PROJECT SUMMARY/ABSTRACT: This proposal addresses the lack of patient-derived model systems in hormone receptor positive (HR+) breast cancer, and also the lack of ethnically representative models of breast cancer. The majority of newly diagnosed breast cancers (>70%) are HR+, and two-thirds of the estimated 42,690 breast cancer deaths will be from HR+ breast cancer. Recurrent HR+ breast cancer has been difficult to study given the prolonged clinical course and the lack of appropriate patient-derived model systems. These models have been difficult to derive and grow in the past, with low take-rate (~10-20%), and the models losing their HR expression over time. In addition, tumor extrinsic factors such as cancer-associated fibroblasts (CAFs) that significantly impact tumor biology and therapy responses, are rarely incorporated in studies or models of HR+ disease. Therefore, to address this gap, we set out to develop more representative models of recurrent and relapsed HR+ breast cancers, and to incorporate elements of the tumor microenvironment into these models. To achieve this, we have developed a method for deriving HR+ patient-derived model systems consisting of both, primary patient-derived tumor organoids (PDOs) isolated from relapsed and metastatic HR+ tumors, and matching primary cancer-associated fibroblasts (CAFs) with high take rate (~50%). These models also better represent the patients’ ethnic and racial diversity, as ~35% of our models are from underrepresented ethnicities (e.g., African-American, Hispanic). Using these innovative tools, we have already identified SUCNR1 as a driver of treatment resistance in HR+ breast cancer. These data led us to our hypothesis that targeting SUCNR1, will reverse treatment resistance observed in metastatic HR+ breast cancers, and that we can use our unique PDO models as a pre-clinical testing platform of these novel treatment strategies. We propose two specific aims: Aim 1 is a more technology driven per the RFA for this R21 and will expand the number of available metastatic and relapsed HR+ patient-derived models isolated from ethnically diverse patient populations. In Aim 2 we will Investigate the therapeutic targeting of SUCNR1 in recurrent HR+ breast cancer using our PDO models. Our proposal is significant because it addresses multiple fundamental challenges in breast cancer treatment and management, including lack of patient-derived models for HR+ breast cancer, lack of tumor models from diverse racial backgrounds, and contribution of CAFs to resistance. Most importantly, we intend to make these models and tools available to the whole field, therefore the impact of this research is well beyond our proposed research.