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Imaging mitochondrial heterogeneity in LKB1 mutant lung cancer

Award Number: R01CA208642
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2016
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Imaging mitochondrial heterogeneity in LKB1 mutant lung cancer - Abstract (30 line): The overarching goal of this R01 renewal is to advance our understanding of the impact that LKB1 inactivation has on mitochondrial bioenergetics, metabolism and therapy response in lung cancer. To accomplish this we will perform a structural and functional study of mitochondrial heterogeneity following LKB1 inactivation in lung adenocarcinomas (LUADs). Inactivating mutations of the LKB1 tumor suppressor gene frequently occur in LUADs. LKB1 functions as a master kinase that regulates cellular energetics and mitochondrial function through activation of adenosine monophosphate activated kinase (AMPK). As such, LKB1 mutations (LKB1-/-) result in severe defects in the cellular energetics and mitochondrial homeostasis of lung tumors, characterized by atypical mitochondria of varying size, morphology, and function. However, there remains a gap in our knowledge at a physiological and mechanistic level of how LKB1 inactivation disregulates mitochondrial structure and function in LUAD. To address this gap, we functionally imaged mitochondrial activity in LUADs utilizing the positron emission tomography (PET) imaging tracer 4-[18F]fluorobenzyl-triphenylphosphonium (18FBnTP) and found that 18FBnTP is an in vivo biomarker of mitochondrial bioenergetics. Expanding upon this, we performed 3-dimensional scanning blockface electron microscopy (3D SBEM) on lung tumors to map mitochondrial structure in vivo. As a direct result of our analysis of mitochondrial networks within LKB1+/+ and LKB1-/- mouse models of lung cancer we discovered the existence of distinct mitochondrial subpopulations. Each mitochondrial subpopulation carries with it a unique set of bioenergetic activities and sensitivities to apoptosis. Importantly, loss of LKB1 directly alters the structural landscape of mitochondrial subpopulations thus altering the functional, metabolic landscape of the tumor. We hypothesize that LKB1 loss induces remodeling and spatial reorganization of mitochondria subpopulations in lung tumors leading to disregulation of OXPHOS and cell survival pathways. To test this hypothesis we will utilize PET imaging in combination with 3- dimensional scanning blockface electron microscopy (3D SBEM) and respirometry to study mitochondrial heterogeneity LKB1 mutant LUADs. In Aim 1 we will investigate the mTORC1-Drp1 axis as a regulator of mitochondrial fission and cristae remodeling following inactivation of LKB1 in lung tumors. In Aim 2 we will investigate the LKB1/AMPK pathway as a novel regulator of peridroplet mitochondria and fatty acid oxidation in lung cancer. In Aim 3 we will test novel PTPMT1 inhibitors as chemosensitizing agents to overcome therapy resistant LKB1 mutant LUADs. The proposed studies hold promise to advance our fundamental understanding of mitochondrial biology and the impact that mitochondrial heterogeneity has on promoting lung tumorigenesis. The proposed work has relevance to human health in the areas of imaging based diagnosis and the development of new therapies to improve the treatment and outcomes of lung cancer patients.


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 = $429,306 )
2026	2026	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Biology Research	000	9	7/3/2026	NON-COMPETING CONTINUATION	$429,306
														Subtotal = $429,306

Issue Date FY: 2025 ( Subtotal = $429,306 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Biology Research	000	8	5/19/2025	NON-COMPETING CONTINUATION	$429,306
														Subtotal = $429,306

Issue Date FY: 2024 ( Subtotal = $356,924 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Biology Research	001	7	5/8/2024	NON-COMPETING CONTINUATION	$407,842
2024	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Biology Research	000	5	10/1/2023	SUPPLEMENT FOR EXPANSION	-$50,918
														Subtotal = $356,924

Issue Date FY: 2023 ( Subtotal = $266,234 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Biology Research	002	6	6/2/2023	COMPETING CONTINUATION	$429,306
2023	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Biology Research	000	5	4/12/2023	NON-COMPETING CONTINUATION	-$133,407
2023	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Biology Research	001	5	4/12/2023	SUPPLEMENT FOR EXPANSION	-$29,665
														Subtotal = $266,234

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Biology Research	000	5	12/1/2020	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $430,609 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Biology Research	001	5	9/9/2020	SUPPLEMENT FOR EXPANSION	$78,334
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Biology Research	000	5	8/11/2020	NON-COMPETING CONTINUATION	$352,275
														Subtotal = $430,609

Issue Date FY: 2019 ( Subtotal = $411,584 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Biology Research	000	4	8/8/2019	NON-COMPETING CONTINUATION	$341,707
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Biology Research	001	4	8/12/2019	SUPPLEMENT FOR EXPANSION	$69,877
														Subtotal = $411,584

Issue Date FY: 2018 ( Subtotal = $507,587 )
2018	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Biology Research	001	3	8/8/2018	SUPPLEMENT FOR EXPANSION	$71,387
2018	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Biology Research	000	3	7/25/2018	NON-COMPETING CONTINUATION	$352,275
2018	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Biology Research	002	3	8/14/2018	SUPPLEMENT FOR EXPANSION	$83,925
														Subtotal = $507,587

Issue Date FY: 2017 ( Subtotal = $506,848 )
2017	2017	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Biology Research	000	2	7/28/2017	NON-COMPETING CONTINUATION	$352,275
2017	2017	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Biology Research	001	2	8/30/2017	SUPPLEMENT FOR EXPANSION	$71,096
2017	2017	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Biology Research	002	2	8/31/2017	SUPPLEMENT FOR EXPANSION	$83,477
														Subtotal = $506,848

Issue Date FY: 2016 ( Subtotal = $352,275 )
2016	2016	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Biology Research	000	1	8/30/2016	NEW	$352,275
														Subtotal = $352,275

Grand Total All Awards = $3,690,673

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Imaging mitochondrial heterogeneity in LKB1 mutant lung cancer

Award Number: R01CA208642

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2016

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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