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Chemoprevention of lung cancer by targeting lonidamine to mitochondria

Award Number: R01CA232433
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Chemoprevention of lung cancer by targeting lonidamine to mitochondria - PROJECT SUMMARY Lung cancer is the leading cause of cancer death in the United States. The development of new and effective chemopreventive agents for lung cancer is urgently needed. Our long-term goal is to identify and advance new and efficacious preventive agents targeting human lung cancer. There is growing evidence that distinct tumor- specific metabolic changes, including reliance on aerobic glycolysis and changes in mitochondrial bioenergetics, are key drivers of malignancy. We made chemical modifications to lonidamine (LON), an anti-glycolytic compound with limited anti-tumor efficacy, to create Mito-LON as a more effective and safe mitochondria- targeted, tumor cell selective agent with a new mechanism, specifically OXPHOS inhibition. Our preliminary data show that Mito-LON, at low micromolar concentrations, is a potent inhibitor of cancer cell mitochondrial bioenergetics, and results in pronounced mitigation of lung cancer development, cell proliferation, growth, progression, and metastasis. We hypothesize that Mito-LON inhibits lung tumor development and metastasis through induction of autophagic cell death (ACD) by suppressing mitochondrial complexes I and II, depleting cellular ATP, stimulating ROS formation, and subsequent effects on AKT/mTOR/p70S6K signaling. We will test our hypothesis in three specific aims. Aim 1 will determine the effects of Mito-LON on mitochondrial bioenergetics and redox status in cellular systems in vitro. Aim 2 will determine the capacity of Mito-LON to induce ACD, with a focus on mitophagy, as a mechanism to mitigate lung cancer progression and metastasis. Aim 3 will determine the capacity of Mito-LON to inhibit lung tumor progression and lung cancer brain metastasis in vivo. We will use state-of-the-art small animal imaging to monitor the growth of primary tumors (using magnetic resonance imaging) and brain metastasis (through bioluminescence imaging). Successful completion of these aims will increase our understanding of the molecular basis of autophagy in the context of lung cancer inhibition and more broadly establish a new approach for using mitochondria-targeting drugs to effectively and selectively block cancer cell metabolism, energy generation, and induce ACD. This proposal is timely and significant since future clinical trials of Mito-LON against lung cancer will require vigorous preclinical characterization of the efficacy and precise mechanisms of action in targeting cancer metabolism.


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 = $0 )
2026	2023	THE METHODIST HOSPITAL RESEARCH INSTITUTE	6565 FANNIN ST STE D200	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	5	1/12/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $383,989 )
2023	2023	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	5	7/25/2023	NON-COMPETING CONTINUATION	$383,989
														Subtotal = $383,989

Issue Date FY: 2022 ( Subtotal = $383,991 )
2022	2022	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	002	4	8/19/2022	NON-COMPETING CONTINUATION	$383,991
2022	2021	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	001	3	1/4/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$103,880
2022	2020	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Cause and Prevention Research	000	2	1/4/2022	NON-COMPETING CONTINUATION	-$103,880
														Subtotal = $383,991

Issue Date FY: 2021 ( Subtotal = $422,579 )
2021	2021	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	3	9/15/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$422,579
2021	2020	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Cause and Prevention Research	001	2	9/17/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $422,579

Issue Date FY: 2020 ( Subtotal = $382,111 )
2020	2020	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Cause and Prevention Research	000	2	4/8/2020	NON-COMPETING CONTINUATION	$382,111
														Subtotal = $382,111

Issue Date FY: 2019 ( Subtotal = $378,872 )
2019	2019	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Cancer Cause and Prevention Research	000	1	4/15/2019	NEW	$378,872
														Subtotal = $378,872

Grand Total All Awards = $1,951,542

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Chemoprevention of lung cancer by targeting lonidamine to mitochondria

Award Number: R01CA232433

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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