P=N/A, N=19, Completed, Mayo Clinic | Active, not recruiting --> Completed

Herein, a series of novel precise carrier-free self-assembled platinum(IV) nanoparticles with lipid regulation effect named FSPNPs (5NPs-8NPs) were constructed via connecting fenofibrate acid (FA) to cisplatin or oxaliplatin-derived platinum(IV)-intermediates with disulfide bonds. The released FA and derivates were docked into the peroxisome proliferator-activated receptor α with activating cholesterol metabolism to destroy membrane integrity. FSPNPs also showed good biocompatibility and superior antitumor activity with no observable tissue damage.

Interestingly, emerging as a critical mediator in the development of oxaliplatin resistance, CDK1 targeting by Δ2S4-Hbpyachieved enhanced cellular uptake, anticancer activity, and oncosis-mediated cell death in oxaliplatin-resistant HCT8/L cells. Mechanistic investigations, including proteomic profiling and CDK1 gene silencing, confirmed the pivotal role of chirality-selective CDK1 targeting in reversing metallodrug resistance. This study introduces a promising platform for constructing and customizing flexible metallohelices with precise conformation and stereochemistry to target drug-resistance-specific proteins, offering innovative insights into the designability of metallodrugs to overcome drug resistance.

P2, N=10, Completed, Liverpool Hospital | Active, not recruiting --> Completed

Compared with parental cells, the levels of UBE2T were also dramatically elevated in oxaliplatin (OXA)- and 5-fluorouracil (5-FU)-resistant colorectal cancer cells. To conclude, UBE2T confers chemoresistance of colorectal cancer by boosting the signal propagation of the Wnt/β-catenin pathway in an ERK-dependent manner. Therefore, UBE2T could be a potential target for overcoming chemoresistance in the treatment of colorectal cancer.

Also, the IC50 of oxaliplatin drug and TSC on MDA-MB-231 cells was 184 µg/ml and 307 µg/ml, respectively. Treatment with Pt@Gln-TSC nanoparticles caused an increase in cell necrosis and primary apoptosis and elevated the expression of the CASP-8 gene by 2.54 folds. This study shows that Pt@Gln-TSC nanoparticles are significantly more toxic to breast cancer cells than to normal cells and can inhibit MDA-MB-231 cells by activating extrinsic apoptosis.

Here, an oral colon-specific drug delivery system (CBS-CS@Lipo/Oxp/MTZ) was constructed by covalently conjugating Clostridium butyricum spores (CBS) with drugs loaded chitosan (CS)-coated liposomes, where the model chemotherapy drug oxaliplatin (Oxp) and anti-anaerobic bacteria agent metronidazole (MTZ) were loaded...Collaborating with blocking the translocation of intestinal pathogenic bacteria from lumen to tumor with the gut microbiota modulation of CB, the intratumoral pathogenic bacteria were eliminated fundamentally, blocking their recruitment to immunosuppressive cells. Furtherly, synchronized with lipopolysaccharide (LPS) released from MTZ-induced dead Fusobacterium nucleatum and the tumor-associated antigens produced by Oxp-caused immunogenic dead cells, they jointly enhanced tumor infiltration of CD8+ T cells and reactivated robust antitumor immunity.

PAD4 appeared to be constitutively expressed in tumor-infiltrating neutrophils but not in GC cells. Our findings highlight unique roles of PAD4, in which origin-dependent PAD4 might work complementarily on the progression and treatment vulnerability of GC.

KL-50-based compounds are a promising new strategy for the treatment of MGMT-deficient, MMR-deficient GBM that recurs after frontline TMZ.

P=N/A, N=60, Completed, Cairo University

P2, N=120, Not yet recruiting, Shandong New Time Pharmaceutical Co., LTD

In summary, the CEA-KRT1-PI3K/AKT axis regulates oxaliplatin sensitivity in GC cells. Treatment with small molecule inhibitors such as evacetrapib to inhibit this interaction constitutes a novel therapeutic strategy.

Furthermore, it investigates the clinical applicability of novel biomarkers and therapeutic strategies in CRC. Abbreviations: ncRNAs, non-coding RNAs; CRC, Colorectal cancer; EV, extracellular vesicle; mRNAs, messenger RNAs; miRNAs, microRNAs; lncRNAs, long non-coding RNAs; circRNAs, circular RNAs; HOTTIP, HOXA transcript at the distal tip; NSCLC, non-small cell lung cancer; 5-FU, 5-fluorouracil; OX, Oxaliplatin; PDCD4, programmed cell death factor 4; Tregs, regulatory T cells; EMT, epithelial-mesenchymal transition; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3; USP2, ubiquitin carboxyl-terminal hydrolase 2; TNM, tumor node metastasis; TAMs, tumor-associated macrophages; RASA1, RAS p21 protein activator 1; PDCD4, programmed cell death 4; ZBTB2, zinc finger and BTB domain containing 2; SOCS1, suppressor of cytokine signaling 1; TUBB3, β-III tubulin; MSCs, mesenchymal stem cells.

