Development of Novel ERRalpha Antagonists as Breast Cancer Therapeutics

点击翻译按钮获取中文摘要

Project Summary/Abstract Dysregulated cellular metabolism is an established hallmark of cancer and thus targeting of metabolic pathways that are causally linked to tumor pathobiology has, and continues to be, an active area of cancer therapeutic development. Of particular importance in this regard is the observation that the ability of cancer cells to utilize mitochondrial metabolism compromises the effectiveness of chemotherapeutics and some targeted therapies, a finding that reinforces the need to develop strategies to selectively target cancer cell mitochondrial metabolism. This puts into context our discovery that the expression and/or activity of estrogen related receptor alpha (ERRa), a druggable transcription factor that specifically regulates mitochondrial metabolism, is elevated in all breast tumor sub-types, most notably in triple negative breast cancer (TNBC) and its expression and activity tracks with a negative outcome in patients. Using genetic and pharmacological approaches we have validated ERRa as a useful therapeutic target the inhibition of which allows the selective disruption of mitochondrial metabolism in cancer cells. Importantly, absent any observable toxicities in normal cells/animals, it was demonstrated that inhibition of ERRa using tool compound antagonists as a means to disrupt mitochondrial function results in the inhibition of tumor growth in animal models of breast cancer. We hypothesize that ERRa antagonists will exhibit single agent activity in patients with TNBC and will increase the efficacy (and reduce the doses required) of standard of care interventions whose activity is negatively impacted by mitochondrial function. However, the exploration of the clinical potential of ERRa inhibitors has been hampered by the lack of potent and drug-like small-molecule ERRa inhibitors. Thus, using established models of TNBC and patient-derived xenografts (PDXs) we will evaluate in Aim 1, how ERRa antagonists impact response to standard of care interventions; studies that will inform how these drugs should be positioned clinically. In Aim 2 we will optimize the potency and drug-like properties of the novel ERRa targeting scaffolds we have already identified to develop small molecule inhibitors of ERRa for in vivo studies and future clinical use. Further, in pilot studies we have determined that a tool ERRa antagonist has single agent efficacy in a mouse model of established brain metastasis and that this compound also increases breast cancer cell sensitivity to methotrexate, a drug currently used to treat breast cancer brain metastasis and leptomeningeal disease. Therefore, we will explore the utility of using ERRa antagonists as single agents and in combination with select chemotherapeutics as new treatment modalities for these debilitating diseases.