Abstract 4478: Up284, A small molecule inhibitor of ADRM1 demonstrates significant anti-tumor efficacy in preclinical models of aggressive breast cancer

Quadruple-negative breast cancer (QNBCs) is a highly aggressive and metastatic disease and remains clinically challenging breast cancer subtype with worst prognosis. Due to its exceeding heterogeneity, absence of the AR, ER, PR, Her2 receptors and lack of established therapeutic targets, QNBC is hard to treat cancer and recurs rapidly with standard chemo regimen. QNBC demonstrated vulnerability to proteasome inhibition due to their higher metabolic needs. But FDA approved 20S proteasome inhibitors failed to treat solid tumors including QNBC. Hence, developing an effective strategy to overcome the limitations associated with current 20S proteasome inhibitors is mandated to provide alternate treatment options for QNBC patients. Preclinical, Up Therapeutics lead candidate small molecule inhibitor Up284 has shown significant tumor growth inhibition as a single agent in animal models. To explore potential synergy of Up284 with other therapeutic agents, we conducted the in vivo combination experiments. In this work, we present ADRM1 amplification in QNBC tumors, identification of a small molecule selective inhibitor of ADRM1, Up284 (Up Therapeutics), Up284 demonstrated efficacy against panel of BC cell lines and patient derived organoids. In vivo combination results for Up284 with widely used BC standard-of care chemotherapy regimen demonstrated strong in vivo synergy in tumor mouse syngeneic models. Taken together, these data demonstrated combination synergy of a small molecule ADRM1 inhibitor with other agents. These results pave the road for potential clinical evaluation of combination treatment of QNBC in patients. Citation Format: Balasubramanyam Karanam, Ravi Anchoori, Yung-Nien Chang, Rachel Martini, Florencia Madorsky Rowdo, Melissa B. Davis. Up284, A small molecule inhibitor of ADRM1 demonstrates significant anti-tumor efficacy in preclinical models of aggressive breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4478.