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Developing and credentialing patient-derived xenograft models to advance therapeutic approaches for chronic myelomonocytic leukemia

Award Number: R37CA234021
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract Chronic Myelomonocytic Leukemia (CMML) is a lethal subtype of leukemia characterized by cytopenias, marrow dysplasia, monocytosis, and a propensity for transformation to acute myeloid leukemia (AML). Until this R37 parent grant, no mouse model of CMML, to include genetically engineered mice harboring CMML mutations, had recapitulated the unique clinical or histological characteristics of the human disease. We have overcome this limitation and generated phenotypically and genetically accurate PDX models of 92 CMML patients through the use of modified NOD/SCID IL2R null (NSG) mouse strains expressing human cytokines that uniquely drive CMML. Moreover, we have utilized these PDX models to identify novel therapies targeting aberrant cytokine- signaling characteristics and mRNA splicing in specific genetic subsets of CMML. In this R37 extension we propose to leverage our CMML PDX model to study a previously unrecognized observation we have made that approximately 20% of CMML patients harbor a very small concomitant mast cell clone. Because these cases are clinically and genetically unique, we hypothesize that there may be an ongoing but unknown biologic cooperativity in these patients. However, to study this accurately, new in vivo systems are needed to model this clone-to-clone communication. We aim to achieve this with our CMML PDX models in two specific aims: In Aim 1 we will generate the first hybrid CMML PDX in which mast cells will be additionally heterotopically xenografted with the goal of modeling clone-to-clone communication. Because our preliminary data suggest that subclonal mast cells may be derived from the same ancestral stem cell as CMML, we will also retrospectively determine if CMML and de novo mast cells were previously xenografted in CMML PDX models already generated from patients with occult subclonal mast cells. Last, we will use these models to identify secreted factors and annotate the clonal architecture of these patients at single cell resolution. In Aim 2 we will determine if SF3B1 mutated clones have distinct biologic cooperativity and secreted factors. Our preliminary clinical data suggests that SF3B1 mutations are enriched in patients with subclonal mast cells. We hypothesize that this is due to a unique genotype specific cooperativity. We will evaluate this by xenografting isogenic leukemic cells with and without SF3B1 mutation in the context of a concomitant mast cell tumor. We will also compare CMML PDX models with and without concomitant mast cell tumors in the context of SF3B1 mutation generated in aim 1. Last, we will compare the secreted factors and clonal trajectories identified in Aim 1 in SF3B1 mutant versus wild type CMML PDX. Collectively, this extension will build on the parent grant by using our CMML PDX model to explore novel biology that could translate to a better understanding of the disease and novel therapeutic strategies.


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: 2024 ( Subtotal = $453,813 )
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	6	8/29/2024	EXTENSION WITH OR WITHOUT FUNDS	$453,813
														Subtotal = $453,813

Issue Date FY: 2023 ( Subtotal = $486,704 )
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	5	8/1/2023	NON-COMPETING CONTINUATION	$486,704
														Subtotal = $486,704

Issue Date FY: 2022 ( Subtotal = $496,638 )
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	4	7/31/2022	NON-COMPETING CONTINUATION	$496,638
														Subtotal = $496,638

Issue Date FY: 2021 ( Subtotal = $496,638 )
2021	2021	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	3	8/13/2021	NON-COMPETING CONTINUATION	$496,638
														Subtotal = $496,638

Issue Date FY: 2020 ( Subtotal = $496,640 )
2020	2020	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	2	7/31/2020	NON-COMPETING CONTINUATION	$496,640
														Subtotal = $496,640

Issue Date FY: 2019 ( Subtotal = $514,636 )
2019	2019	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	1	8/12/2019	NEW	$514,636
														Subtotal = $514,636

Grand Total All Awards = $2,945,069

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Developing and credentialing patient-derived xenograft models to advance therapeutic approaches for chronic myelomonocytic leukemia

Award Number: R37CA234021

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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