Project 1: FLASH vs. Standard radiotherapy for treatment of PDAC and sparing normal intestine tissues

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY Radiation therapy (RT) is used in the curative setting for many cancers including sarcomas and lung and pancreatic cancer. Despite significant improvements over the past few decades, there is still much room for improvement as patients still develop RT-induced injuries or second malignant neoplasms. FLASH radiotherapy, which delivers a large dose of radiation at an ultra-high dose rate could potentially reduce toxicity. Our overall hypothesis is that Proton/Carbon Particle FLASH RT is superior to Standard Particle RT in protecting normal tissues while the two modalities will be equipotent in controlling malignant growth. Project 1, which focuses on pancreatic cancer, will define the dosimetric and biophysical parameters that will maximally spare normal intestine tissues using FLASH proton therapy (F-PRT) without compromising antitumor effects. It will delineate mechanistic aspects of differential response of normal intestinal tissues, by focusing on the relative sparing of the stem/progenitor cell population. Project 1 will also employ p53+/- transgenic mouse models to dissect the genetic determinants of differential GI toxicity of Standard proton therapy (S-PRT) vs F-PRT. Project 2 will explore the ability of F-PRT to ameliorate adverse events (inflammation, fibrosis, lymphedema, changes to bone structure, radiation-induced cancers) that pose barriers to the treatment of sarcomas with RT. We will also carry out a phase 1/2 trial that will treat canine patients with osteosarcomas definitively with F-PRT. Project 3 will compare the efficacy of FLASH-RT given with carbon ion radiotherapy (C- RT) vs. standard dose rate and compare it to electron F-RT. Studies will focus on the mitigation of normal tissue injury in NSCLC with an emphasis on the impact of normal tissue and intratumoral hypoxia to response following C-RT. Lastly, Project 4 will develop and validate the use of pencil beam scanning (PBS) technology for particle F-RT. It will analyze spatiotemporal variations and SOBP (spread out Bragg peak) vs. shoot through PBS and develop dose delivery algorithms for modeling biological effects for PBS-based FLASH proton therapy. These tools will be incorporated in the experimental plans of project 1-3. These Projects are supported by 4 Cores including an Administrative Core (Core A), Physics-Dosimetry Core (Core B), which will offer infrastructure services to harmonize dosimetry between various sites and a Comparative Pathology core (Core C) for tissue preparation for histopathological evaluation. Statistical services will be provided by Core D. Collectively, this highly integrated effort led by recognized leaders in Radiation and Tumor Biology, aims to define the biological, dosimetric and biophysical parameters and molecular mechanisms under which FLASH RT is most effective in tumors and tissues we deem the most likely to be first tested in clinical trials. It is our belief that only by acquiring this knowledge will this exciting and novel modality be ushered into the clinic in a safe and effective manner to improve therapeutic outcome and quality of life of cancer patients.

Public health relevance public domain (NIH RePORTER)

Overall Narrative Radiotherapy (RT) is frequently used to treat patients with a variety of cancers; however, despite our ability to target RT with sophisticated techniques, it can still lead to high rates of normal tissue toxicity that significantly affect patients’ quality of life. The exciting new modality of ultra-high dose rate radiotherapy (FLASH-RT) could help in alleviating these complications due to its reported ability to spare normal tissues while being equivalent in controlling tumor growth. We will test the overall hypothesis that FLASH RT with particle therapy (protons, carbon ions, or electrons) is superior to the same therapy delivered at standard dose rates, providing for the protection of normal tissues without compromising tumor control; thus, the overall goal of this P01 application is to complete pre-clinical studies, specifically focusing on sarcomas and lung and pancreatic cancers, aimed at addressing key gaps in knowledge regarding FLASH-RT to move it into human clinical trials.