Simulating Ancestrally Unbiased Tumor Evolution To Interrogate Drug Resistance

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PROJECT SUMMARY Among cancer patients of distinct ancestries, there are molecular differences in the composition of their tumors, and their responses to therapies. These molecular distinctions extend well beyond germline differences, and encompass somatic and non-mutational alterations as well. Compared to European-American patients, African- American prostate cancer patients ’have a markedly higher risk of both developing and dying from prostate cancer. This mortality is related to inevitable drug resistance, and often from bone metastases. Although access- to-care contributes, there is also a higher risk of cancer progression for African-American patients enrolled in active surveillance programs. Collectively, there is evidence that molecular distinctions enriched among different ancestries can play a role in altering tumorigenesis and response to therapies. There are significant challenges in addressing the above. Large molecular profiling cohorts of patient tumors are underrepresented for non-European American patients, and there are only limited cell-lines derived from such patients. We also need effective ways to rapidly model tumor evolution in vivo in an immunocompetent and hormone-sensitive manner, to develop corresponding therapies that are biologically relevant. To address these significant challenges, my central vision is to interrogate tumor evolution in an ancestrally unbiased manner. This would enable us to identify powerful driver molecular alterations that are currently underappreciated due to the limited nature of existing non-European American patient cohorts, and also develop effective therapies against such tumors. Inspired by a subset of my own patients, the centerpiece of this proposal is the development of BRUTE (BaRcoded Unsupervised Tumor Evolution FIGURE), an immunocompetent organoid-based tumor graft system. The first proof-of-principle iteration of BRUTE tumors in an androgen- dependent prostate-tissue derived system strongly identified ERF and other underappreciated oncogenic alterations enriched uniquely among African-American patients. Using our tractable BRUTE system and orthologous approaches, we will investigate in an ancestrally unbiased manner A) how the anatomic niche and immune system alter the selection of tumorigenic and drug-resistant cells, B) the biology of the future drug-resistant cells among the precancerous bulk population, and C) how to target the molecular alterations that are enriched among non-European American patients. This is the first tumor evolution system of which we are aware that spontaneously recapitulates molecular driver alterations observed in underrepresented patient cohorts. Thus, we can use it to ask: why are African-American prostate cancer patients more likely to die of bone metastases than European-American patients? Can we detect and eliminate the future drug resistant cells in underrepresented patients’ tumors prior to drug exposure? And can we develop targeted therapies to exploit the molecular alterations observed in African-American prostate cancer patients?