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Synergistic combinatorial DNA damage response/repair inhibition and Sacituzumab Govitecan in triple-negative breast cancer

Award Number: R01CA260890
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary The long-term objective of this project is to identify new, more effective, and less toxic therapeutic approaches for triple-negative breast cancer (TNBC), the most aggressive and poor-prognosis breast cancer subtype. Our team recently led the clinical development of the first antibody-drug conjugate (ADC) for metastatic TNBC (mTNBC), Sacituzumab Govitecan (SG, aka Trodelvy), achieving dramatically improved objective response rates (ORRs), progression-free survival (PFS), and overall survival (OS), and resulting in accelerated FDA approval in 2020. SG comprises the topoisomerase 1 (TOP1) inhibitor SN-38 (the active metabolite of irinotecan) coupled to a humanized monoclonal antibody targeting Trop-2, a tumor antigen expressed in >90% of mTNBC. While it represents a paradigm-changing therapy, only approximately 30% of mTNBC patients experience a therapeutic response to SG, highlighting the need to identify combination therapies with SG that will uniquely complement and enhance its efficacy. Our preliminary data lead to the hypothesis that PARP inhibition (PARPi) is synergistic with SG in mTNBC. Accordingly, we are carrying out a funded investigator- initiated phase 1b/2 clinical trial (NCT04039230) of SG and PARPi (talazoparib) for mTNBC, notably delivered via a sequential dosing schedule to minimize toxicity and improve the therapeutic window. Here, our team of clinical, translational, and basic science investigators seeks to move forward the rational therapeutic use of SG and SG/PARPi, and to discover new combinatorial therapies incorporating SG. Our aims are: i) to establish the association of therapeutic response with pre-treatment and pharmacodynamic markers of DNA damage and repair with SG/talazoparib versus SG alone for mTNBC through analysis of clinical trial and other patient samples; ii) to determine mechanisms of resistance to SG monotherapy and SG/PARPi through CRISPR screens and analysis of post-progression patient samples, and to test select druggable targets to overcome them; and iii) to optimize drug scheduling and in vivo efficacy for novel combinations to overcome SG/PARPi resistance. Collectively, these studies will enable and inform the next generation of mechanism-based therapeutic trials investigating SG-based combinatorial therapy for patients with mTNBC.


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 = $503,805 )
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Treatment Research	000	4	12/4/2024	NON-COMPETING CONTINUATION	$503,805
														Subtotal = $503,805

Issue Date FY: 2024 ( Subtotal = $531,794 )
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Treatment Research	001	3	4/22/2024	NON-COMPETING CONTINUATION	$27,989
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Treatment Research	000	3	12/29/2023	NON-COMPETING CONTINUATION	$503,805
														Subtotal = $531,794

Issue Date FY: 2023 ( Subtotal = $548,587 )
2023	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Treatment Research	000	2	1/10/2023	NON-COMPETING CONTINUATION	$503,805
2023	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Treatment Research	001	2	9/22/2023	NON-COMPETING CONTINUATION	$44,782
														Subtotal = $548,587

Issue Date FY: 2022 ( Subtotal = $559,783 )
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Treatment Research	000	1	12/29/2021	NEW	$559,783
														Subtotal = $559,783

Grand Total All Awards = $2,143,969

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Synergistic combinatorial DNA damage response/repair inhibition and Sacituzumab Govitecan in triple-negative breast cancer

Award Number: R01CA260890

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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