Project 3: Enhanced Sensitivity of Tumors to Proton Beam Therapy: Mechanisms and Biomarkers.

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Project 3 - SUMMARY While proton beam therapy (PBT) has superior physical characteristics compared to standard photon radiation, its biological properties have been thought to be similar to photons. This is reflected in the use of a generic relative biological effectiveness (RBE) of 1.1 to scale the physical dose delivered for both cancer and normal tissues. However, pre-clinical data from our groups and others are emerging to indicate that the RBE of PBT varies and may be dependent on intrinsic tumor cell biology. Such RBE variations are likely genomically defined and exist across individual tumors of a given cancer type. This is a vastly understudied area with potential for substantial clinical impact as we are advancing our ability to genomically profile cancers to identify candidate predictive biomarkers. Thus, our overall objective is to establish distinct biological properties of PBT relative to photon radiation and determine if these differential properties result in variable RBE values across genomically diverse tumors. By combining synergistic MGH and MDACC expertise, we will integrate advanced physical computation techniques with novel biological tools, such as nucleosome-resolution genomic mapping of DNA double-strand breaks, to study the hypothesized unique biological damage produced by protons. We will conduct the following Specific Aims: (1) Simulate DNA damage induction and repair for proton vs photon irradiation; (2) Experimentally elucidate targetable differences in the induction and removal of DNA breaks following proton vs photon irradiation; (3) Identify candidate genomic biomarkers that predict increased proton RBE in annotated cancer cell lines; (4) Validate biomarker-correlated proton sensitivity in clinically relevant tumor models and in patients. These studies will leverage extensive pre-clinical tumor model collections as well as clinical trial specimens at both institutions. The knowledge gained will quickly influence the treatment of cancer patients through the introduction of novel clinical trials with stratification based on genomic biomarkers that predict sensitivity to PBT.