Monday, June 30, 2025 6/30/2025

HRD-IA signatures in pancreatic ductal adenocarcinoma

Award Number: UH3CA238926
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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HRD-IA signatures in pancreatic ductal adenocarcinoma - ABSTRACT Tumors deficient in homologous recombination display high levels of copy number variants (CNVs) including amplifications, deletions, and breakpoints in their genomes. This homologous recombination deficiency (HRD) phenotype has been associated with pathogenic BRCA mutations in multiple cancers and can be exploited clinically through a synthetic lethal interaction with agents, such as inhibitors of poly ADP- ribose polymerase (PARP) and chemotherapy regimens such as FOLFIRINOX, that increase the level of DNA damage in tumor genomes. Strikingly, subsets of tumors that are wild type for BRCA1 and BRCA2 have shown similar clinical responses to these agents. Preliminary studies suggest that responder tumors have elevated numbers of genomic aberrations even in the absence of variants in the BRCA genes or in other mediators of homologous recombination mediated DNA repair (e.g. PALB2, ATM, and BRIP1). Thus the nature and extent of these lesions in tumor genomes, regardless of genotype, provides a biomarker for patients who will respond to DNA damage and repair targeting therapies. It is estimated that in 2019, 56,770 Americans will be diagnosed with pancreatic ductal adenocarcinoma (PDA) and 45,750 will die from the disease, making PDA the third most common cause of cancer death. Recent clinical trials have made modest improvements in overall survival. Studies suggest that similar to other tumors, elevated numbers of chromosomal aberrations define a HRD signature in a subset of PDAs. A fundamental hypothesis is that this genomic signature predicts those PDA patients likely to respond to PARP inhibitors and to DNA damaging agents. However PDA biopsies are difficult to characterize due to complex genomes and heterogeneous cellularity, as cancer cells represent on average only 25% of the cells within the tumor. Furthermore, biopsies frequently contain multiple neoplastic populations that cannot be distinguished by morphology based methods. To address these clinical challenges we validated DNA content based flow sorting of PDA tissues. Our published methods yield highly purified (>95%) samples suitable for whole genome analyses from a variety of clinical samples. These include both fresh frozen and formalin fixed paraffin embedded (FFPE) tissues with low tumor cell content (<10-20%) and high amounts (>90%) of necrosis and debris. We have identified PDAs with extensive numbers of interstitial aberrations (IAs) in their genomes similar to those observed in HRD-positive BRCAmut tumors. Our results suggest that elevated numbers of IAs correlate with clinical response in PDA. In this study we will establish analytical and processing procedures for our HRD-IA assay then establish a score that distinguishes HRD+ BRCAmut tumors. We will then exploit samples treated with FOLFIRINOX to validate the application of our HRD-IA assay to identify those PDA patients, BRCAmut and BRCAwt, who respond to DNA damage targeting agents. The final phase of this work will validate our sorting and CNV based HRD-IA assay for CLIA application and clinical use.


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 = -$12,986 )
2025	2024	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Cancer Detection and Diagnosis Research	000	4	2/14/2025	NON-COMPETING CONTINUATION	$0
2025	2024	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Cancer Detection and Diagnosis Research	001	4	6/11/2025	NON-COMPETING CONTINUATION	-$12,986
														Subtotal = -$12,986

Issue Date FY: 2024 ( Subtotal = $325,709 )
2024	2024	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Cancer Detection and Diagnosis Research	000	4	1/30/2024	NON-COMPETING CONTINUATION	$308,488
2024	2024	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Cancer Detection and Diagnosis Research	002	4	7/24/2024	NON-COMPETING CONTINUATION	$0
2024	2024	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Cancer Detection and Diagnosis Research	001	4	4/18/2024	NON-COMPETING CONTINUATION	$17,221
														Subtotal = $325,709

Issue Date FY: 2023 ( Subtotal = $330,396 )
2023	2023	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Cancer Detection and Diagnosis Research	000	3	2/1/2023	NON-COMPETING CONTINUATION	$330,396
														Subtotal = $330,396

Issue Date FY: 2022 ( Subtotal = $310,005 )
2022	2022	MAYO CLINIC ARIZONA	13400 E SHEA BLVD	SCOTTSDALE	AZ	85259	MARICOPA	USA	Cancer Detection and Diagnosis Research	000	2	1/17/2022	EXTENSION WITH OR WITHOUT FUNDS	$310,005
														Subtotal = $310,005

Grand Total All Awards = $953,124

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HRD-IA signatures in pancreatic ductal adenocarcinoma

Award Number: UH3CA238926

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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