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A Convergent Node in Melanoma to Block Multiple Oncogenic Pathways Simultaneously

Award Number: R01CA251608
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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A Convergent Node in Melanoma to Block Multiple Oncogenic Pathways Simultaneously - ABSTRACT Despite recent major advances in targeted therapy for melanoma, the nearly universal eventual acquisition of drug resistance remains a major hurdle that prevents durable gains in patient survival. To address this critical unmet need, we have recently used patient samples and model systems to identify S6K1 as a critical counter-resistance therapy target that lies at the downstream convergence point of the MAPK, CDK4/6, and PI3K pathways. Importantly, these are the primary drivers of both melanomagenesis and of known BRAF and MEK inhibitor resistance mechanisms, positing S6K1, an understudied drug target, as a potential broad-use salvage and/or frontline therapy. Our preliminary data is consistent with this hypothesis, as pharmacological S6K1 inhibition reversed MAPK inhibitor resistance in several drug and genetic contexts. Our central hypothesis is that understanding the mechanistic basis and clinical applicability of S6K1 inhibition in melanoma will allow for improved design of next-generation S6K1 inhibitors and combination therapies, as well as a deeper functional understanding of drug resistance mechanisms operating through and downstream of S6K1. Specific Aim 1 will focus on developing S6K1 as a key drug target in the contexts of both drug resistance and tumor initiation, and its clinical relevance will be interrogated in a series of clinical biopsies. Specific Aim 2 will determine the oncogenic mechanisms downstream of S6K1, with distinct focuses on its impact on cell cycle and metabolism. Overall, successful completion of this study will provide an evidential basis for S6K1 as a promising broad-use therapeutic target, with a mechanistic underpinning to further refine future designs and uses of pharmacological S6K inhibitors.


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 = -$8,911 )
2026	2024	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	5	12/2/2025	NON-COMPETING CONTINUATION	-$8,911
														Subtotal = -$8,911

Issue Date FY: 2024 ( Subtotal = $489,697 )
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	5	6/6/2024	NON-COMPETING CONTINUATION	$489,697
														Subtotal = $489,697

Issue Date FY: 2023 ( Subtotal = $505,159 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	4	6/7/2023	NON-COMPETING CONTINUATION	$505,159
														Subtotal = $505,159

Issue Date FY: 2022 ( Subtotal = $495,751 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	3	7/22/2022	NON-COMPETING CONTINUATION	$495,751
														Subtotal = $495,751

Issue Date FY: 2021 ( Subtotal = $516,411 )
2021	2021	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	2	6/16/2021	NON-COMPETING CONTINUATION	$516,411
														Subtotal = $516,411

Issue Date FY: 2020 ( Subtotal = $519,100 )
2020	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	1	6/11/2020	NEW	$519,100
														Subtotal = $519,100

Grand Total All Awards = $2,517,207

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A Convergent Node in Melanoma to Block Multiple Oncogenic Pathways Simultaneously

Award Number: R01CA251608

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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