We also combined CCMV-poly(I:C) with oxaliplatin and found the combination therapy to be even more potent, strongly inhibiting tumor growth and increasing survival...The combined treatment also enhanced the rate of apoptosis and immunogenic cell death (ICD). Our data support the development of combination therapies involving immunomodulatory plant virus nanoparticles and antineoplastic drugs to attack tumors directly and via the activation of innate and adaptive immune responses.

Although current first- and second-line therapies stratify for KRAS/NRAS/BRAF mutations, microsatellite instability, tumour location and co-morbidities, the therapeutic mainstay for the first- and second-line treatment of the majority of patients consists of 5-fluorouracil (5-FU)-based chemo-immunotherapy. By exchanging the chemotherapeutic combination partner from oxaliplatin to irinotecan or vice versa, plus the additive anti-epidermal growth factor receptor/anti-vascular endothelial growth factor antibody, the negative factor of non-response to first-line therapy could not be overcome by second-line treatment in this study population. These findings must be confirmed in larger studies, but indicate the need for novel treatment options, especially for patients not responding to first-line 5-FU-based chemo-immunotherapy.

Overall, our proposed combination therapy modulated the dormant tumor microenvironment which resulted in effective tumor cell death. This study demonstrates the potential for clinical combination of chemotherapy and CPMV intratumoral immunotherapy.

IDH could be a promising therapeutic agent for inhibiting DTs and CRC by targeting TOPO II.

This study demonstrated the involvement of spinal PACAP/PAC1 receptors in OXA-induced acute cold allodynia. We propose PAC1 receptor inhibition as a new strategy for the treatment and prevention of OXA-induced acute cold allodynia.

These results revealed that in FAT1-L AML cells, inhibiting autophagy by CQ enhances the cytotoxic effect of IDA, but leads to immune escape, resulting in AML recurrence. Our study supports the use of a combination of autophagy and PD-L1 inhibitors with IDA to increase the cytotoxic effect of IDA while inhibiting AML recurrence.

Functionally, IGF2BP1 emerged as an oncogenic factor that accelerated HCC aerobic glycolysis (glucose uptake, lactate, ATP generation and ECAR) and oxaliplatin resistance...In addition, transcription factor c-Myc targeted the programmed death ligand 1 (PD-L1) promoter region to strengthen its transcription. Taken together, this study illustrates IGF2BP1 as a potential therapeutic target in HCC, aiming to disrupt the interplay between aberrant metabolism and immune escape.

P=N/A, N=216, Recruiting, Hospital Alemão Oswaldo Cruz | Trial primary completion date: Apr 2024 --> Apr 2027

The patient was subsequently treated with an idarubicin and cytarabine-based regimen for four cycles. Unfortunately, the patient passed away in April 2016 due to a cerebral hemorrhage. In this report, we also review 42 additional cases to discuss the pathological characteristics, treatment strategies, and clinical outcomes of GS.

Hsa_circ_0088036 promoted HCC tumorigenesis and chemotherapy resistance by activating the PI3K/Akt and Notch pathways through regulating miR-140-3p/KIF2A signaling. Thus, hsa_circ_0088036 may be a potential therapeutic target in chemotherapy-resistant HCC.

Combined administration with KRAS siRNA, MEK1/2 inhibitor trametinib, and NF-κB inhibitor dimethyl fumarate (DMF), suppressed L-OHP- and 5-FU-induced EMT. These results suggest that KRAS/ERK/NF-κB pathway activation is important for EMT induction by L-OHP and 5-FU treatment. Thus, MEK1/2 and NF-κB inhibitors may facilitate the resistance acquisition to L-OHP and 5-FU therapy in KRAS G13D-mutated colon cancer.

P=N/A, N=30, Not yet recruiting, Universidad Europea de Madrid

We concluded that XELOX + DC-CIK immunotherapy for postsurgical CRC patients offers reduced rates of treatment-induced adverse events, extended 2-year DFS, enhanced immunity, and increased physiological antitumor responses.

The patient underwent laparoscopic total colectomy with abdominoperineal resection and end ileostomy, then received 4 cycles adjuvant chemotherapy of oxaliplatin with capecitabine. This patient was followed up to April 2024 and performed well without abnormalities in serum cancer biomarkers and radiological examinations.

