This clinical trial focuses on how mitochondrial signaling dysregulation, an established hallmark of cancer, leads to the development of therapy resistance in tumor cells. We have identified a novel signaling axis, involving dysregulation of the mitochondrial antioxidant enzyme, manganese superoxide dismutase (MnSOD). The resulting aberrant oxidative signaling in estrogen receptor positive (ER+) breast cancer cells causes them to develop stem cell-like properties, making them resistant to multiple cancer treatments, including combined endocrine therapy and CDK4/6 inhibitor, which is the standard first line therapy for metastatic ER+ breast malignancies. Thus, we hypothesize that in some wome...

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This clinical trial focuses on how mitochondrial signaling dysregulation, an established hallmark of cancer, leads to the development of therapy resistance in tumor cells. We have identified a novel signaling axis, involving dysregulation of the mitochondrial antioxidant enzyme, manganese superoxide dismutase (MnSOD). The resulting aberrant oxidative signaling in estrogen receptor positive (ER+) breast cancer cells causes them to develop stem cell-like properties, making them resistant to multiple cancer treatments, including combined endocrine therapy and CDK4/6 inhibitor, which is the standard first line therapy for metastatic ER+ breast malignancies. Thus, we hypothesize that in some women with metastatic ER+ breast cancer, dysregulation of MnSOD disrupts cellular oxidative metabolism, leading to therapy resistance and disease progression on first line therapy. We will test whether treatment with Avasopasem (Galera Therapeutics, Inc.), which functionally replaces the activity of MnSOD by chemically removing superoxide, will reverse therapy resistance in women with metastatic ER+ breast cancer who progress on combined endocrine therapy and CDK4/6 inhibitor. In addition, we will use established models and human tumor samples to identify mechanisms linking altered oxidative metabolism, stem cell characteristics, and treatment response. Our goal is to study a novel therapeutic option for women with metastatic ER+ tumors, by chemically replacing MnSOD activity with a new therapeutic. Finally, we will use PET-FES, a very sensitive and specific imaging modality, to determine treatment response. In this way, each woman on this trial acts as their own control by taking scans before therapy and again after four months. This clinical trial is of significant clinical importance since this population of women has limited treatment options.

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