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Immunomodulatory Effects of Targeting DNA Repair with Novel Temozolomide Combinations in Colorectal Cancer

Award Number: K08CA255465
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/05/2021
PERIOD OF PERFORMANCE END DATE: 09/30/2026

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Immunomodulatory Effects of Targeting DNA Repair with Novel Temozolomide Combinations in Colorectal Cancer - ABSTRACT DNA repair plays an important role in the pathogenesis of virtually all cancer types, and the identification of aberrant DNA repair pathways has identified predictive and prognostic biomarkers to targeted therapies. For example, epigenetic hypermethylation of the promoter of O6-methylguanine DNA methyltransferase (MGMT) predicts for better patient survival and increased sensitivity to temozolomide (TMZ) in multiple cancers, including colorectal cancer (CRC). TMZ is a monofunctional alkylator, and the DNA damage caused by TMZ is principally repaired by MGMT, which is silenced by promoter hypermethylation. The base excision repair (BER) pathway also serves as a critical pathway to repair TMZ DNA damage. Preclinically, the simultaneous inhibition of BER with polyp ADP ribose polymerase (PARP) inhibitors further sensitizes MGMT deficient tumors to TMZ. However, our preliminary findings reveal an alternative and parallel mechanism: TMZ damage causes acute replication stress and fork collapse leading to Ataxia Telangiectasia and Rad3 related (ATR) dependent phosphorylation of Checkpoint Kinase 1 (Chk1). We have leveraged these findings, and additional in vivo experiments, to advance novel TMZ combinations into the clinic with two investigator-initiated clinical trials for MGMT silenced CRC: 1) TMZ + olaparib (PARP inhibitor) and TMZ + AZD 6738 (ATR inhibitor). Enrollment will proceed at Yale Smilow Cancer Hospital with future opportunities expand to collaborating sites through our CRC Stand up to Cancer (SU2C) Dream Team. Furthermore, we aim to develop new biomarker assays including a biomarker assessing MGMT heterogeneity to identify tumors most sensitive to TMZ combinations, and perform genomic profiling. Leveraging DNA damage additionally represents a potential tool to stimulate an immune response, and through ancillary studies and using specimens obtained from our trials we will study the effects TMZ combinations on the immune microenvironment to lend support to the addition of immunotherapy in the future. I am a medical oncologist focusing on the treatment of advanced gastrointestinal (GI) cancers with an emphasis on innovative therapies for CRC. This award will facilitate my development as a physician- scientist equipped to design and conduct investigator-initiated early phase clinical trials based on innovative preclinical evidence regarding DNA repair and immunotherapies. My training will include didactic coursework for tumor immunology, practical experience of clinical trial implementation, and formal instruction in biomarker techniques. To achieve these goals, I have assembled a multidisciplinary mentorship team led by my primary mentor, Dr. Patricia LoRusso who has a proven track record of successfully mentoring junior faculty and extensive expertise in investigator-initiated clinical trials. At the conclusion of this award, I will have gained valuable skills into the underpinnings of clinical research generically, and specifically for clinical trial design, and biomarker identification for DNA repair and immunology. This award will help establish me as an independent investigator conducting early phase clinical trials for CRC and other GI cancers.


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	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	5	6/24/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $260,958 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	5	7/11/2025	NON-COMPETING CONTINUATION	$260,958
														Subtotal = $260,958

Issue Date FY: 2024 ( Subtotal = $260,958 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	4	6/26/2024	NON-COMPETING CONTINUATION	$260,958
														Subtotal = $260,958

Issue Date FY: 2023 ( Subtotal = $260,958 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	3	7/12/2023	NON-COMPETING CONTINUATION	$260,958
														Subtotal = $260,958

Issue Date FY: 2022 ( Subtotal = $260,958 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	2	8/1/2022	NON-COMPETING CONTINUATION	$260,958
														Subtotal = $260,958

Issue Date FY: 2021 ( Subtotal = $260,958 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	1	8/5/2021	NEW	$260,958
														Subtotal = $260,958

Grand Total All Awards = $1,304,790

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Immunomodulatory Effects of Targeting DNA Repair with Novel Temozolomide Combinations in Colorectal Cancer

Award Number: K08CA255465

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/05/2021

PERIOD OF PERFORMANCE END DATE: 09/30/2026

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