Finally, five compounds were obtained, including two FDA-approved drugs (flufenamic acid and fludarabine), one endogenous metabolite, one immunology/inflammation-related compound, and one inhibitor of DNA methyltransferase (N4-methylcytidine, a cytosine nucleoside analogue that, like zebularine, has the mechanism of inhibiting DNA methyltransferase). Based on the tumor microenvironment characteristics of ccRCC, five ccRCC-specific compounds were identified, which would give direction of the clinical treatment for ccRCC patients.

O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status is the central molecular biomarker linked to both the response to temozolomide, the standard chemotherapy drug employed for GBM, and to patient survival...Our method provides promising results, reducing dimensionality (by more than 95%) when employed on two large-scale proteomic datasets (7k SomaScan® panel and CPTAC) for all our analyses. The computational results indicate that the proposed approach provides 14 shared serum biomarkers that may be helpful for diagnostic, prognostic, and/or predictive operations for GBM-related processes, given further validation.

We established MIA-GEM cells, a PDAC cell line resistant to gemcitabine (GEM), a first-line anticancer drug, using the human PDAC cell line-MIA-PaCa-2...Elevated MAST4 expression correlated with a poorer prognosis in PDAC. Consequently, nuclear MAST4 emerges as a potential marker for GEM resistance and poor prognosis, representing a novel therapeutic target for PDAC.

Furthermore, DNA damage tolerance and cellular stress management pathways were enriched. This novel, syngeneic model provides a valuable platform for investigating the underlying mechanisms of cisplatin resistance in a clinically relevant context, contributing to the development of targeted therapies tailored to combat resistance in stem-like ovarian cancer.

Key processes related to DNA and extracellular vesicles were found to be altered. The increased number of extracellular vesicles in resistant cells may contribute to acquired resistance in wild-type cells.

High expression of miR-1206, miR-10a-5p, miR-141-3p, and miR-96-5p correlated with poor prognosis in OC patients according to the KM plotter database. These nine miRNAs could be used as targets for therapy and as markers of cisplatin response.

Cisplatin (CIS) is a platinum-based chemotherapeutic agent used in the treatment of a wide variety of malignancies such as lung, breast, ovary, testis, bladder, cervix, and head and neck cancers...Gal-3 plays a pivotal role in orchestrating cellular responses by interacting with prosurvival signal pathways and engaging with autophagy proteins. Notably, our observations highlight that the absence of Gal-3 can enhance autophagy in CIS-induced ATN.

The combination of evodiamine and cisplatin may be a novel strategy for combating cisplatin resistance in NSCLC.

The apoptotic pathways activated by DTX@C8-MSN, evidenced by the increased levels of cleaved caspase-3 and PARP, point to a potent therapeutic mechanism. Collectively, the results advocate DTX@C8-MSN as a promising candidate for targeted therapy in TMZ-resistant GBM, optimizing drug delivery and bioavailability to overcome current therapeutic limitations.

This study employs both in vivo and in vitro models of cisplatin ototoxicity to explore this possibility. Our results reveal that hesperidin mitigates cisplatin-induced ototoxicity by activating the Nrf2/NQO1 pathway in sensory hair cells, thereby reducing ROS accumulation, preventing hair cell apoptosis, and alleviating hearing loss.

SOX4 regulated DDR by activating CTHRC1, thereby enhancing cisplatin resistance in LUAD cells. The finding provides a novel approach to address clinical cisplatin resistance in LUAD, with CTHRC1 possibly serving as a candidate for targeted therapies in addressing cisplatin resistance within LUAD.

Sensitivity of tumor cells to gemcitabine was evaluated...We concluded that MSLN could induce chemoresistance by enhancing migration, invasion, EMT and cancer stem cell traits of pancreatic cancer cells. Targeting MSLN could represent a promising therapeutic strategy for reversing EMT and chemoresistance in pancreatic cancer cells.

In addition, high-risk patients showed better sensitivity to Erlotinib, Oxaliplatin, and Gefitinib. Furthermore, three novel molecular subtypes of STAD were identified based on the 2-DRLs features, with evaluation of the immune microenvironment and chemotherapy drug sensitivity for each subgroup, which holds significant implications for achieving precise treatment in STAD. Overall, our 2-DRLs prognostic model demonstrates high predictive value for patient survival in STAD, potentially providing new targets for individualized immune and chemical therapy.

