Wednesday, January 28, 2026 1/28/2026

Exploiting Ecology and Evolution to Prevent Therapy Resistance in EGFR-Driven Lung Cancer

Award Number: R37CA244613
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Exploiting Ecology and Evolution to Prevent Therapy Resistance in EGFR-Driven Lung Cancer - ABSTRACT Lung cancer is the leading cause of cancer deaths in the USA, with an estimated 158,000 deaths in 2016. The direct cause of the majority of these deaths is the eventual emergence of resistance to initially effective therapies. This evolution of drug resistance represents one of the greatest unmet needs in oncology. While most research is focused on the individual molecular alterations that confer this resistance, we instead propose to focus on the eco-evolutionary processes that generate these alterations. To study the Darwinian evolution and ecological interactions occurring within heterogeneous tumors, we will tightly integrate bespoke mathematical models and experimental techniques designed to inform them. Focusing on EGFR mutated non-small cell lung cancer, a cancer type with a highly efficacious targeted therapy with which we have experience in our lab, we will approach this problem with three, orthogonal, integrated mathematical-experimental Aims. First, to understand the ecological interactions occurring at the inter-cellular level in heterogeneous tumors, we will couple our experience with evolutionary game theory with our first-in-class evolutionary game assay, which we have designed to specifically for this purpose. Here, we hope to learn to target the interactions that drive resistance – a novel strategy which could open up entirely new avenues of drug design. Second, we will allow evolution to show us the convergent phenotypes it creates in the face of specific selective pressures through long-term directed evolution. During this long-term evolution, we will measure phenotype, in the form of drug sensitivity to a panel of chemotherapeutics and targeted therapies at regular intervals, creating the first temporal collateral sensitivity map in any solid tumor. By pooling common phenotypes observed throughout the evolutionary life history, we will then use interactomic and seed-based protocols to generate molecular signatures of these states of sensitivity, which we will validate in publicly available data and in an in library of PDX lines. Finally, we will delve deeply into the relevant time scales of the ecological and evolutionary processes we study in the first two aims. We plan to apply the replicator-mutator framework of evolutionary game theory to a spatial transform that we pioneered in cancer. To validate and parameterize these models, we will also test the evolutionary stability of the ecological dynamics we measure with our game assay by performing the assay through evolutionary time during a long-term evolution experimental. Each of our three orthogonal aims is supported by recent high impact publications, and each represent tightly coupled experimental and computational protocols. Our clean, well- designed integration, together with innovative focus on the direct study of the evolutionary biology, promises to shed light on this difficult area of cancer research, and offers the possibility of providing generalizable insights.


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 = $447,758 )
2026	2026	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Detection and Diagnosis Research	000	7	12/23/2025	NON-COMPETING CONTINUATION	$447,758
														Subtotal = $447,758

Issue Date FY: 2025 ( Subtotal = $497,509 )
2025	2025	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Detection and Diagnosis Research	002	6	6/11/2025	EXTENSION WITH OR WITHOUT FUNDS	$49,752
2025	2025	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Detection and Diagnosis Research	000	6	2/19/2025	EXTENSION WITH OR WITHOUT FUNDS	$447,757
2025	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	001	5	4/21/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $497,509

Issue Date FY: 2024 ( Subtotal = $425,251 )
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	000	5	11/29/2023	NON-COMPETING CONTINUATION	$402,867
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	001	5	4/17/2024	NON-COMPETING CONTINUATION	$22,384
														Subtotal = $425,251

Issue Date FY: 2023 ( Subtotal = $557,982 )
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Detection and Diagnosis Research	001	4	2/22/2023	SUPPLEMENT FOR EXPANSION	$119,304
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	000	4	1/31/2023	NON-COMPETING CONTINUATION	$438,678
														Subtotal = $557,982

Issue Date FY: 2022 ( Subtotal = $702,991 )
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Detection and Diagnosis Research	003	3	12/10/2021	SUPPLEMENT FOR EXPANSION	$50,982
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Detection and Diagnosis Research	005	3	6/9/2022	SUPPLEMENT FOR EXPANSION	$19,870
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	004	3	6/8/2022	NON-COMPETING CONTINUATION	$44,924
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Detection and Diagnosis Research	006	3	6/10/2022	SUPPLEMENT FOR EXPANSION	$5,672
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Detection and Diagnosis Research	002	3	12/9/2021	SUPPLEMENT FOR EXPANSION	$178,836
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	000	3	12/2/2021	NON-COMPETING CONTINUATION	$402,707
2022	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	001	2	12/8/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $702,991

Issue Date FY: 2021 ( Subtotal = $706,792 )
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	002	2	9/17/2021	SUPPLEMENT FOR EXPANSION	$76,968
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	001	2	1/22/2021	NON-COMPETING CONTINUATION	$31,492
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	000	2	12/3/2020	NON-COMPETING CONTINUATION	$598,332
														Subtotal = $706,792

Issue Date FY: 2020 ( Subtotal = $564,909 )
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	001	1	1/17/2020	NEW	$0
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	000	1	11/29/2019	NEW	$459,966
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Detection and Diagnosis Research	005	1	9/23/2020	SUPPLEMENT FOR EXPANSION	$40,000
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Cause and Prevention Research	002	1	1/27/2020	NEW	$8,529
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Detection and Diagnosis Research	004	1	9/21/2020	SUPPLEMENT FOR EXPANSION	$22,102
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Detection and Diagnosis Research	003	1	9/18/2020	SUPPLEMENT FOR EXPANSION	$34,312
														Subtotal = $564,909

Grand Total All Awards = $3,903,192

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Exploiting Ecology and Evolution to Prevent Therapy Resistance in EGFR-Driven Lung Cancer

Award Number: R37CA244613

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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