Efficacy of Gemcitabine, Paclitaxel, and Oxaliplatin Protocol in the Treatment of Relapsed or Refractory Germ Cell Tumours.

OBJECTIVE: To determine the survival endpoints and treatment-related adverse events after the use of the gemcitabine, paclitaxel, and oxaliplatin (GemPOx) protocol in relapsed/refractory germ cell tumours (GCTs) who had previously received multi-line systemic treatments including high-dose chemotherapy. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Clinic of Medical Oncology, Gulhane School of Medicine, Ankara, Turkey, between January 2017 and August 2021. METHODOLOGY: Clinical characteristics of adult patients with relapsed/refractory GCTs treated with the GemPOx protocol were recorded from the hospital's patient registry database. Patients without a medical record were not included in the study. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), one-year PFS rate, one-year OS rate, and treatment-related haematological side effects were determined after GemPOx. RESULTS: Fifty-three adult patients were included (47 of them were male). Seventy-eight percent had Stage 3 at initial diagnosis. Twenty-four percent of the patients received more than four lines of systemic chemotherapy. Ninety-six percent of the patients received high-dose chemotherapy prior to GemPOx. ORR, which is the sum of the complete and partial response rates, was 69.8%. PFS was determined as 8.5 ± 5.4 months. The one-year PFS rate was 30.3%. OS was 15.9 ± 10.6 months. The one-year OS rate was 72.6%. Febrile neutropenia was observed in 15.1% of the patients. CONCLUSION: In patients with relapsed/refractory GCTs receiving multi-line systemic chemotherapy, significant PFS and OS are achievable, and a manageable spectrum of haematological side effects is observed with GemPOx. KEY WORDS: Gemcitabine, Paclitaxel, Oxaliplatin, Germ cell tumour.

Enhanced cytotoxicity of a novel family of ATPase inhibitors in colorectal cancer cells with high NAT2 activity.

Loss of heterozygosity (LOH) is a hallmark feature of cancer genomes that reduces allelic variation, thereby creating tumor specific vulnerabilities which could be exploited for therapeutic purposes. We previously reported that loss of drug metabolic arylamine N-acetyltransferase 2 (NAT2) activity following LOH at 8p22 could be targeted for collateral lethality anticancer therapy in colorectal cancer (CRC). Here, we report a novel compound CBK034026C that exhibits specific toxicity towards CRC cells with high NAT2 activity. Connectivity Map analysis revealed that CBK034026C elicited a response pattern related to ATPase inhibitors. Similar to ouabain, a potent inhibitor of the Na+/K+-ATPase, CBK034026C activated the Nf-kB pathway. Further metabolomic profiling revealed downregulation of pathways associated with antioxidant defense and mitochondrial metabolism in CRC cells with high NAT2 activity, thereby weakening the protective response to oxidative stress induced by CBK034026C. The identification of a small molecule targeting metabolic vulnerabilities caused by NAT2 activity provides novel avenues for development of anticancer agents.