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Defining the role of persistent DNA bridges in tumor-intrinsic immune activation in hereditary breast and ovarian cancer

Award Number: F31CA278265
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Defining the role of persistent DNA bridges in tumor-intrinsic immune activation in hereditary breast and ovarian cancer - PROJECT SUMMARY Chromosome segregation errors such as persistent DNA bridges accelerate genome instability, a hallmark of cancer. These toxic DNA lesions occur at a higher frequency in hereditary breast and ovarian cancer (HBOC) cells with DNA repair deficiencies, and thus defective genome maintenance. PARP inhibitors (PARPi) cause targeted tumor cell death in BRCA-mutant HBOC and have been suggested to further increase the frequency of DNA bridges in cultured BRCA-mutant cells. Despite the therapeutic promise of PARPi, BRCA-deficient cancers develop acquired resistance to this therapy. Recent studies show that immunotherapies can prevent or delay PARPi resistance in HBOC tumors; however, the mechanisms by which PARPi synergizes with immunotherapies remain poorly defined. My preliminary data shows that PARPi treatment leads to coating of persistent DNA bridges with the innate immune DNA sensor cGAS in BRCA-mutant cells, which coincides with increased type I interferon signaling. I hypothesize that PARPi-induced persistent DNA bridges are central to the mechanism of PARPi cytotoxicity and synergy with immunotherapies, therefore requiring rigorous further study to identify strategies that maximize the therapeutic potential of PARPi treatment in DNA repair-deficient tumors. The overall objective of this proposal is to thus define the mechanisms by which PARPi-induced persistent DNA bridges lead to tumor-intrinsic immune activation in HBOC. The proposed research will investigate this objective in two specific aims. Aim 1 will define the structure and nuclear integrity of PARPi-induced persistent bridges by use of transposase-mediated fluorescence imaging, immunofluorescence, live-cell imaging, and correlative light and electron microscopy. How these factors affect cGAS-STING activation will be assessed using immunoblotting, RT-qPCR, and enzyme immunoassays. Aim 2 will establish persistent DNA bridges and bulky anaphase bridges as potential predictive biomarkers that reflect DNA repair defects, chromosome segregation failure, and subsequent cGAS-STING activation in PARPi olaparib-treated BRCA- mutant breast cancer. I will leverage digital images of hematoxylin and eosin (H&E)-stained samples and perform immunohistochemistry staining on a tissue microarray of de-identified, paired clinical samples before and during olaparib treatment, which will be interrogated in the context of ongoing phospho-STING staining. Defining the interplay between chromosomal instability-driven immune activation and tumor response to PARPi will be a first step towards improved HBOC treatment. This proposal will be completed in a supportive, collaborative, and interdisciplinary environment that will allow me to perform fundamental and translational cancer biology research. This training will advance my experimental design, rigorous data analysis, and technical skills in molecular biology, high-resolution microscopy, and cytopathology. My training plan also provides ample opportunities to improve oral presentation, writing, teaching, and mentorship skills to prepare me for a successful career as an academic cancer biologist leading a research group to mentor and train the next generation of scientists.


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 = $48,502 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	3	8/4/2025	NON-COMPETING CONTINUATION	$48,502
														Subtotal = $48,502

Issue Date FY: 2024 ( Subtotal = $47,938 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	2	8/14/2024	NON-COMPETING CONTINUATION	$47,938
														Subtotal = $47,938

Issue Date FY: 2023 ( Subtotal = $46,658 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	1	8/3/2023	NEW	$46,658
														Subtotal = $46,658

Grand Total All Awards = $143,098

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Defining the role of persistent DNA bridges in tumor-intrinsic immune activation in hereditary breast and ovarian cancer

Award Number: F31CA278265

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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