Abstract LB446: Development of drug candidate for metastatic cancer by targeting pathogenic mitochondrial DNA

Abstract The 5-year survival rate for stage 4 advanced cancer is 5.8% for stomach cancer, 17% for colon cancer, 8.4% for lung cancer (NSCLC), 4.4% for liver cancer and 38.6% for breast cancer, 5.1% for cervical cancer and 27.1% for ovarian cancer in Japan (Cancer Statistics 2024). So, development of new modalities for the treatment of metastatic cancer is essential. Mitochondria-targeted cancer drugs may have the potential to become Pan-Cancer Drugs for advanced cancers, and is recently focused on induction of ferroptosis by promoting oxidative stress in cancer cells. However, there are no drugs that can induce cancer-specific apoptosis by specifically removing abnormal mitochondria by mitophagy (mitochondria-specific autophagy) and promote cell membrane destruction by super-excess of reactive oxygen species (ROS) released from mitochondria during the mitophagic process. We have synthesized a pyrrole imidazole polyamide that can bind sequence-specifically to the minor-groove of double-stranded DNA conjugated with the mitochondria-localized lipophilic cation triphenylphosphonium (TPP). Metastatic cancers are near homoplasmy of the mutant mtDNA and mitophagy was induced in almost all mitochondria. In advanced cancer cells, ROS was generally over-presented and endogenous antioxidant, which reactively express and inhibit against ROS excess and cell death as seen in normal cells, were exhausted and apoptosis or cell destruction were induced instead of ferroptosis. We further developed a compound, CCCh-560-TPP, targeting the ATP6 gene variant m.8860A>G, which does not affect mitochondrial membrane potential and is almost always coexisted with any mtDNA mutations in various cancer types, as a passenger variant. Thus, CCCh-560-TPP may overcome the irrationality of drug development for each cancer mutation and be used as a pan-cancer drug candidate especially for metastatic cancers. We confirmed its induction of cancer cell death and safety in a mouse toxicity study. This lead compound CCCh-560-TPP is applicable to highly malignant pan-cancer, in which ROS-producing mitochondrial mutations exist, and is considered a promising new compound and is currently being prepared for the Phase I clinical trial. Citation Format: Hiroki Nagase. Development of drug candidate for metastatic cancer by targeting pathogenic mitochondrial DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB446.