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Decoding And Targeting The LKB1-AMPK Signaling Pathway In Cancer

Award Number: R35CA220538
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2017
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Decoding And Targeting The LKB1-AMPK Signaling Pathway In Cancer - Summary / Abstract Research over the past decade has begun to reveal several direct linkages between genes mutated in human cancer and genes that control cell metabolism. The LKB1 tumor suppressor is a serine/threonine kinase mutationally inactivated in the familial cancer disease Peutz-Jeghers Syndrome, as well as in ~25% of non-small cell lung cancers, making it the third most frequent gene altered in this cancer type, which is responsible for the most deaths by cancer each year. Thirteen years ago, the Shaw lab and others discovered that LKB1 directly phosphorylates the activation loop of the AMP-activated protein kinase (AMPK) and 12 related kinases. AMPK is a serine/threonine kinase that is activated by LKB1 under conditions of low cellular energy, such as those that accompany loss of nutrients, in particular glucose and oxygen. AMPK plays a highly conserved role as an energy sensor and acts to restore metabolic homeostasis on a cellular and ultimately organismal level by downregulating anabolic biosynthetic ATP- consuming processes (like protein and lipid biosynthesis), and upregulating catabolic ATP-restoring processes (like autophagy and fatty acid oxidation). Studies by the Shaw lab over the past decade have sought to: 1) understand the mechanistic basis for how AMPK reprograms growth and metabolism by decoding direct substrates of AMPK that mediate its downstream effects, and 2) identify new cancer therapy approaches based on their understanding of the rate-limiting nodes of metabolism and growth that AMPK endogenously utilizes under low energy conditions. The Shaw lab has used a number of genetically engineered mouse models of non-small cell lung cancer to perform preclinical studies with novel cancer metabolism drugs, and this grant builds upon their expertise accumulated over the past decade. Three lines of research are proposed. First, advances in proteomics and genetic technologies will be used by the Shaw lab to conduct phospho-proteome screens in primary tumors that are with or without intact LKB1 to identify relevant targets required for tumor suppression in lung. These events will be rapidly modeled genetically in cell lines and ultimately in murine cancer models using CRISPR. Second, based on their understanding of how AMPK inhibits growth, the Shaw lab has explored the use of direct inhibitors of the lipogenesis enzyme Acetyl-CoA carboxylase (ACC) and found broad anti-cancer activity in genetic models of lung cancer. This proposal seeks to examine whether other fatty acid synthesis enzymes may offer therapeutic windows in lung cancer. Third, this proposal will explore the role of AMPK and its target the autophagy kinase ULK1 in promoting tumor cell survival, particularly in the context of therapeutic response. Altogether, these studies emphasize the need to gain a deep understanding of the molecular wiring of this signaling network and how it interfaces with key cellular processes in order to reveal novel vulnerabilities that can be exploited to selectively kill cancer cells.


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: 2025 ( Subtotal = $0 )
2025	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	7	2/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $1,140,000 )
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	8	8/1/2024	COMPETING CONTINUATION	$1,140,000
														Subtotal = $1,140,000

Issue Date FY: 2023 ( Subtotal = $1,140,720 )
2023	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	7	7/20/2023	NON-COMPETING CONTINUATION	$1,140,720
														Subtotal = $1,140,720

Issue Date FY: 2022 ( Subtotal = $1,140,720 )
2022	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	6	7/18/2022	NON-COMPETING CONTINUATION	$1,140,720
														Subtotal = $1,140,720

Issue Date FY: 2021 ( Subtotal = $1,164,000 )
2021	2021	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	5	7/9/2021	NON-COMPETING CONTINUATION	$1,164,000
														Subtotal = $1,164,000

Issue Date FY: 2020 ( Subtotal = $1,164,000 )
2020	2020	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	4	7/23/2020	NON-COMPETING CONTINUATION	$1,164,000
														Subtotal = $1,164,000

Issue Date FY: 2019 ( Subtotal = $1,129,078 )
2019	2019	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	3	7/4/2019	NON-COMPETING CONTINUATION	$1,129,078
														Subtotal = $1,129,078

Issue Date FY: 2018 ( Subtotal = $1,164,000 )
2018	2018	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	2	7/9/2018	NON-COMPETING CONTINUATION	$1,164,000
														Subtotal = $1,164,000

Issue Date FY: 2017 ( Subtotal = $996,270 )
2017	2017	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	1	8/1/2017	NEW	$996,270
														Subtotal = $996,270

Grand Total All Awards = $9,038,788

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Decoding And Targeting The LKB1-AMPK Signaling Pathway In Cancer

Award Number: R35CA220538

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2017

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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