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Crosstalk Between the ER Stress Response and Mitochondrial Fatty Acid Oxidation in MYC-driven Breast Cancer

Award Number: R37CA228304
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/12/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Crosstalk Between the ER Stress Response and Mitochondrial Fatty Acid Oxidation in MYC-driven Breast Cancer - ABSTRACT It is well known that cancer metabolism is highly dynamic and context- and oncogene-dependent. However, the underlying mechanism, particularly that of interorganelle communication in oncogene-dependent metabolic reprogramming, is largely unknown. Our preliminary studies establish that oncogenic MYC regulates Endoplasmic Reticulum (ER)-localized transmembrane sensor IRE1a and its substrate XBP1 via multiple mechanisms. Importantly, our pilot studies suggest the increased susceptibility of MYC-overexpressing triple negative breast cancer (TNBC) to IRE1a/XBP1 inhibition, possibly mediated via altered interorganelle communication and metabolic reprogramming to fatty acid oxidation (FAO). These findings provide a framework to seek biological insight into this altered communication between the ER, mitochondria, and nucleus in MYC-overexpressing TNBC cells, and to further explore the effects of pharmacological inhibition of IRE1a as an anti-tumor approach for MYC-driven TNBC by disrupting the interorganelle communication. We hypothesize that oncogenic MYC hijacks the ER stress sensor IRE1a, and its substrate XBP1, to promote mitochondrial FAO and sustain TNBC tumorigenesis and resistance to chemotherapy. This proposal will elucidate the function and mechanism of the ER in regulating MYC-driven oncogenic stress and mitochondrial metabolic reprogramming in TNBC. In Aim 1, we will investigate the biological significance of IRE1a/XBP1 mediated ER-nucleus communication in MYC-driven TNBC. Aim 2 will determine the role of mitochondrial FAO activation by the IRE1α/XBP1 pathway in MYC-driven TNBC. Lastly, Aim 3 will investigate the in vivo efficacy and mechanisms of combination therapy with IRE1a inhibitor and docetaxel in treating MYC-driven TNBC. The updated Aims for the 2-year extension period are based on the data generated from the original aims and represent a logical extension of the original aims to study the IRE1-mediated metabolic reprogramming and organelle dysfunction in regulating immunogenic cell death of MYC-driven TNBC. The resulting data from this proposal will be significant as they will promote the development of novel, mechanism-based therapeutic approaches to disrupt these altered metabolic pathways and improve the treatment of MYC-driven TNBC.


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 = -$3,484 )
2026	2024	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	7	12/4/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$3,484
														Subtotal = -$3,484

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	7	1/27/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$88,527
2025	2024	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	003	7	1/27/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$247,521
2025	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	002	6	1/27/2025	EXTENSION WITH OR WITHOUT FUNDS	-$247,521
2025	2022	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	1/27/2025	NON-COMPETING CONTINUATION	-$88,527
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $355,307 )
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 Biology Research	001	7	9/11/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$355,307
2024	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	6	9/11/2024	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $355,307

Issue Date FY: 2023 ( Subtotal = $358,680 )
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	6	7/14/2023	EXTENSION WITH OR WITHOUT FUNDS	$358,680
														Subtotal = $358,680

Issue Date FY: 2022 ( Subtotal = $362,569 )
2022	2022	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	7/1/2022	NON-COMPETING CONTINUATION	$362,569
														Subtotal = $362,569

Issue Date FY: 2021 ( Subtotal = $362,569 )
2021	2021	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	4	7/1/2021	NON-COMPETING CONTINUATION	$362,569
2021	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	3	3/5/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $362,569

Issue Date FY: 2020 ( Subtotal = $362,569 )
2020	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	3	6/4/2020	NON-COMPETING CONTINUATION	$362,569
														Subtotal = $362,569

Issue Date FY: 2019 ( Subtotal = $351,691 )
2019	2019	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	2	6/6/2019	NON-COMPETING CONTINUATION	$351,691
														Subtotal = $351,691

Issue Date FY: 2018 ( Subtotal = $362,569 )
2018	2018	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	7/12/2018	NEW	$362,569
														Subtotal = $362,569

Grand Total All Awards = $2,512,470

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Crosstalk Between the ER Stress Response and Mitochondrial Fatty Acid Oxidation in MYC-driven Breast Cancer

Award Number: R37CA228304

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/12/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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