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Optimization of MeV FLASH radiotherapy for normal tissue preservation

Award Number: U01CA260446
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/06/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Optimization of MeV FLASH radiotherapy for normal tissue preservation - ABSTRACT Significant improvement in the effectiveness of radiation therapy (RT) now seems possible because of recent exciting research results using ultra-high dose rates (UHDR), indicating that normal tissue damage can be reduced (the `FLASH' effect), compared to conventional radiation for the same total dose. FLASH RT delivery has shown reduced morphological and functional damage to normal tissues such as brain, colon, lung, and skin. Although significant research remains, early indications are that the normal tissue sparing effect may as high 50% at some dose levels. If proven in translation, this effect would be the most significant improvement in RT therapeutic ratio since the advent of treatment planning. While intriguing mechanisms for this result have been postulated, they remain only well-reasoned speculations because of a lack of direct in vivo data on the physico- chemical mechanisms including oxygen depletion and free radical species alterations. Dartmouth has created the first reversible MeV FLASH beam on a clinically commissioned linac with >100 Gy/s at the patient treatment bed, and prototyped an open-source treatment planning system, expanding research access. Additionally, the team has invented unique technological capabilities to directly measure the highest dose rates and in vivo tissue oxygen transients. The key technological barriers solved in the proposed research with preliminary data are: 1) demonstration of conversion to a UHDR irradiator within a clinically commissioned linac, 2) verification of per- pulse and per-fraction dose rates, 3) direct in vivo observation of oxygen transients, 4) direct measurements of free radical species changes in vitro, and 5) access to functional tissue assays and genetic and proteomic assays. Single-pulse and single-fraction dose rates will be quantified by high frame rate imaging. Additionally, the in vivo oxygen changes will be quantified by two independent methods for co-validation, including electron paramagnetic resonance oximetry and optical luminescence oximetry. Free radical species changes produced from transient hypoxia will also be assessed through systematic in vitro analyses, and the potential linkages to functional, proteomic and DNA damage examined. The FLASH beam conditions that minimize normal tissue damage for a fixed dose will be established with this baseline data. The work is pre-clinical but can be readily adapted to ongoing NIH sponsored spontaneous canine cancer studies has relevance to future large animal and first-in-human translation. Multiple Dartmouth centers partnered to initiate and support this FLASH program. Taken altogether, this bioengineering research project will advance the state of the art in high dose rate radiation therapy using tools that have been uniquely developed by our 3 research groups, and the project results will build the basic science needed to support proposed human translation of this ground-breaking field. The team has leading expertise in radiation physics, in vivo molecular measurement, and radiation genetics and immunomolecular biology and pathology. The work is supported by an External Advisory Board of international expert FLASH consultants, as well as an internal Radiation Oncology Advisory Group.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $614,605 )
2025	2025	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Treatment Research	001	4	6/9/2025	NON-COMPETING CONTINUATION	$61,497
2025	2025	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Treatment Research	000	4	3/13/2025	NON-COMPETING CONTINUATION	$553,108
														Subtotal = $614,605

Issue Date FY: 2024 ( Subtotal = $589,189 )
2024	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Treatment Research	003	3	4/17/2024	NON-COMPETING CONTINUATION	$31,008
2024	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Treatment Research	002	3	3/29/2024	NON-COMPETING CONTINUATION	$558,181
2024	2023	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Treatment Research	001	2	3/27/2024	NON-COMPETING CONTINUATION	$0
2024	2022	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Treatment Research	000	1	3/15/2024	NEW	$0
														Subtotal = $589,189

Issue Date FY: 2023 ( Subtotal = $607,371 )
2023	2023	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Treatment Research	000	2	3/30/2023	NON-COMPETING CONTINUATION	$607,371
														Subtotal = $607,371

Issue Date FY: 2022 ( Subtotal = $642,155 )
2022	2022	TRUSTEES OF DARTMOUTH COLLEGE	6001 PARKHURST HALL STE 207	HANOVER	NH	03755	GRAFTON	USA	Cancer Treatment Research	000	1	4/6/2022	NEW	$642,155
														Subtotal = $642,155

Grand Total All Awards = $2,453,320

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Optimization of MeV FLASH radiotherapy for normal tissue preservation

Award Number: U01CA260446

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/06/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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