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Linking Genetic, Epigenetic and Signaling Mechanisms of Oncogene Addiction

Award Number: R01CA249229
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Linking Genetic, Epigenetic and Signaling Mechanisms of Oncogene Addiction - PROJECT SUMMARY Our long-term goal is to build a network-level and single-cell understanding of the interplay between genetic, epigenetic and signaling mechanisms that determine the state of MAP kinase (MAPK) pathway dependency in tumor cells. Such understanding will be key to our ability to predict and ultimately improve the responsiveness of tumor cells to therapeutic inhibitors of MAPK signaling. Our focus, in this application, is on BRAFV600 mutated cancers, particularly melanomas, where hyperactivation of MAPK signaling has motivated the clinical evaluation of MAPK-targeted therapies, but they often lead to variable responses and no durable cure in most patients. While genetic alterations are associated with late resistance, epigenetic heterogeneity associated with tumor differentiation state or tissue lineage and its adaptive plasticity within a tumor influence the dynamic state of BRAF/MAPK dependency, thereby diminishing the therapeutic efficacy of MAPK inhibitors. Here, we propose a systems pharmacology approach to test the hypothesis that heterogeneity in the state of MAPK dependency may result from a subset of key epigenetic variations across tumor cells of heterogeneous differentiation states. To identify regulator of such variations, we screened 276 small-molecule epigenetic modulators individually or in combination with BRAF/MEK kinase inhibitors in melanoma cell lines that represent a wide spectrum of differentiation states. Integrating multiplexed single-cell analysis with multivariate statistical modeling and genetic experiments, we identified three classes of inhibitors that target seemingly distinct epigenetic states in melanoma cells: (1) a lysine demethylase 1A (KDM1A)-dependent state associated with undifferentiated (AXLHigh), MAPK inhibitor-resistant (p-ERKHigh) cells, (2) a Jumonji histone demethylase (Jmj-KDM)-dependent state associated with neural crest-like (NGFRHigh/AXLLow) cells, and (3) a state induced by BET bromodomain inhibitors in NGFRHigh cells, which substantially enhances their requirement for MAPK signaling. Single-cell analysis shows that these states might co-exist in different combinations and frequencies, highlighting mutual epigenetic vulnerabilities among genetically diverse melanoma cell populations. In this proposal, we aim to: (1) examine the molecular specificity of the identified small molecule inhibitors as well as mechanisms that govern each of the phenotypically consequential epigenetic states, (2) identify predictors of epigenetic switching in BRAF-mutated cell lines and patient-derived tumors, and (3) test new epigenetic strategies to overcome heterogeneous populations of MAPK inhibitor-tolerant cells in vitro and in vivo. This will be achieved through a systems pharmacology approach, combining genetic experiments, high-throughput single-cell imaging, proteomic measurements, and network-level computational modeling. We will use these tools as a means to measure, model, modulate and ultimately overcome heterogeneous populations of drug- tolerant cells. Our work is expected to provide rational approaches to improve the clinical benefit and durability of treatment response in patients with melanoma and potentially other BRAF-mutated cancers.


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 = $282,800 )
2026	2026	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Treatment Research	000	6	5/12/2026	NON-COMPETING CONTINUATION	$282,800
														Subtotal = $282,800

Issue Date FY: 2025 ( Subtotal = $349,448 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Treatment Research	001	5	5/22/2025	NON-COMPETING CONTINUATION	$34,945
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Treatment Research	000	5	4/7/2025	NON-COMPETING CONTINUATION	$314,503
														Subtotal = $349,448

Issue Date FY: 2024 ( Subtotal = $54,269 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Treatment Research	000	4	5/14/2024	NON-COMPETING CONTINUATION	$54,269
														Subtotal = $54,269

Issue Date FY: 2023 ( Subtotal = $347,713 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Treatment Research	000	3	3/27/2023	NON-COMPETING CONTINUATION	$347,713
														Subtotal = $347,713

Issue Date FY: 2022 ( Subtotal = $347,709 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Treatment Research	000	2	3/30/2022	NON-COMPETING CONTINUATION	$347,709
														Subtotal = $347,709

Issue Date FY: 2021 ( Subtotal = $375,444 )
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Treatment Research	000	1	4/13/2021	NEW	$375,444
														Subtotal = $375,444

Grand Total All Awards = $1,757,383

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Linking Genetic, Epigenetic and Signaling Mechanisms of Oncogene Addiction

Award Number: R01CA249229

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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