Program Project Grant (P01): Translational Studies in FLASH Particle Radiotherapy

NIH Grant # P01-CA257904-01

Contact Principal Investigator:

• Costas Koumenis, PhD, University of Pennsylvania

Co- Principal Investigator:

•  Alex Lin, MD, University of Pennsylvania

Project Overview:

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 (CRT) 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

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

Project 1 will define the dosimetric and biophysical parameters that maximize normal tissue sparing and antitumor effects of F-PRT, by performing dose-escalation studies in syngeneic models; it will investigate mechanisms of differential response of normal intestinal tissues to standard proton radiotherapy (S-PRT) vs FLASH proton radiotherapy (F-PRT) using single-cell transcriptomics and genetic mouse models

• Costas Koumenis
• Andy Minn
• David Kirsch

Project 2: Mitigation of radiation toxicity in treatment of sarcoma with FLASH vs. Standard dose rates

Project 2 will use murine models to: (i) understand when and how F-PRT can lead to reduced inflammation, lymphedema, fibrosis, and vascular effects and (ii) define the clinical uses of F-PRT to avoid second malignancies that can be associated with S-PRT and exploit its positive impact on therapeutic window when employed in combination with surgery. Finally, Project 2 will conduct a phase 1-2 trial using FLASH radiation in the definitive setting (no surgery) for osteosarcomas in dogs.

• Theresa Busch
• Keith Cengel
• Amit Maity

Project 3: Carbon vs. Electron FLASH radiotherapy for mitigation of normal lung injury in treatment of NSCLC

Project 3 will compare FLASH dose-rate RT generated with electrons (Oxford) and carbon (Heidelberg) and compare to protons (UPenn) to provide evidence for equipotency of FLASH vs. standard RT to tumor growth control, while sparing normal tissues (lung, vascular, heart and esophagus) in preclinical models of thoracic irradiation. Interaction with online O2 monitoring (Oxford) combined with the ability to modulate LET with carbon ions (Heidelberg) will provide a unique ability to dissect the impact of oxygen on FLASHeffects.

• Amir Abdollahi
• Amato Giaccia

Project 4 : Development and validation of Pencil Beam Scanning methodology for proton FLASH radiotherapy

Project 4 will (i) establish a beam-control system for the research beamline to create a variable dose rate delivery to simulate the spatiotemporal nature of pencil beam scanning (PBS), (ii) compare FLASH effects at the high LET Spread-Out-Bragg Peak (SOBP) with those at the entrance region, (iii) develop a dose model to investigate the potential biological effects related to the high instantaneous dose rate and dynamic beam delivery scheme in PBS, (iv) develop real-time dose rate monitoring system and high-speed dose recording to ensure accurate F-PRT dose delivery and (v) develop FLASH-specific quality assurance procedures.

• Lei Dong
• Rodney Wiersma

Core A: Administrative: coordinates administrative and financial aspects of the collaboration, oversee day-to-day operations globally (Oxford, Heidelberg), and the US (UPenn and Duke) and organize EAB meetings, symposia, and annual reporting to the NCI.

• Costas Koumenis
• Alex Lin
• Amanda Snyder

Core B: Physics-Dosimetry will offer infrastructure services to (i) perform the RT studies at Penn, (ii) ensure physical dose between proton/carbon/electron and FLASH/standard and (iii) develop animal-specific treatment planning for mice and dogs. Critically, it will also develop and implement approaches for harmonization of dosimetry between the various sites.

• Eric Diffenderfer
• Michele Kim

Core C: Comparative Pathology located at UPenn Vet School, will provide services including tissue preparation for histopathological evaluation, optimized immunofluorescence and IHC staining of immune infiltrates, histochemical stains (e.g. trichrome), and quantitative image analysis.

• Enrico Radaeli

Core D: Biostatistics will help develop rigorous study designs and analytic plans appropriate for the research goals of each project. It will also provide resources need to assess sample size and statistical power, with particular attention to the dog study in Project 2

• Mary Putt

External Advisory Board:

• Mary Hellen Barcellos-Hoff
• Sandra DeMaria
• Sandra Gollnick
• Ted Lawrence
• Harald Paganetti

Internal Advisory Board:

• Kristy Weber
• Lily Duda
• Robert Vonderheide

Calendar of Events:

FLASH P01 Monthly Meeting: the first Friday of every month at 9:00AM

Publications: