future development of a fully self-contained system facilitating the rapid detection of mutations in cfDNA.

P1, N=24, Recruiting, M.D. Anderson Cancer Center | Active, not recruiting --> Recruiting

Accordingly, the combination of olaparib and radiotherapy was indicated in vivo and in vitro to specifically reduce the growth of SMAD4-deficient PDAC by attenuating PARP1 activity. Collectively, our results revealed a novel molecular mechanism for the involvement of the SMAD4-PARP1 interaction in DNA repair with a vital role in radiotherapy response in PDAC. Based on our set of findings, our findings offer a new combined therapeutic strategy for SMAD4 deficient PDAC that can significantly reduce pancreatic cancer radiotherapy resistance.

P2, N=603, Completed, Merck Sharp & Dohme LLC | Active, not recruiting --> Completed

Machine learning radiomics models can accurately predict PNI status in patients with pancreatic ductal adenocarcinoma. The combined model, which incorporates clinical and radiomics features, enhances preoperative diagnostic performance and aids in the selection of treatment methods.

The signature also helped stratification of patients with different circulating tumor DNA and imaging subtypes. Plasma miRNAs associated with oncogenic pathways may serve as PDAC early detection biomarkers.

The pathomic model constructed using machine learning serves as a valuable prognostic target for PAAD. The histopathological features cluster 2 are closely associated with the downregulation of oxidative phosphorylation levels and Tregs immune infiltration.

The combination of JQ1 + a pan CDC25 inhibitor was synergistic in gemcitabine-resistant Panc1.gemR cells that had relatively high levels of CDC25B expression compared to parent cells. The data suggest that CDC25B may be an independent indicator of sensitivity to BET inhibitors and that CDC25B may contribute to gemcitabine insensitivity in this tumor type.

P=N/A, N=1000, Not yet recruiting, Zhongshan Hospital Fudan University; Zhongshan Hospital Fudan University

P2, N=130, Not yet recruiting, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology; Union Hospital, Tongji Medical College, Huazhong University of

P2, N=20, Not yet recruiting, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine; Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

P2, N=20, Recruiting, Jiangsu Province Hospital; Jiangsu Province Hospital

P2, N=38, Recruiting, Fudan University Shanghai Cancer Center; Fudan University Shanghai Cancer Center

P2, N=30, Recruiting, First Affiliated Hospital of Soochow University; First Affiliated Hospital of Soochow University

P2, N=49, Not yet recruiting, Department of Integrative Medicine, Affiliated Cancer Hospital of Fudan University; Affiliated Cancer Hospital of Fudan University

P1/2, N=340, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Oct 2026 --> Jan 2025 | Trial primary completion date: Oct 2025 --> Jan 2025

Our study used two prognosis-favorable genes to divide M2-like TAMs of PDAC into anti-tumor bM2-like TAMs and pro-tumor mM2-like TAMs. The bM2-like TAMs activate T cells through ALCAM/CD6 and generate prognosis-favorable αSMA+ myofibroblasts through secreting TGFβ, which brings insight into heterogeneity of TAMs, prognosis prediction and immunotherapy of PDAC.

P=N/A, N=19, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting

Our data showed that KRASG12D inhibitor MRTX1133 combined with PKF-118-310 could enhance the effectiveness of MRTX1133 treatment response through induction of ferroptosis via inhibiting MGST1 expression in MRTX1133-resistant PDAC cells and tumors. This evidence may provide a promising strategy to overcome KRASG12D inhibitor MRTX1133 resistance in PDAC patients with KRASG12D mutations.

P2, N=14, Active, not recruiting, Barts & The London NHS Trust | Unknown status --> Active, not recruiting | Trial completion date: Jun 2021 --> Jun 2025 | Trial primary completion date: Jun 2021 --> Jun 2025

Moreover, MPD3 elicited robust anti-tumor activities in both local and liver metastatic PDAC tumor models in mice. Overall, this work establishes a paradigm for developing translational pan-KRAS cancer treatment and broadens the applicability of albumin binding peptide-drug conjugate against albumin-metabolism enriched cancers.

P1, N=26, Not yet recruiting, PanTher Therapeutics

Importantly, circPNIT-loaded CD109+ EVs are established to dramatically promote PNI in a KRASG12D/+ Trp53R172H/+ Pdx-1-Cre mouse model. Collectively, the findings highlight the mechanism underlying how EV-packaged circRNAs mediate the PNI of KRAS-mutant PDAC cells through the Rab5B endosomal bypass, identifying circPNIT as an effective target for the treatment of neuro-metastatic PDAC.

The combined application of the EP300 inhibitor inobrodib and gemcitabine exerts a synergistic effect on PDAC. Overall, these findings reveal that the EP300-CMTM6-IGF2BP1 positive feedback loop facilitates gemcitabine resistance via epigenetic reprogramming and the combined use of inobrodib and gemcitabine represents a promising strategy for overcoming chemoresistance in PDAC, warranting further investigation in clinical trials.

ADCmin values are useful for predicting prognosis in patients with PDAC. XRCC1 gene polymorphism may affect the age at diagnosis.

A serum biomarker panel of Ca-125 and Ca19-9 could be used for effective clinical management of PDAC patients undergoing NAC treatment.

Animal experiments confirmed that ILL also inhibited PDAC development in vivo with minimal toxicity. In summary, our study identified ILL as a potential therapeutic compound for PDAC treatment.