OncoLoop: A network-based precision cancer medicine framework

Vasciaveo A, Arriaga JM, Nunes de Almeida F, Zou M, Douglass EF, Picech F, Shibata M, Rodriguez-Calero A, de Brot S, Mitrofanova A, Chua CW, Karan C, Realubit R, Pampou S, Kim JY, Afari SN, Mukhammadov T, Zanella L, Corey E, Alvarez MJ, Rubin MA, Shen MM, Califano A, Abate-Shen C.

Cancer Discov.

November 14, 2022

Prioritizing treatments for individual cancer patients remains challenging, and performing co-clinical studies using patient-derived models in real-time is often unfeasible. To circumvent these challenges, we introduce OncoLoop, a precision medicine framework that predicts drug sensitivity in human tumors and their pre-existing high-fidelity (cognate) model(s) by leveraging drug perturbation profiles. As proof-of-concept, we applied OncoLoop to prostate cancer (PCa) using genetically-engineered mouse models (GEMMs) that recapitulate a broad spectrum of disease states, including castration-resistant, metastatic, and neuroendocrine prostate cancer. Interrogation of human PCa cohorts by Master Regulator (MR) conservation analysis revealed that most advanced PCa patients were represented by at least one cognate GEMM-derived tumor (GEMM-DT). Drugs predicted to invert MR activity in patients and their cognate GEMM-DTs were successfully validated in allograft, syngeneic, and patient-derived xenograft (PDX) models of tumors and metastasis. Furthermore, Oncoloop-predicted drugs enhanced the efficacy of clinically-relevant drugs, namely the PD1 inhibitor, nivolumab, and the AR-inhibitor, enzalutamide.

Last updated: February 02, 2023