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Reading mitochondrial apoptotic signaling to identify active cancer therapeutics

Award Number: R35CA242427
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2019
PERIOD OF PERFORMANCE END DATE: 09/29/2025

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Reading mitochondrial apoptotic signaling to identify active cancer therapeutics - Summary I am an oncologist and cancer biologist supervising a laboratory focused on identifying therapies that selectively induce apoptosis in cancer cells. My initial contributions to the apoptosis field came with separating certain pro-death BCL-2 family BH3-only proteins into “sensitizers” and “activators” based on pro-apoptotic function. This finding drove my interest in the possibilities of inhibiting BCL-2 function with drugs that mimicked the BH3 domain of pro-apoptotic proteins. I designed the first mouse model that demonstrated that loss of BCL-2 function by itself could be sufficient to drive a cancer into remission. Following this, I designed a tool called BH3 profiling – exposing mitochondria to synthetic oligo-peptides based on the amphipathic alpha- helical BH3 domains of proapoptotic proteins and measuring mitochondrial outer membrane permeabilization (MOMP). By using certain selectively-interacting BH3 peptides, I could use BH3 profiling to identify cells that were especially sensitive to BH3 inhibition. I used BH3 profiling to help launch clinical trial programs of the BCL-2 inhibitor venetoclax in several diseases. Most successful among these so far have been programs in chronic lymphocytic leukemia and acute myelogenous leukemia, the former of which has already yielded FDA approvals. Using different BH3 peptides, BH3 profiling can measure overall apoptotic priming, or proximity to the threshold of apoptosis. We used this aspect to demonstrate that differential apoptotic priming is perhaps the most significant determinant of successful chemotherapy treatment. Moreover, differential apoptotic priming is the main reason that there is a therapeutic index for conventional chemotherapy – most non-malignant somatic cells are far less primed for apoptosis than chemosensitive cancer cells. Building on this finding, we asked whether we could identify drugs that could enhance apoptotic priming selectively in cancer cells. We found that we could measure increased apoptotic priming within hours of exposing cancer cells to effective drugs using dynamic BH3 profiling (DBP). Increased priming is measured as increased sensitivity of mitochondria in treated cells to BH3 peptides compared to untreated controls. Over the past few years, we have found that an increased priming by a drug in DBP is an excellent predictor of in vivo activity in human and mouse models, in solid and liquid tumors. An important advantage of DBP over most other ex vivo drug sensitivity strategies is that DBP requires no more than 24 hours of ex vivo culture. This overcomes the major obstacle to the general application of such strategies, since many cancers cannot adapt to long-term ex vivo culture, and if they do, they are phenotypically altered so as to degrade the information they can provide. We are exploring DBP as a discovery tool and predictive biomarker in many liquid and solid tumors. Moreover, we are using it as a tool to identify drugs that can make target tumor cells more sensitive to immuno-oncology therapies.


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	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	7	11/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $1,060,200 )
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	7	7/1/2025	NON-COMPETING CONTINUATION	$1,060,200
														Subtotal = $1,060,200

Issue Date FY: 2024 ( Subtotal = $1,007,191 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	6	7/31/2024	NON-COMPETING CONTINUATION	$1,007,191
														Subtotal = $1,007,191

Issue Date FY: 2023 ( Subtotal = $1,016,184 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	5	6/19/2023	NON-COMPETING CONTINUATION	$1,016,184
														Subtotal = $1,016,184

Issue Date FY: 2022 ( Subtotal = $1,038,996 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	4	7/21/2022	NON-COMPETING CONTINUATION	$1,038,996
														Subtotal = $1,038,996

Issue Date FY: 2021 ( Subtotal = $1,037,388 )
2021	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	3	7/30/2021	NON-COMPETING CONTINUATION	$1,037,388
														Subtotal = $1,037,388

Issue Date FY: 2020 ( Subtotal = $1,060,200 )
2020	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	2	6/17/2020	NON-COMPETING CONTINUATION	$1,060,200
														Subtotal = $1,060,200

Issue Date FY: 2019 ( Subtotal = $810,207 )
2019	2019	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	1	7/26/2019	NEW	$810,207
														Subtotal = $810,207

Grand Total All Awards = $7,030,366

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Reading mitochondrial apoptotic signaling to identify active cancer therapeutics

Award Number: R35CA242427

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2019

PERIOD OF PERFORMANCE END DATE: 09/29/2025

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