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Targeting phenethyl isothiocyanate to mitochondria in lung carcinogenesis

Award Number: R01CA280746
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/02/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Targeting phenethyl isothiocyanate to mitochondria in lung carcinogenesis - Project Summary Disruption of normal mitochondrial bioenergetics and oxidative phosphorylation represents an early event during oncogenesis by changing the energy metabolism of precancerous and cancerous cells. Phenethyl isothiocyanate (PEITC), a natural compound present in cruciferous vegetables, has been shown to inhibit the development of several types of cancer in animal models. PEITC has been shown to inhibit oxidative phosphorylation and to induce cancer cell apoptosis through a mitochondria-dependent mechanism and ROS formation, suggesting the role of mitochondrial bioenergetic function and redox homeostasis in oncogenesis. This provides the rationale for conjugating PEITC to a targeting agent that drives it into mitochondria to specifically study the role of mitochondrial function and ROS formation in lung cancer development and to increase the efficacy of PEITC. Preliminary studies demonstrate that mitochondria-targeted PEITC (Mito-PEITC) is a significantly more potent inhibitor of lung carcinogenesis in mice. We hypothesize that lung oncogenesis and metastasis depend on mitochondrial respiration and that Mito-PEITC is a novel, potent inhibitor of lung carcinogenesis and metastasis acting primarily through mitochondrial mechanisms. This hypothesis will be tested using three specific aims. Aim 1 will evaluate the preventive potential and mechanisms of action of Mito-PEITC in vitro. We will use Mito-PEITC and lung cancer cells with genetically modified expression of the members of the mitochondrial electron transport chain to decipher the oncogenic mechanism and evaluate the mechanisms of action of Mito-PEITC. Aim 2 will determine preventive efficacy of Mito-PEITC on lung tumor initiation and progression in A/J mice. Aim 3 will determine the in vivo mechanism and the efficacy of Mito-PEITC to inhibit lung cancer brain metastasis. We will use state-of-the-art in vitro and in vivo assays, including small animal imaging technology to monitor the growth of primary tumors (magnetic resonance imaging) and engraftment of metastatic cells. Innovative approaches for in vivo monitoring of changes in cancer cell bioenergetics and cellular oxidant production (bioluminescence imaging) will be employed. Defining mitochondrial mechanisms of lung oncogenesis and brain metastasis and developing a novel, well-tolerated efficacious agent for prevention and treatment of lung cancer will be highly significant.


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 = $625,471 )
2025	2025	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	001	2	6/12/2025	NON-COMPETING CONTINUATION	$62,546
2025	2025	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	2	1/8/2025	NON-COMPETING CONTINUATION	$562,925
														Subtotal = $625,471

Issue Date FY: 2024 ( Subtotal = $645,107 )
2024	2024	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Cause and Prevention Research	000	1	2/2/2024	NEW	$645,107
														Subtotal = $645,107

Grand Total All Awards = $1,270,578

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Targeting phenethyl isothiocyanate to mitochondria in lung carcinogenesis

Award Number: R01CA280746

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/02/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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