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Stapled Peptides for Protein Interaction Research and Therapeutic Targeting in Human Cancer

Award Number: R50CA211399
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2016
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Stapled Peptides for Protein Interaction Research and Therapeutic Targeting in Human Cancer - PROJECT SUMMARY / ABSTRACT Deregulated protein interactions contribute to the development, maintenance, and chemoresistance of human cancer. The critical contact points of cancer-causing proteins are often mediated by so-called “helix-in-groove” interactions, whereby an alpha-helical subcomponent of one protein inserts into the surface groove of another to drive oncogenic signaling. For example, BCL-2 family proteins regulate the critical balance between cellular life and death and cancer cells overexpress the anti-apoptotic members, which contain a surface groove that effectively traps the “killer” helix of pro-apoptotic members, to enforce cellular immortality. We have inserted all- hydrocarbon struts into natural alpha-helices to restore their shape, stability, and bioactivity so that they can be used as both powerful chemical tools to dissect oncogenic protein interactions and as prototype therapeutics to drug them. Over the last 15 years, I have developed special expertise in the design of stapled peptides for diverse applications in cancer research and treatment. I have generated spin-labeled analogs for NMR structural analyses, photoreactive constructs for rapid binding-site analysis by mass spectrometry, cysteine-reactive variants for covalent targeting of oncogenic proteins, fluorescent derivatives for binding affinity quantitation and cellular imaging, radiolabeled constructs for in vivo imaging, and iteratively-optimized analogs for preclinical testing and translation. The remarkable impact of stapled peptides is best reflected by their capacity to identify new cancer targets, mechanisms, and druggable binding sites and their advancement to clinical trials in adults and children with relapsed cancers. The goal of this competitive renewal application is to continue to expand the breadth and depth of stapled peptide innovation in support of critical cancer research programs that harness these reagents in proteomic discovery, structural determination, mechanism-of-action studies, and therapeutic development. Specifically, I aim to robustly support the NCI-funded R35 research program of my Unit Director, Dr. Loren Walensky, who as a chemical biologist and pediatric oncologist, focuses on characterizing the BCL-2 family interaction mechanisms that drive human cancer by neutralizing the mitochondrial apoptosis pathway. Reactivating apoptosis in cancer is essential to overcoming chemoresistance and the pathologic alpha-helical interactions of the BCL-2 family are ideally suited for interrogation by stapled peptides. In running the Stapled Peptide Design Group of the Walensky lab and Dana-Farber’s Program in Cancer Chemical Biology, I am personally responsible for developing and optimizing the chemistry that drives stapled peptide innovations, and creating a high-throughput consultation, production, purification, quantitation, and characterization workflow that is also relied upon by dozens of our internal and external collaborators. As a Research Specialist operating at the interface of chemistry, cancer biology, and experimental therapeutics, I am committed to mining the potential of next-generation stapled peptides to advance our understanding of fundamental oncogenic mechanisms and to create novel therapeutics for cancer treatment.


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: 2024 ( Subtotal = $332,082 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	9	8/19/2024	NON-COMPETING CONTINUATION	$332,082
														Subtotal = $332,082

Issue Date FY: 2023 ( Subtotal = $332,082 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	8	8/22/2023	NON-COMPETING CONTINUATION	$332,082
														Subtotal = $332,082

Issue Date FY: 2022 ( Subtotal = $332,082 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	002	7	8/12/2022	NON-COMPETING CONTINUATION	$332,082
2022	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	6	11/29/2021	COMPETING CONTINUATION	$40,130
2022	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	5	11/29/2021	NON-COMPETING CONTINUATION	-$40,130
														Subtotal = $332,082

Issue Date FY: 2021 ( Subtotal = $332,082 )
2021	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	6	9/21/2021	COMPETING CONTINUATION	$332,082
														Subtotal = $332,082

Issue Date FY: 2020 ( Subtotal = $264,110 )
2020	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	5	7/23/2020	NON-COMPETING CONTINUATION	$264,110
														Subtotal = $264,110

Issue Date FY: 2019 ( Subtotal = $264,110 )
2019	2019	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	4	8/1/2019	NON-COMPETING CONTINUATION	$264,110
														Subtotal = $264,110

Issue Date FY: 2018 ( Subtotal = $264,110 )
2018	2018	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	3	7/31/2018	NON-COMPETING CONTINUATION	$264,110
														Subtotal = $264,110

Issue Date FY: 2017 ( Subtotal = $264,110 )
2017	2017	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	2	8/8/2017	NON-COMPETING CONTINUATION	$264,110
														Subtotal = $264,110

Issue Date FY: 2016 ( Subtotal = $264,110 )
2016	2016	DANA-FARBER CANCER INSTITUTE	44 BINNEY STREET	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	1	9/15/2016	NEW	$264,110
														Subtotal = $264,110

Grand Total All Awards = $2,648,878

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Stapled Peptides for Protein Interaction Research and Therapeutic Targeting in Human Cancer

Award Number: R50CA211399

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2016

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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