P1, N=10, Active, not recruiting, University of Florida | Trial completion date: May 2026 --> May 2028 | Trial primary completion date: May 2024 --> May 2026

Western blotting indicated that Dex alleviated CP-induced AKI by inhibiting pyroptosis mediated by NLRP-3 and caspase-1. Dex protected rats from CP-induced AKI, and the mechanism may be related to NLRP-3/Caspase-1-mediated pyroptosis.

STAD patients with a high DPS score had a lower IC50 value of common chemotherapy and targeted therapy regimens (Cisplatin, Docetaxel, Gefitinib, etc). Our study developed an optimal DPS for STAD. The DPS could predict the prognosis, risk stratification and guide treatment for STAD patients.

The tumor reduction rate calculated from MRI T2-weighted images may be a predictor of local recurrence in patients with maxillary sinus cancer treated with RADPLAT. Patients with lower reduction rates may benefit from early salvage surgeries.

In a cohort of patients with glioblastoma treated with surgery, radiotherapy and temozolomide, we retrospectively analyzed tumor expression of CD99 by immunohistochemistry (IHC) and by quantitative real-time polymerase chain reaction (qRT-PCR) for both the wild type (CD99wt) and the truncated (CD99sh) isoforms...This study confirms a high expression of CD99 in glioblastoma but does not show any significant impact on survival. Further preclinical studies are needed to define its role as a therapeutic target in glioblastoma.

P4, N=642, Not yet recruiting, Health Science Center of Xi'an Jiaotong University

Our study demonstrated that cisplatin could induce ferroptosis in granulosa cells, while EnSCs could inhibit ferroptosis and thus exert repair effects on the cisplatin-induced injury model both in vivo and in vitro. Meanwhile, Nrf2 was validated to participate in this regulatory process and played an essential role.

In addition, we demonstrate through in vivo and in vitro experiments that BCAT1 phosphorylation inhibiting its ubiquitination at multiple sites is associated with GBM proliferation and that inhibition of the BCKDK-BCAT1 axis enhances the sensitivity to temozolomide (TMZ). Overall, we identified novel mechanisms for the regulation of BCAT1 modification and elucidated the importance of the BCKDK-STUB1-BCAT1 axis in GBM progression.

It was identified that betulinic acid (BetA) and antimycin A can directly induce mitochondrial dysfunction through mPT-mediated mechanisms, while cisplatin and staurosporine cannot...Intriguingly, BetA induces caspase-independent cell death, even in the absence of Bax/Bak, thereby overcoming drug resistance. The presented findings offer new insights into mPT-mediated mitochondrial dysfunction using nFCM, emphasizing the potential for targeting such dysfunction in innovative cancer therapies and interventions.

Thus, the expression of resistance genes in resistant cells treated with PBPD was lower than cisplatin. As a result, PBPD is a promising anticancer agent for CDDP-resistant ovarian cancer.

Nucleoside analogs such as gemcitabine (GEM; dFdC) and cytarabine (Ara-C) require nucleoside transporters to enter cells, and deficiency in equilibrative nucleoside transporter 1 (ENT1) can lead to resistance to these drugs. In A549 cells treatment with Ara-C, CP-4055 and EA-4126 decreased the p-P38/P38 after 6 hr. The findings suggest that both parent drugs, prodrugs, and the EA chain influence cell survival and signaling pathways.

In addition to its excellent antitumor activity, Oxa@Mil-100(Fe) has no obvious toxic or side effects. This study provides a new idea and method for the combined treatment of gastric cancer.

The ARID1A gene is a critical predictive biomarker for glioma. Mutations at the ARID1A locus alter the stability of the SWI/SNF complex, leading to changes in transcriptional regulation in glioma cells. This contributes to an increased malignant phenotype of GBM and plays a pivotal role in mediating chemoresistance.

P1/2, N=47, Recruiting, Ohio State University Comprehensive Cancer Center | Suspended --> Recruiting

In cell survival assay, (2 S)-OMPT suppressed the cell survival to cisplatin (CDDP) of MG-63 cells irradiated with X-rays (8 Gy)...The cell survival to CDDP of X-ray irradiated cells was increased by LPA2 agonist GRI-977143 and reduced by LPA2 knockdown. These results suggest that LPA receptor-signaling participates in the modulation of cellular functions induced by X-ray irradiation in osteosarcoma cells.

