Metastasis is a complex systems problem, with critical changes across cell, tissue, organ, and organism scales. The limited efficacy of current therapies in metastatic patients argues that we do not fully understand metastasis. The metastatic capacity of prostate cancer (PCa) behaves along a spectrum of disease that contains an oligometastatic state where metastases are limited in number and location. Radiation consolidation of all tumor deposits in oligometastatic PCa to forestall further progression is now backed by small randomized studies in the recurrent setting, but the utility in the de novo space is unknown. These are important early clinical data suggesting the existence of an oligometastatic state and the importance of radiation consolidation in altering underlying metastatic proclivity which has immediate impact for the management of these patients. Our U54 ROBIN Oligometastasis (ROBIN OligoMET) Center brings together pre-eminent faculty from the University of Maryland (UM), Weill Cornell Medicine (WCM) and Thomas Jefferson University (TJU) to study mechanisms of how radiation therapy (RT) can affect the metastatic process in de novo oligometastatic PCa. This multidisciplinary perspective enables us to bring the latest clinical trial, profiling and computational methods to bear on the most clinically relevant aspects of oligometastasis. This in turn will lead to the development of new approaches for using RT to combat metastases. This U54 ROBIN OligoMET Center will be led by Drs. Phuoc Tran, Nicole Simone and Amit Sawant (MPI). Project leadership comprises faculty with strong backgrounds in radiation biology, physics and metastasis research: Project 1 (Genomics, radiomics and liquid biopsies) is led by Drs. Tran, Ren and Sawant; Project 2 (Metabolomics and disparities) is led by Dr. Simone; and the Resource Sharing and Cross-Training Cores are led by Drs. Luigi Marchionni, Sawant and Ren. We bring a diversity of model systems, experimental methods, and conceptual frameworks. The projects integrate state-of-the-art tissue, liquid and radiomic multi-parametric profiling techniques from humans complimented with syngeneic mouse tumor models in the context of a first-in-man phase 2 randomized trial. Data will be integrated using novel network methods to prioritize candidates for functional validation across projects. Scientific and logistical integration will be ensured by an Administrative Core. Multi-omics analysis and integration, quantitative image analysis, and network analysis will be conducted in the Cross-Training Core. The ROBIN OligoMET Center will test the global hypothesis that consolidative radiation can alter cancer cell state plasticity and host-tumor metabolism that drives metastasis formation. AIM #1 – Identify cancer cell intrinsic and tumor microenvironment plasticity mechanisms modulated by radiation that change metastatic proclivity. AIM #2 – Determine metabolic changes that regulate anti-tumor immunity and metastasis in African American versus Caucasian oligometastatic prostate cancer following SABR consolidation. AIM #3 – Multi-scale integration embedded with training initiatives towards the elucidation of novel therapeutic vulnerabilities of metastatic cancers following consolidative SABR.

The limited efficacy of current therapies in metastatic patients argues that we do not fully understand metastasis. The metastatic capacity of prostate cancer (PCa) behaves along a spectrum of disease that contains an oligometastatic state where metastases are limited in number and location. The ROBIN OligoMET Center will test the global hypothesis that consolidative radiation can alter cancer cell state plasticity and host-tumor metabolism that drives metastasis formation.