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Identifying Combination Therapies in Ovarian Tumors using High Throughput Dynamic BH3 Profiling

Award Number: F32CA254118
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Identifying Combination Therapies in Ovarian Tumors using High Throughput Dynamic BH3 Profiling - Project Summary/Abstract Ovarian cancer is the fifth leading cause of cancer deaths overall in women. The most recent estimates indicate that over 20,000 new cases will be diagnosed this year and nearly 14,000 women will die of the disease in the US in 2019 alone. The platinum-based standard of care cytotoxic regimen has remained largely stagnant for the last 15 years and recurrent disease is frequently platinum-resistant. Despite some recent success using molecular targeted agents and maintenance therapies (such as PARP inhibitors), the genetic complexity and lack of common molecular drivers make predicting patient responses difficult. Additionally, in relapsed patients, molecular changes induced by cancer therapies are multifaceted. Combining multiple drugs to treat ovarian cancer may be the most direct path to overcoming this intra-tumoral heterogeneity and acquired resistance to achieve more durable clinical responses. In an effort to capitalize on drugs that are approved and show patient benefit, this proposal seeks to identify compounds that can sensitize cells to apoptosis when combined with one of three drugs that act as cornerstones in ovarian cancer therapy: carboplatin, the PARP inhibitor olaparib, and doxorubicin. In the first aim a novel high-throughput screening platform called high-throughput dynamic BH3 profiling, will be used to identify whether a 24-hour ex vivo chemical treatment sensitizes tumor cells to mitochondrial mediated apoptosis. This will be performed using three ovarian cancer models: (1) freshly isolated tumor cells from primary patient ascites fluid, (2) organoid cultures derived from primary tumors, and (3) ovarian tumor cell lines. Preliminary data indicates that BH3 mimetics in combination with the standard of care drugs can increase apoptotic induction. In the second aim, the mechanism of drug-induced BH3 mimetic sensitivity will be investigated on the cellular, mitochondrial, and molecular level to determine which cellular contexts are likely to benefit from specific BH3 mimetic combinations. In the third and final aim compounds identified that increase apoptotic induction in combination with each of the three standard of care drugs will be tested in recently developed patient-derived luciferized tumor xenograft models of ovarian cancer. This will provide in vivo validation of the ability of specific drug combinations to cause tumor regression. This innovative approach offers both the potential to identify effective combinations to use in the platinum-sensitive, PARP-sensitive, and platinum-resistant settings, and the opportunity to determine molecular features that can identify populations that would benefit from these combinations. Supplementing the research component of the proposal with select courses and workshops, engagement in research meetings and seminars, and participation in scientific conferences will ensure an understanding of current concepts and techniques, constant feedback regarding the project's results and progress, and enhanced exposure to more translational work. Collectively, the research and training plan will provide a strong foundation upon which to build a career as a productive, independent cancer researcher.


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 = -$23,290 )
2025	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Research Manpower	002	3	1/23/2025	NON-COMPETING CONTINUATION	-$23,290
2025	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Research Manpower	001	3	11/20/2024	NON-COMPETING CONTINUATION	$0
2025	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Research Manpower	000	2	11/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = -$23,290

Issue Date FY: 2023 ( Subtotal = $73,772 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Research Manpower	002	3	8/28/2023	NON-COMPETING CONTINUATION	$0
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	001	3	5/22/2023	NON-COMPETING CONTINUATION	$2,038
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	000	3	11/28/2022	NON-COMPETING CONTINUATION	$71,734
														Subtotal = $73,772

Issue Date FY: 2022 ( Subtotal = $69,802 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	000	2	12/6/2021	NON-COMPETING CONTINUATION	$68,562
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	001	2	6/9/2022	NON-COMPETING CONTINUATION	$1,240
														Subtotal = $69,802

Issue Date FY: 2020 ( Subtotal = $65,310 )
2020	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Research Manpower	000	1	8/12/2020	NEW	$65,310
														Subtotal = $65,310

Grand Total All Awards = $185,594

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Identifying Combination Therapies in Ovarian Tumors using High Throughput Dynamic BH3 Profiling

Award Number: F32CA254118

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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