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Genomic and Microenvironmental Determinants, Temporal Dynamics, and Treatment Efficacy of Radiation-Based Combination Therapies

Award Number: U54CA274513
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Genomic and Microenvironmental Determinants, Temporal Dynamics, and Treatment Efficacy of Radiation-Based Combination Therapies - PROJECT SUMMARY Overall Section Our ROBIN center focuses on elucidating the genomic and microenvironmental determinants, and temporal dynamics underlying efficacy of radiation-based combination therapies. Radiotherapy (RT), alone or in combination with other treatments, is used to treat about two-thirds of all cancer patients. Despite the widespread use of radiation therapy in oncology, our understanding of the mechanisms driving response and resistance remains poor. Our long-term goal is to understand the mechanisms that underlie efficacy and resistance of radiation-based therapies. New efforts to improve treatment for many cancer types now focus on using combination therapies in which radiation is used with systemic agents, highlighting the urgent need to understand the drivers of efficacy. Among the most promising new biologics being studied for use with radiation are antibody-drug conjugates (ADC) and immune checkpoint inhibitors (ICI). We will use an innovative molecular characterization trial testing radiation plus ADC in bladder cancer and radiation plus ICI in head and neck cancer to characterize the mechanistic drivers underlying these next generation RT-based combinations. The central hypothesis of this U54 application is that specific genetic and immunologic mechanisms underlie sensitivity and resistance to radiation-based combination therapies. We will address these questions through 3 specific aims. In Aim 1, we will work to understand the molecular mechanisms that underlie efficacy of treatment with radiation plus ADC. Here, our working hypothesis is that specific genetic and immunologic events underlie response to RT plus sacituzumab govitecan (SG) treatment. We will leverage our molecular characterization trial (Part A) investigating the use of RT and sacituzumab for bladder preservation therapy. We will determine the differential molecular effects with standard-of-care RT + cisplatin versus RT + SG. In Aim 2, we will improve identification of patients who are sensitive or resistant to RT-based therapies based on new insights into transcriptional dynamics and temporal reprogramming during treatment with radiation-based therapies. Here, we will leverage our molecular characterization trial treating head and neck squamous cell carcinoma (HNSCC) or bladder cancer patients with RT + chemotherapy versus RT + SG or ICI. We will build on recent experimental and clinical breakthroughs led by our research groups, which have identified highly refined gene expression programs associated with RT sensitivity and delta radiomics. In Aim 3, we will identify the differential mechanisms underlying the anti-tumor activities of RT + cisplatin versus RT + immune checkpoint blockade. Here, using our head and neck trial (Part B), we will uncover the unique genetic and immunologic factors that govern response to RT when combined with these two classes of agents. We will elucidate the differential molecular effects of the two approaches, immune reprogramming, and mechanisms of acquired resistance. Our studies will help build a foundation to optimize multimodal, radiation- based definitive treatment strategies.


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 = $0 )
2025	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Centers Support Grants	000	3	5/2/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $1,526,335 )
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Centers Support Grants	003	3	7/22/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Centers Support Grants	005	3	7/31/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Centers Support Grants	002	3	7/16/2024	SUPPLEMENT FOR EXPANSION	$64,603
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Centers Support Grants	000	3	7/9/2024	NON-COMPETING CONTINUATION	$1,428,130
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Centers Support Grants	004	3	7/29/2024	NON-COMPETING CONTINUATION	$0
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Centers Support Grants	001	3	7/15/2024	SUPPLEMENT FOR EXPANSION	$33,602
														Subtotal = $1,526,335

Issue Date FY: 2023 ( Subtotal = $1,648,135 )
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Centers Support Grants	003	2	8/1/2023	SUPPLEMENT FOR EXPANSION	$70,904
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Centers Support Grants	005	2	8/10/2023	NON-COMPETING CONTINUATION	$0
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Centers Support Grants	004	2	8/2/2023	SUPPLEMENT FOR EXPANSION	$66,643
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Centers Support Grants	002	2	7/31/2023	NON-COMPETING CONTINUATION	$1,473,606
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Centers Support Grants	000	1	3/20/2023	SUPPLEMENT FOR EXPANSION	$36,982
2023	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Centers Support Grants	001	1	3/29/2023	NEW	$0
														Subtotal = $1,648,135

Issue Date FY: 2022 ( Subtotal = $1,566,249 )
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Centers Support Grants	001	1	9/21/2022	NEW	$0
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Cancer Centers Support Grants	000	1	9/14/2022	NEW	$1,566,249
														Subtotal = $1,566,249

Grand Total All Awards = $4,740,719

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Genomic and Microenvironmental Determinants, Temporal Dynamics, and Treatment Efficacy of Radiation-Based Combination Therapies

Award Number: U54CA274513

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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