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Lipid Unsaturation Drives Ovarian Cancer Progression

Award Number: R01CA224275
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Lipid Unsaturation Drives Ovarian Cancer Progression - Lipid desaturation is required for generating unsaturated fatty acids (UFAs) which maintain the membrane fluidity and the lipid pool for β-oxidation. UFAs also facilitate cellular signaling and the functioning of the endoplasmic reticulum (ER). Stearoyl-CoA desaturase (SCD) is the key enzyme which catalyzes the addition of double carbon bonds in acyl chains, converting saturated fatty acids (SFAs) to UFAs. Our collaborative research groups have studied how the dynamics between SFAs and UFAs regulated by SCD influences cancer stem cell (CSC) and cancer cell survival under stressful conditions. During the previous funding period, we developed sensitive stimulated Raman spectroscopy (SRS) based methods to measure UFAs and SFAs in live cells and showed that SCD is highly expressed in ovarian tumors compared to fallopian tube epithelium and in CSCs compared to non-CSCs. We demonstrated that SCD is critical to protecting cancer cells from ER and oxidative stress. Based on our preliminary results and evidence from the literature, we hypothesize that lipid unsaturation regulated by SCD improves metabolic fitness of cancer and immune cells, promoting metastasis of high grade serous ovarian cancer (HGSOC). Our project focused on further defining the functions of SCD in HGSOC proposes this enzyme as a potential new cancer target. In this revised renewal application we will pursue three research objectives which address the remaining gap in knowledge. Aim 1: We will determine single-cell- level SCD activity by mid-infrared photothermal (MIP) imaging and demonstrate that elevated SCD activity is a cellular response to oxidative stress. We will apply the methods developed here to the research questions addressed in the other Aims. Aim 2: We will demonstrate how the balance between UFAs and SFAs regulated by SCD promotes metastatic dissemination. We will measure the effects of SCD overexpression, knockdown or inhibition on metastasis in HGSOC orthotopic models and we will assess the dependence of cells that survive the process of dissemination on SCD activity in response to ER and oxidative stress. We will define mechanisms of resistance to SCD inhibitors. Aim 3: Lastly, we will investigate how SCD modulates anti-tumor immune responses in the tumor microenvironment by using syngeneic ovarian cancer models. We will measure the effects of SCD inhibition on immune cell infiltration in the peritoneal milieu and the possibility of augmenting the effects of immune checkpoint inhibitors by blocking SCD. Three collaborating MPIs will use mechanistic biological assays, murine models of ovarian cancer, and metabolic imaging techniques to dissect the roles of unsaturated lipids in cancer. The results will define the effects of SCD inhibitors in HGSOC and lead to new options to target this deadly cancer.


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 = $641,081 )
2026	2026	THE METHODIST HOSPITAL RESEARCH INSTITUTE	6565 FANNIN ST STE D200	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	6	6/18/2026	COMPETING CONTINUATION	$641,081
														Subtotal = $641,081

Issue Date FY: 2025 ( Subtotal = -$106,337 )
2025	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	000	5	1/2/2025	NON-COMPETING CONTINUATION	-$106,337
														Subtotal = -$106,337

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	000	5	11/29/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $507,981 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	001	5	7/21/2022	NON-COMPETING CONTINUATION	$507,981
2022	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	000	4	1/26/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $507,981

Issue Date FY: 2021 ( Subtotal = $650,166 )
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	001	4	8/6/2021	NON-COMPETING CONTINUATION	$0
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	000	4	7/30/2021	NON-COMPETING CONTINUATION	$533,761
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	002	4	8/6/2021	SUPPLEMENT FOR EXPANSION	$116,405
														Subtotal = $650,166

Issue Date FY: 2020 ( Subtotal = $662,790 )
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	000	3	8/19/2020	NON-COMPETING CONTINUATION	$547,720
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	001	3	9/16/2020	SUPPLEMENT FOR EXPANSION	$115,070
														Subtotal = $662,790

Issue Date FY: 2019 ( Subtotal = $551,416 )
2019	2019	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	000	2	7/31/2019	NON-COMPETING CONTINUATION	$551,416
														Subtotal = $551,416

Issue Date FY: 2018 ( Subtotal = $567,557 )
2018	2018	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	000	1	8/1/2018	NEW	$567,557
														Subtotal = $567,557

Grand Total All Awards = $3,474,654

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Lipid Unsaturation Drives Ovarian Cancer Progression

Award Number: R01CA224275

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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