Radiobioeffect Modeling of αRPT

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If absorbed dose is to be used in treatment-planning based α-particle emitter radiopharmaceutical therapy (αRPT), the impact of DNA double-strand break (DSB) repair status- the process most likely to affect response - must be considered in order to reliably predict toxicity and efficacy. Projects 1 through 3 have focused on estimating tissue absorbed doses for αRPT. In project 4, we take these absorbed dose estimates and examine whether clinically implementable methods for evaluating DNA DSB repair (DSBR) status will improve the absorbed dose vs response relationship for patients undergoing αRPT. Our overall hypothesis is that tissue absorbed dose will better predict αRPT response when adjusted by quantitative measures of DNA DSB repair pathway functionality. To test this hypothesis, we introduce a novel approach to assessing repair pathway functionality and couple it with preclinical and clinical scenarios that will allow us to rigorously evaluate the impact of accounting for DSBR functionality in relating absorbed dose to response. We will use prostate cancer (PCa) as a model system for the proposed studies. Prostate cancer patients are already treated with 223RaCl2 (Xofigo), an FDA approved, αRPT. There is also evidence that the efficacy of this treatment is impacted by somatic and/or germline deficiencies in DNA DSB repair. Accordingly, the proposed studies, will test our hypothesis in a context that is immediately clinically relevant. Aim 1: Using PCa cell lines and their repair deficient isogenic variants, relate absorbed dose (D) to DNA DSB damage and repair, in vitro, in the context of BRCA2-/- and ATM-/- -related DNA DSB repair deficiencies; since response is impacted by cell-cell interactions, perform these studies in (a) monolayer and (b) spheroid culture. Aim 2: Collect dose- vs DSBR data, in vivo, analogous to that collected in Aim 1. Perform these studies in (a) mice bearing xenografts of the cell lines and their isogenic variants used in Aim 1 and (b) extend the normal organ studies of (a) using porcine marrow and kidney tissues from the dose vs toxicity studies of Aim 3 in Project 3. (c) In PCa patients treated with 223Ra, use normal tissue and tumor D estimates, with estimates of DSBR functionality to assess the impact of DSBR deficiencies on D vs tumor and normal tissue response. DSBR deficiencies will be assessed using DNA DSB repair (DDR) pathway mutation status obtained from liquid biopsies. Aim 3: Develop a mathematical model that may be used to optimize the selection and dosing schedule of DSBR inhibitors (DSBRi) and identify patients whose genomic/transcriptomic profile and dosimetry would make them likely high or low responders to αRPT±DSBRi therapy. By coupling αRPT dosimetry with the DSBR functionality, the work proposed in this project completes the transition depicted in figure 1 of the overview while also providing and validating a novel technique that can be applied to investigating the role of DSBR inhibitors in αRPT of cancer.