Subclonal determinants of radiation response in soft tissue sarcomas

PROJECT SUMMARY Although more than half of patients with cancer receive radiotherapy, the molecular mechanisms that determine the success of radiotherapy remain unclear. Subclonal populations of malignant cells with mutations that occur later during tumor development play an important role in response to treatments like radiotherapy. The overall goal of this study is to understand the non-genetic mechanisms that enable subclonal tumor populations to survive radiotherapy. By analyzing tumor and blood samples collected from patients undergoing preoperative radiotherapy for soft tissue sarcomas, this study will determine the cell intrinsic and extrinsic factors that contribute to subclonal radioresistance. Using genomic and computational biology approaches, this research aims to 1) identify and validate epigenetic changes such as changes in DNA methylation or chromatin accessibility that cause subclonal radioresistance, 2) define and validate critical interactions between radioresistant subclones and non-malignant cell populations in the tumor microenvironment, and 3) develop approaches to non-invasively localize and monitor radioresistant subclones within human tumors. Future studies targeting radioresistant subclones with combination therapies and new radiation delivery approaches could improve the efficacy of radiotherapy for patients with soft tissue sarcomas and other cancers.