Radiation modulation of cell plasticity programs determine prostate cancer oligometastatic potential

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Patterns of disease failure in prostate cancer (PCa) suggest understanding metastasis will result in the largest therapeutic gains and allow for more rationale clinical management. The importance of consolidating all sites of macroscopic disease including the primary to impede further metastatic dissemination is backed by limited prospective randomized studies. However, the question of whether total consolidation by treating the metastases with radiation in PCa further impedes the metastatic process and survival is unanswered. It is generally assumed that metastasis is a unidirectional flow of circulating tumor cells (CTCs) leaving the primary tumor and seeding a metastasis at a distant site with each metastasis growing independently of the others. However, CTCs may undergo a cyclical “self-seeding” process, wherein cells with metastatic potential return to the “idealized” microenvironment of the primary tumor and other macroscopic tumor deposits resulting in more robust CTCs. Epithelial-mesenchymal plasticity (EMP) programs composed of the epithelial-mesenchymal transition (EMT) and the mesenchymal-epithelial transition (MET) are developmental programs that can engender epithelial cells with metastatic properties. We propose the dynamic EMP program directs PCa cells to revert back and forth from EMT-MET to facilitate self-seeding. Stereotactic ablative radiation (SABR) is a highly focused, high-dose short radiation course that is suited for treatment of metastases as it targets the cancer cells and tumor microenvironment (TME) cells. Interventions that effectively target the TME component, such as SABR, appear poised to arrest self-seeding and subsequent maturation of metastases. We are in the final stages to launch our TERPS trial - Phase 2 randomized Total Eradication of metastatic lesions following definitive Radiation to the Prostate in de novo oligometaStatic prostate cancer. Thus, we have developed the following HYPOTHESES: (1) EMP programs control self-seeding and the metastatic potential of PCa; (2) CTCs with low EMT and/or high MET markers are representative of men with oligometastatic PCa; (3) Consolidative SABR of metastases alters the natural history of oligometastatic PCa; and, (4) Consolidative SABR alters the potential for maturation of future metastases that can be detected by changes in CTC marker profiles and enumeration levels and/or tissue, liquid or imaging biomarkers. We will test the following two aims. AIM #1: Epithelial-mesenchymal plasticity of circulating tumor cells (CTCs) are biomarkers for men with oligometastatic prostate cancer treated with SABR. We will pursue a number of correlative tissue, liquid, imaging and immune studies from our TERPS trial to examine for EMP markers - EMT and MET. AIM #2: To determine the effects of SABR on prostate cancer self-seeding in epithelial- mesenchymal plasticity prostate cancer mouse models. Use cell based EMP PCa models and serial non- invasive imaging in mice to test the self-seeding hypothesis for PCa and if EMP factors modulate self-seeding.