(609d) Mitochondria-Targeted Gene Therapy in Combination with Chemotherapy to Treat Triple-Negative Breast Cancers

Out of 1.7 million breast cancers, Triple-negative breast cancer (TNBC) is the most aggressive and metastatic subtype. Conventional chemotherapeutics administered to TNBC patients induce synthetic lethality and have a response rate less than 20%. We have in turn developed a cancer specific luminoptogenetics based gene therapy that causes severe mitochondrial dysfunction thereby causing cancer cell death. We also developed the gene delivery vehicle, i.e. anti-CD276 mAb-tagged exosome-associated adeno-associated virus (mAb-Exo-AAV), to target and kill TNBC cells in vivo. The objective of this study was to fully evaluate the novel gene therapy as monotherapy, in combination with a chemotherapy, i.e. poly (ADP-Ribose) polymerase inhibitor (PARPi), and in combination with antibody drug conjugate (ADC), to treat TNBCs. The anti-TNBC efficacy was assessed in multiple animal models, including primary xenograft, metastatic, and PDX mice models. Our results showed that the CD276 mAb-Exo-AAV specifically targeted TNBC cells in vivo; the delivered gene therapy effectively depolarized cancer mitochondria; and TNBC tumour burden was eliminated with severe cancer cell death and collapse of tumour microenvironment. The metastasis was significantly reduced by our gene therapy in distant metastatic models. The long-term treatment using combined therapies showed that TNBC recurrence was blocked. Taken together, an innovative gene therapy and delivery vehicle were developed successfully to treat TNBCs. In our future study, we will further investigate the mechanisms of metastasis inhibition and evaluate its toxicology.