P3, N=64, Recruiting, Tanta University | Trial primary completion date: Nov 2023 --> Apr 2024

P2, N=20, Enrolling by invitation, University of Vermont Medical Center | Not yet recruiting --> Enrolling by invitation

The PSGMK-induced reduction of CLDN14 protein was inhibited by chloroquine, a lysosome inhibitor, and monodansylcadaverine, a clathrin-dependent endocytosis inhibitor, indicating that PSGMK may enhance endocytosis and lysosomal degradation of CLDN14. The cell viability of spheroids was decreased by anticancer drugs such as doxorubicin and oxaliplatin, which was exaggerated by the cotreatment with PSGMK. Our data indicate that CLDN14-targeting peptide, PSGMK has an anti-chemoresistance effect in CRC cells.

The second one, by Li et al, identified the lncRNA prion protein testis specific (PRNT) as a factor in oxaliplatin resistance by sponging ZNF184 to regulate HIPK2 and influence colorectal cancer progression and chemoresistance, suggesting PRNT as a potential therapeutic target for colorectal cancer...This review systematically examines the recently reported biological functions, related molecular mechanisms, and potential clinical significance of SNHG16 in various digestive system cancers, and explores the relationship between SNHG16 and digestive system cancers. The findings suggest that SNHG16 may serve as a potential biomarker and therapeutic target for human digestive system cancers.

Particularly, patients in high-risk group exhibited higher sensitivity to fluorouracil, oxaliplatin and lapatinib compared to the low-risk group. This study highlights the prognostic potential of PANoptosis-related features in CRC, demonstrating their role as key biomarkers significantly associated with patient survival and aiding in the identification of high-risk patients, thereby advancing immunotherapy approaches.

Three anticancer agents (oxaliplatin, cisplatin, paclitaxel) and a developmental compound (NVS-1) were assessed in male rats (Wistar Han). NfL levels in plasma proved to be the most sensitive indicator of PNS toxicities, capturing moderate nervous degeneration in DRG. A combined approach that includes both functional assessments and biomarker measurements offers a more comprehensive evaluation than histopathological analysis alone when monitoring drug-induced neurotoxicity in rat models.

Background : Treatment (tx) of MSS/MMRp mCRC relies mainly on oxaliplatin (oxa)- or irinotecan-based doublet chemotherapy regimens, with no biomarker reported so far, allowing the selection of one tx over the other. HR-DDRa is associated with MSI-H or TMB-H. Pts with MSS HR-DDRa tumors benefit from oxa-based first line treatment. Longer FU, allowing mature OS data, and wider cohorts are warranted.

AC105118.1 facilitates glycolysis and increases CRC cells' resistance to oxaliplatin by targeting the miR-378a-3p/KIF26B axis. The present work shed new insights into the function and mechanism of AC105118.1 in molecular function and suggested that the AC105118.1/miR-378a-3p/KIF26B axis is a promising target for intervening CRC oxaliplatin resistance.

PCs with a low BM-related score had a better outcome and were more likely to benefit from oxaliplatin, irinotecan, and KRAS(G12C) inhibitor-12, and immunotherapy. Molecular docking indicated that epigallocatechin gallate had a strong binding activity with DSG3, MET, and PLAU and may be used as a potential therapeutic agent for PC. In conclusion, this study developed a BM-related model associated with PC prognosis, immune infiltration, and treatment, which provided new insights into PC stratification and drug intervention.

Silencing METTL3 promoted apoptosis of CRC cells and increased their sensitivity to OXA by inhibiting the Wnt/β‑catenin signaling pathway. Huaier downregulated the expression of METTL3, thereby promoting apoptosis of drug‑resistant CRC cells and increasing their sensitivity to OXA by inhibiting the Wnt/β‑catenin signaling pathway.

Gastric cancer patients with age <60 years, TNM stage of Ⅰ ∼ Ⅱ, lymph node metastasis N0 ∼ N1, high expression of FOXP1, GGT <387.2, and combined with drug chemotherapy had higher survival rate. Capecitabine effectively enhanced the sensitivity of intermediate and advanced gastric cancer to oxaliplatin, improved the therapeutic effect, reduced the proportion of patients with low FOXP1 expression rate and serum GGT level, decreased the recurrence rate and ameliorated the prognosis of patients.

The CRC-PDX model established in this study can maintain the biological characteristics of primary tumors and can be used as a reference model for the individualized treatment of CRC patients. The degree of malignancy of the primary tumor is the primary factor affecting the tumorigenesis rate of the PDX model.

However, the prognosis of patients in the low-risk group with high CEA levels improved with a 6-month adjuvant treatment with oxaliplatin to a similar level to that of all patients with low CEA levels in the low-risk group. In conclusion, the present study suggested that the duration of adjuvant chemotherapy with oxaliplatin should not be shortened in patients with high preoperative CEA levels, even in the low-risk group.

Compound 4a represents a potentially safe and effective agent for the treatment of liver cancer. The characteristics of Compound 4a-triggered paraptosis was clarified and a unique function of CRT in paraptosis was revealed.

P=N/A, N=30, Recruiting, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine