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Characterizing cytotoxic therapy induced shifts in the cost-to-benefit ratio of high ploidy

Award Number: R37CA266727
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Characterizing cytotoxic therapy induced shifts in the cost-to-benefit ratio of high ploidy - SUMMARY Traditional phase I dose-finding strategies monitor drug response only for two weeks, based on the assumption that it will suﬃce to observe how therapy aﬀects doubling time of a homogeneous population over 2-4 generations. But with the paradigm shift that most cancers are heterogeneous comes an urgent need to consider that therapy-induced shifts in population composition manifest over longer time frames. We previously coined the “tip-over hypothesis of DNA damage therapy sensitivity”, proposing that cytotoxic therapy is eﬀective if it pushes a cell’s somatic copy number alteration (SCNA) load above a tipping point. Variable proximity of co-existing tumor cells to this tipping point imply that dose-response relations need not be monotonic. Cytotoxic therapy can drive one cell into apoptosis, while skyrocketing another cell into malignant proliferation. As the developers of widely used computational and mathematical methods, with established research programs in tumor metabolism, and with a broad record of modeling dynamic processes and integrating various omics- and imaging platforms, our team brings complementary expertise to develop a personalized cytotoxic therapy strategy that confines therapy-induced selection of resistant clones. We will test the potential of tumor cell DNA content and dNTP substrate availability to predict a tumor’s vulnerability to increasing SCNA rate. Hereby, the aforementioned tipping point is accounted for not by elevated SCNA load alone, but by an inability of the tissue micro-environment (TME) to provide the necessary resources. Experiments are proposed in stomach and brain tumors—two cancer types whose TME can “aﬀord” vastly diﬀerent amounts of DNA. Our preliminary studies show that energetic costs of DNA content levels required for >75% SCNA load do not, in the absence of cytotoxic therapy, justify the masking benefits they bring. In particular, we showed that limiting dNTP concentrations amplify divergence in S-phase duration between high- and low-ploidy cells. Our hypothesis is that cytotoxic therapy causes a net-increase in fitness of tumors that exceed the SCNA tipping point. This hypothesis is founded on two unexpected recent findings: (i) integrated single-cell RNA- and DNA-sequencing analyses of stomach cancer cells suggests that the risk of cell death immediately after an SCNA event, rather than just SCNA rate, impacts clonal diversity. Aim 1 will integrate single cell sequencing with imaging and mathematical modeling of heterogeneous populations that evolve through chromosome missegregations, to examine observed SCNA landscapes and missegregation tolerances, and to predict effective cytotoxic therapy doses. (ii) Even minimal changes in DNA content among co-existing clones within the same Glioblastoma can result in significantly longer S-phases. Aim 2 will evaluate Oxygen, Phosphate and Glucose as rate-limiting substrates of dNTP synthesis of co-evolving subpopulations in stomach and brain tissue environments. This is the first study to investigate if and how clinical decisions can benefit from integrating a tumor environment’s energetic provision with the energetic demands of cancer cells’ genomic makeup.


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 = $520,099 )
2026	2026	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	5	9/7/2026	NON-COMPETING CONTINUATION	$520,099
														Subtotal = $520,099

Issue Date FY: 2025 ( Subtotal = $562,055 )
2025	2025	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	4	8/25/2025	NON-COMPETING CONTINUATION	$562,055
														Subtotal = $562,055

Issue Date FY: 2024 ( Subtotal = $480,392 )
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	3	8/21/2024	NON-COMPETING CONTINUATION	$480,392
														Subtotal = $480,392

Issue Date FY: 2023 ( Subtotal = $532,569 )
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	2	8/29/2023	NON-COMPETING CONTINUATION	$532,569
														Subtotal = $532,569

Issue Date FY: 2022 ( Subtotal = $520,099 )
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Biology Research	000	1	8/22/2022	NEW	$520,099
														Subtotal = $520,099

Grand Total All Awards = $2,615,214

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Characterizing cytotoxic therapy induced shifts in the cost-to-benefit ratio of high ploidy

Award Number: R37CA266727

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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