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Modelling the dynamics of spontaneous clonal hematopoiesis in pet dogs during cancer therapy

Award Number: R01CA294792
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2025
PERIOD OF PERFORMANCE END DATE: 07/31/2030

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Modelling the dynamics of spontaneous clonal hematopoiesis in pet dogs during cancer therapy - PROJECT SUMMARY Somatic mutations with leukemogenic potential confer selective cellular advantages leading to clonal expansion of hematopoietic stem cells, a phenomenon termed “clonal hematopoiesis” (CH). CH represents a premalignant lesion associated with aging, as it occurs in >10% of people 70 years of age or older, conferring an approximate 20-fold increased risk for future hematologic malignancy. Importantly, cancer patients with CH that undergo chemotherapy or radiotherapy exhibit a substantially increased risk for secondary neoplasia. In one study of 750+ human cancer patients undertaken by Dr. Bick (mPI), a greater than 5-fold increase in CH was observed for those that underwent radiation treatment (with or without chemotherapy) compared to those that did not receive radiation. Given its expanding role in cancer survivorship, there is a growing need for novel therapeutic strategies that target CH to mitigate risk for future malignancy and modify its potential impact on cancer treatment. However, a major barrier to better understanding the influence of CH on cancer pathophysiology remains the absence of an in vivo model system that recapitulates the development and evolution of CH during aging, tumorigenesis and subsequent cancer treatment. Studies of aged (>25 months) mice reveal that CH is a relatively rare event, suggesting that their comparatively short lifespans preclude its development. Genetically engineered mouse models have been generated in which hematopoietic stem cells typically carry one of the known human CH driver genes, but these typically necessitate bone marrow transplantation (often myeloablative) which induces a variety of systemic changes. Xenograft mouse models employing transplanted human hematopoietic cells have also been used, but these are immunodeficient and thus not ideal. As pet dogs with spontaneous cancers have been increasingly used as a preclinical translational model, we asked whether CH may also occur naturally in this species. We found that within a cohort of 600 dogs without cancer, 12% carried a CH mutation, comparable to the rate of CH in humans. Importantly, CH was not detected in dogs less than 6 months of age and is thus similarly associated with aging. Building upon these findings, the purpose of this proposal is to credential pet dogs as a relevant tool for studying CH in the context of onco-aging. Our interdisciplinary team will leverage completed and ongoing studies in pet dogs with cancer to optimize resources necessary to study CH in this species, interrogate how CH evolves in the context of cancer treatment, and explore the impact of CH on the tumor immune microenvironment. We will also employ single cell whole genome sequencing using the new primary template-directed amplification technique to improve sensitivity and precision of variant calling. Lastly, we will validate findings in dogs using biobanked samples from comparable human studies. These studies will establish a blueprint for incorporation of CH analytics into canine translational cancer work, with a future goal of using this unique model system to evaluate novel CH targeted therapies.


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: 2026 ( Subtotal = $693,642 )
2026	2026	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cancer Treatment Research	000	2	7/15/2026	NON-COMPETING CONTINUATION	$693,642
														Subtotal = $693,642

Issue Date FY: 2025 ( Subtotal = $742,391 )
2025	2025	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Cancer Treatment Research	000	1	7/28/2025	NEW	$742,391
														Subtotal = $742,391

Grand Total All Awards = $1,436,033

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Modelling the dynamics of spontaneous clonal hematopoiesis in pet dogs during cancer therapy

Award Number: R01CA294792

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2025

PERIOD OF PERFORMANCE END DATE: 07/31/2030

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