Abstract IA028: Renal medullary carcinoma: Discovery and validation of tailored treatment strategies

Abstract

Abstract Renal medullary carcinoma (RMC) is a rare but highly aggressive malignancy that predominantly afflicts young individuals of African descent harboring the sickle cell trait and is defined by loss of the SMARCB1 tumor suppressor. Notably, the anti-VEGF and mTOR targeted therapies and standard immune checkpoint inhibitor strategies developed for clear cell renal cell carcinoma (ccRCC) are completely ineffective against RMC. Conversely, platinum-based cytotoxic chemotherapy regimens are the preferred first-line therapy yielding a response rate of 29% and median survival of 13 months from diagnosis. There is clearly a need for tailored treatment strategies for this deadly disease. To meet this challenge, we have developed a dedicated research and clinical team and bench-to-bedside pipeline that supported the comprehensive profiling of patient samples and the development of multiple RMC cell lines, three patient-derived xenografts, and the first genetically engineered mouse model of RMC. These tools informed the development of the first three clinical trials dedicated to RMC (NCT03587662, NCT03274258, and NCT05347212 at clinicaltrials.gov), as well as the establishment of effective second-line, and more recently third-line, therapeutic strategies that produce objective responses and occasionally cures for this deadly disease. Using these approaches, the majority of patients diagnosed with RMC today will survive beyond a year from diagnosis. The progress made has been supported by a passionate patient advocacy group and the awareness raised has resulted in our current clinical volume of caring for 3-5 patients with RMC per week. Emerging insights into the pathophysiology of RMC have allowed us to uncover an "exercise paradox" whereby the hypoxia induced by high-intensity exercise in the setting of sickle cell trait may be the strongest modifiable risk factor for RMC. The unique biological processes behind the exercise paradox also underlie the distinct biological adaptation of RMC to true hypoxia via the loss of SMARCB1, as opposed to the pseudohypoxia observed in ccRCC driven by VHL loss. Whereas pseudohypoxic tumors are sensitive to VEGF targeting, SMARCB1 loss confers resistance to the hypoxia induced by in vivo inhibition of angiogenesis. These insights have allowed us to identify immediately actionable therapeutic targets paving the way for the next generation of clinical trials for RMC. The benchmark goal is to improve the median survival of patients with RMC to 24 months by 2025 and to 5 years by 2030. Citation Format: Pavlos Msaouel. Renal medullary carcinoma: Discovery and validation of tailored treatment strategies [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr IA028.