Furthermore, the proliferation of silencing PCDHA11 was significantly slower than that of overexpression of PCDHA11, which means PCDHA11 overexpression weakened the anticancer effects of cisplatin, and silencing PCDHA11 enhanced the effects. This study demonstrated that miR-185-5p was involved in chemoresistance of LUSC cells to cisplatin partly via down-regulating PCDHA11, which may promote understanding the underlying molecular mechanisms of drug response.

These differences have extended to the methylation of the MGMT promoter, which critically impacts temozolomide resistance...After propensity score matching, females maintained a significant survival benefit (18.7 vs. 10.0 months, p = 0.004) compared to males (13.0 vs. 13.6 months, p = 0.76), and the pattern of difference was significant (P for CpG-sex interaction = 0.03). In this study, females had higher mean and individual CpG site methylation and received a greater PFS and OS benefit by MGMT methylation that was not seen in males despite equal degrees of CpG methylation.

The aim of the study was to assess the efficacy and toxicity of fludarabine, cytarabine, and granulocyte-colony stimulation factor (FLAG) with or without idarubicin (-Ida) and to discuss novel therapies in this setting. Among the variables, including age, FLT3 mutation status, European LeukemiaNet (ELN) 2022 classification risk, FLAG vs. FLAG-Ida, and aHSCT, a multivariate analysis revealed that only aHSCT significantly influenced overall survival. (4) FLAG(-Ida) chemotherapy remains an effective salvage chemotherapy for patients with r/r and secondary AML with a plan of proceeding to aHSCT.

On the other hand, cleaved- poly-ADP ribose polymerase (PARP) and -caspase-9, which are known as pro-apoptotic markers, were upregulated in the combination group compared with the solo treatments. Taken together, the addition of pioglitazone to cisplatin further reduced the viability of MDA-MB-231 cells and enhanced apoptosis compared with chemotherapy alone.

Both groups had worse survival with confusion/altered mental status (P = 0.023 vs < 0.000) and an improved survival with a Temozolomide prescription...Age-dependent novel associations between clinical symptoms and medications prescribed for co-morbid conditions were demonstrated in patients with GBM. The results of the current work support future mechanistic studies that investigate the negative relationship(s) between increased age, comorbidities, and drug therapies for differential clinical decision-making across the lifespan of patients with GBM.

P2, N=81, Recruiting, Fudan University

The roles of WNK1 on cisplatin resistance were explored using CCK-8, colony formation, and flow cytometry in vitro...In xenograft tumor tissues, the downregulation of WNK1 significantly reduced HIF-1α expression. These data demonstrated that the CREB1/WNK1 axis could promote the tumorigenesis of ovarian cancer via accelerating HIF-1 expression, suggesting that the CREB1/WNK1 axis could be a potential target during the therapy of ovarian cancer.

Furthermore, neutral lipid emulsion-based miR-29a delivery improved the therapeutic effect of cisplatin in an LLC spontaneous tumor model in vivo. In summary, this study shows that targeting collagen I expression in the TME contributes to chemotherapy drug influx and improves therapeutic efficacy in lung cancer.

In the hypoxic microenvironment, glioma cells become resistant to TMZ due to the delivery of PKM2 by exosomes. Targeted modulation of exosomal PKM2 may be a promising strategy for overcoming TMZ resistance in glioma.

Randomized clinical trials are needed to confirm these findings and establish the efficacy of the medications in ototoxicity prevention. Further research is also warranted to investigate the potential mechanisms underlying this protective effect.

Furthermore, plasma ctDNA detection of new MMR gene mutations not present in the initial tissue biopsy may provide an early indication of the development of chemotherapy resistance. Additional clinical validation in larger cohorts is needed.

Furthermore, we observed that Gem-miR-15a significantly inhibits PDAC tumor growth in vivo without observing any noticeable signs of toxicity. Overall, our results demonstrate the therapeutic potential of Gem-modified miRNAs as a treatment strategy for PDAC.

This study shows that MCTS are interesting models to study the impact of first line therapies using conditions close to clinical practice and also to identify more adapted second line or concomitant therapies for lung cancer treatment.

P2, N=124, Recruiting, Rajiv Gandhi Cancer Institute & Research Center, India | Initiation date: Oct 2023 --> Apr 2024