Selective pressures on bone cancer evolution and treatment resistance emerging from the interactions with the bone ecosystem

Abstract The bone is the organ of origin of several types of cancer including multiple myeloma, as well as a host to many metastatic lesions such as those characterizing prostate and breast cancer. The evolutionary dynamics that drive primary and metastatic progression in the bone, as well as those that explain the emergence of resistance to treatments such as proteosome inhibitors and hormonal deprivation therapies, result from the interactions between the tumor and the bone ecosystem. Models that can capture the complex ecological interactions in the bone are key to define the selective pressures underpinning somatic evolution in the bone. Our approach combines computational agent-based models with both in vitro and pre-clinical models in order to shed lights on some open questions in regard to tumor-stromal interactions. As well as the integration of biological and computational models, our approach is hypotheses-driven and captures the homeostasis of the bone that emerges from the interactions of key cellular species such as osteoblasts and osteoclasts. We have explored our models to investigate explore how prostate cancer cells can successfully initiate metastases in the bone, novel therapeutic approaches to treat bone metastatic prostate cancer, explore the emergence of treatment resistance in multiple myeloma and tease apart the contribution of environmentally-mediated drug resistance from cell-intrinsic resistance to proteosome inhibitors. Citation Format: David Basanta, Conor Lynch, Anna Miller, Ryan Bishop. Selective pressures on bone cancer evolution and treatment resistance emerging from the interactions with the bone ecosystem [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A028.