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The Immunomodulatory Function of Cyclin E1 in Ovarian Cancer and Therapeutic Targeting

Award Number: R37CA279440
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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The Immunomodulatory Function of Cyclin E1 in Ovarian Cancer and Therapeutic Targeting - A. Project Summary/Abstract Ovarian cancer is the second most common cause of gynecologic cancer death in women around the world. High-grade serous ovarian cancer (HGSOC) accounts for more than 70% of all ovarian cancer deaths. Approximately 50% of HGSOCs harbor alterations in the genes involved in homologous recombination (HR) DNA repair pathway. These tumors tend to respond well to PARP inhibitors and chemotherapy. CCNE1 (Cyclin E1) gene amplification and overexpression is frequently found in HR-proficient ovarian cancer and is associated with primary chemoresistance and poor clinical outcomes. CCNE1 gene amplification is present in 15-20% ovarian tumors, and overexpression of Cyclin E1 is detected in over 40% of ovarian cancer specimens. Currently, there are no effective treatment approaches for this type of HGSOC. By using Cyclin E1-overexpressing syngeneic and humanized ovarian patient-derived xenograft (PDX) models of HGSOC, we will identify novel therapies for the treatment of HGSOC cancers with amplification or high expression of Cyclin E1. Our preliminary data suggests that Cyclin E1 downregulates IRF1 and type I interferon (IFN) expression in a CDK2 kinase-independent manner in ovarian cancer cells. Our preliminary data also reveal that overexpression of Cyclin E1 in ovarian cancer cells promotes pro-tumor polarization of tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Expression of IRF1 and type I IFNs has been implicated in pro-tumor polarization of TAMs in cancers. We plan to investigate the molecular mechanisms underlying the regulation of Cyclin E1 on the type I IFN signaling pathway and TAMs in Cyclin E1-amplified/overexpressing HGSOC tumors and to develop therapeutic approaches for this type of ovarian cancer. We hypothesize that downregulation of IRF1 and type I IFNs by Cyclin E1 in tumor cells fosters an immunosuppressive TME in HGSOC with Cyclin E1- amplification/overexpression by promoting pro-tumor macrophage polarization. We also hypothesize that targeting the conventional tumor cell-intrinsic oncogenic function of Cyclin E1 with CDK2i (CDK2 inhibitors) or ATRi (Ataxia telangiectasia, and Rad3-related inhibitors), in combination with remodeling the pro-tumor TAMs that induced by expression of Cyclin E1 in the TME with immunomodulators, such as STING agonists, will provide promising therapeutics for ovarian cancer patients with Cyclin E1-amplification/overexpression. In Aim 1, we will determine how cyclin E1 regulates IRF1 and type I IFNs in both human and mouse ovarian cancer cell lines. In Aim 2, we will determine how the Cyclin E1-regulated type I IFN signaling pathway promotes pro-tumor polarization of TAMs and immunosuppression in the TME of HGSOC tumors with Cyclin E1- amplification/overexpression both in vitro and in vivo. In Aim 3, based on our recent findings that STING agonism activates type I IFN signaling pathway and repolarizes pro-tumor macrophages to an anti-tumor status, we will assess the therapeutic efficacy and toxicity of STING agonists in combination with CDK2i or ATRi, in both syngeneic mouse models and humanized PDX models.


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 = $505,851 )
2026	2026	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	000	3	3/19/2026	NON-COMPETING CONTINUATION	$505,851
														Subtotal = $505,851

Issue Date FY: 2025 ( Subtotal = $505,851 )
2025	2025	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	001	2	5/22/2025	NON-COMPETING CONTINUATION	$50,584
2025	2025	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	000	2	3/10/2025	NON-COMPETING CONTINUATION	$455,267
														Subtotal = $505,851

Issue Date FY: 2024 ( Subtotal = $505,851 )
2024	2024	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	000	1	3/11/2024	NEW	$505,851
														Subtotal = $505,851

Grand Total All Awards = $1,517,553

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The Immunomodulatory Function of Cyclin E1 in Ovarian Cancer and Therapeutic Targeting

Award Number: R37CA279440

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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