The Origins of Metabolic Reprogramming in Prostate Cancer

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PROJECT SUMMARY More than 33,000 individuals in the United States were estimated to die from prostate cancer in 2020, predominantly due to treatment-resistance. As our current therapies are not working for a large number of patients with metastatic castration-resistant prostate cancer, we need innovative strategies to identify new therapeutic approaches. Suppression of the androgen signaling axis with potent androgen receptor pathway inhibitors (ARPIs) has increasingly led to the outgrowth of AR-indifferent tumors that exhibit loss of luminal features and gain of basal and/or neuroendocrine features, termed lineage plasticity or lineage infidelity. Limited knowledge of the factors regulating lineage identity in prostate epithelium has stalled efforts to prevent or reverse lineage plasticity, promote sensitivity to ARPIs, and reduce lethality in CRPC. This proposal stems from our discovery that altering fuel preference is sufficient to modulate lineage identity in prostate epithelium, based on early results from the parent R01. We hypothesize that fuel preference regulates lineage identity and may modulate resistance to ARPIs in CRPC. In Aim 1, we will utilize a 3D organoid assay to modulate fuel preference and define transcriptional and proteomic changes to evaluate lineage identity in normal prostate epithelium. In Aim 2, we will utilize distinct genetic models of prostate cancer driven by tumor suppressor loss (Pten, Rb1) to determine how fuel preference modulates prostate cancer lineage identity. Defining the factors that regulate lineage identity is fundamental to understanding prostate cancer treatment-resistance and may yield therapeutic targets for this lethal disease.