Inhibitors of Monocarboxylate Transporters for the Treatment of Triple Negative Breast Cancer
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The rapid transport of lactic acid by monocarboxylate transporters (MCTs), part of the solute carrier SLC16A gene family, represents a pivotal mechanism to sustain the growth of cancer cells but also preventing apoptosis and acidosis. Clinical evidence supports the potential therapeutic target of MCT1 in triple negative breast cancer (TNBC), a highly metastatic and deadly form of breast cancer. TNBC remains incurable as it lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and lacks human epidermal growth factor receptor 2 (HER2) overexpression. Importantly, there is an ongoing phase I clinical trial being investigated in the UK on a first-in-class, potent and selective inhibitor of MCT1, AZD3965, for advanced solid tumors and lymphoma (NCT01791595). Currently, research on MCT inhibitors as chemotherapeutic agents in cancer, and particular in TNBC, are very limited. Overexpression of MCT1 has been evidenced and significantly correlated with poor survival and prognosis in human breast tumors categorized as TNBC, suggesting potential therapeutic target of MCT1 in this form of breast cancer. This dissertation evaluated the research hypothesis that inhibition of MCT1 can reduce tumor growth and metastasis and represents a potential novel therapeutic treatment strategy for TNBC. The overall objective of the current research was to assess the therapeutic potential of MCT inhibitors in TNBC to better guide and provide proof of concept for clinical development and evaluation of MCT1 inhibitors.