Abstract A41: Ovarian cancer as an infectious disease. Targeting of mitochondrial activity to prevent and treat recurrent ovarian cancer
Authors: Martina Bazzaro
Journal: Clinical Cancer Research (2018)

Abstract Targeting of the mechanisms responsible for ovarian cancer recurrence and chemoresistance serves the two most pressing needs for the clinical management of this disease: prevent recurrence in women who are in remission and provide effective treatment for patients who have recurred (1). Ovarian cancer recurrence is due to the presence of a relatively small population of cancer cells (floating in the abdominal cavity as spheroids and circulating in the bloodstream) that were not removed during surgery and was able to survive chemotherapy treatment (2-4). These cells, after a period of latency, grow back and cause recurrent and chemoresistant ovarian cancer. Recent evidences suggest that spheroids’ and cancer cells’ resistance to conventional chemotherapy is due to their ability to increase mitochondrial respiration as a way to survive the highly hostile tumor microenvironment caused by chemotherapy and hypoxia (5-9). To prevent recurrence and to treat chemoresistance we need to: 1) find the “Achille’s heel” of the small population of cancer cells that are capable of escaping chemotherapy and kill them, and 2) use therapeutic strategies that are already FDA approved because their known toxicology and pharmacology makes them ideal repurposed drugs rapidly implementable in the clinics. We propose that: a) ovarian cancer spheroids and chemoresistant metastasis share the unique Achille’s heel of having high dependency upon mitochondrial activity, b) targeting of mitochondrial activity leads to effective killing of ovarian cancer cells in spheroids and in chemoresistant metastasis with no toxicity on normal cells, and c) the FDA-approved antimitochondrial antibiotics inhibit cancer cells’ mitochondrial activity and can safely and effectively be used to prevent ovarian cancer recurrence and to treat chemoresistance (10, 11). This research is clinically relevant in that antimitochondrial antibiotics can be quickly implemented in the clinic as a mantainance therapy for women in remission and as a combination therapy for patients with recurrent and chemoresistant ovarian cancer. Of note, several antimitochondrial antibiotics have long half-life, are well tolerated, and are affordable, rendering them the ideal repurposed drug. References: 1. Jelovac D, Armstrong DK. Recent progress in the diagnosis and treatment of ovarian cancer. CA Cancer J Clin 2011;61(3):183-203. 2. Ishiguro T, Ohata H, Sato A, et al. Tumor-derived spheroids: Relevance to cancer stem cells and clinical applications. Cancer Sci 2017. 3. Pan Y, Robertson G, Pedersen L, et al. miR-509-3p is clinically significant and strongly attenuates cellular migration and multi-cellular spheroids in ovarian cancer. Oncotarget 2016;7(18):25930-48. 4. He M, Wang D, Zou D, et al. Re-purposing of curcumin as an anti-metastatic agent for the treatment of epithelial ovarian cancer: in vitro model using cancer stem cell enriched ovarian cancer spheroids. Oncotarget 2016;7(52):86374-87. 5. Skrtic M, Sriskanthadevan S, Jhas B, et al. Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia. Cancer Cell 2011;20(5):674-88. 6. Caino MC, Seo JH, Aguinaldo A, et al. A neuronal network of mitochondrial dynamics regulates metastasis. Nat Commun 2016;7:13730. 7. Chae YC, Vaira V, Caino MC, et al. Mitochondrial Akt regulation of hypoxic tumor reprogramming. Cancer Cell 2016;30(2):257-72. 8. Seo JH, Rivadeneira DB, Caino MC, et al. The mitochondrial unfoldase-peptidase complex ClpXP controls bioenergetics stress and metastasis. PLoS Biol 2016;14(7):e1002507. 9. Caino MC, Altieri DC. Molecular pathways: Mitochondrial reprogramming in tumor progression and therapy. Clin Cancer Res 2016;22(3):540-45. 10. Zhang X, Fryknas M, Hernlund E, et al. Induction of mitochondrial dysfunction as a strategy for targeting tumor cells in metabolically compromised microenvironments. Nat Commun 2014;5:3295. 11. Fryknas M, Zhang X, Bremberg U, et al. Iron chelators target both proliferating and quiescent cancer cells. Sci Rep 2016;6:38343. Citation Format: Martina Bazzaro. Ovarian cancer as an infectious disease. Targeting of mitochondrial activity to prevent and treat recurrent ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A41.