R01CA266419

Using experimentally-guided multi-scale modeling to determine the mechanism of flash tissue sparing - Abstract

Flash irradiations, irradiations with dose rates >40 Gy/s, have been shown to greatly reduce radiation damage for normal tissue while not affecting tumor control. This sparing effect was demonstrated in multiple animal models, mostly using electron flash irradiations. The pre-clinical data generated a strong push to translate flash radiation therapy (RT) into the clinic.

Only a few human patients have so far been treated with flash-RT. The first patient, a single cutaneous lymphoma lesion, was treated with electron flash-RT. Recently, Varian announced the first clinical trial of proton flash-RT (Phase 1) and treated the first patients with symptomatic bone metastases. Yet many questions remain unanswered. Most significantly, the underlying mechanism of flash induced sparing of healthy tissue still remains elusive.

As a corollary, the constraints imposed on the clinical parameters (e.g. dose, dose rate, and time within and between treatment fields) to induce the flash tissue sparing effect are still not determined. While there are many experimental efforts currently being pursued, my team has worked on understanding flash both from an experimental as well as theoretical point of view.

Our experimental preliminary data show proton flash tissue sparing in intestine, brain, and skin. Our theoretical preliminary data include modeling oxygen depletion and simulations of radiochemistry using TOPAS-NBIO, a mechanistic Monte Carlo framework developed by our group.

Our central hypothesis is that the flash effect is caused by a combination of (STEM) cells in a low-oxygen niche and long-lived (μs to ms) daughter products of chemical reactions involving oxygen. We propose an interplay between experiments and modeling to determine the underlying mechanism of flash-RT tissue sparing by employing TOPAS-NBIO to investigate the involved chemical reactions based on their intrinsic time features.

We propose to test the hypothesis and validate the model with the following aims:

SA 1: Investigate the mechanisms of proton flash-RT
1. Conduct multi-scale experiments to guide the modeling efforts.
2. Model the mechanism and chemical processes at relevant time scales in TOPAS-NBIO.

SA 2: Validate the model and determine clinical parameters for flash tissue sparing.

The General Hospital Corporation

TO DEVELOP THE MEANS TO CURE AS MANY CANCER PATIENTS AS POSSIBLE AND TO CONTROL THE DISEASE IN THOSE PATIENTS WHO ARE NOT CURED. CANCER TREATMENT RESEARCH INCLUDES THE DEVELOPMENT AND EVALUATION OF IMPROVED METHODS OF CANCER TREATMENT THROUGH THE SUPPORT AND PERFORMANCE OF BOTH FUNDAMENTAL AND APPLIED LABORATORY AND CLINICAL RESEARCH. RESEARCH IS SUPPORTED IN THE DISCOVERY, DEVELOPMENT, AND CLINICAL TESTING OF ALL MODES OF THERAPY INCLUDING: SURGERY, RADIOTHERAPY, CHEMOTHERAPY, AND BIOLOGICAL THERAPY INCLUDING MOLECULARLY TARGETED THERAPIES, BOTH INDIVIDUALLY AND IN COMBINATION. IN ADDITION, RESEARCH IS CARRIED OUT IN AREAS OF NUTRITIONAL SUPPORT, STEM CELL AND BONE MARROW TRANSPLANTATION, IMAGE GUIDED THERAPIES AND STUDIES TO REDUCE TOXICITY OF CYTOTOXIC THERAPIES, AND OTHER METHODS OF SUPPORTIVE CARE THAT MAY SUPPLEMENT AND ENHANCE PRIMARY TREATMENT. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.395 - Cancer Treatment Research

National Cancer Institute (NCI) [HHS - NIH]

Boston, Massachusetts 021142621 United States

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NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 562% from $499,419 to $3,306,088.