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Endogenous Circular RNAs limit abemaciclib anti tumor immune responses

Award Number: R01CA295834
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/17/2025
PERIOD OF PERFORMANCE END DATE: 02/28/2030

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Endogenous Circular RNAs limit abemaciclib anti tumor immune responses - ABSTRACT Soft-tissue sarcomas (STS) pose a substantial global health challenge with a low survival rate for advanced cases. Despite current treatments, there is a pressing need for effective therapeutic strategies. This proposal focuses on investigating the potential of Abemaciclib, a CDK4/6 inhibitor, alone or in combination with circRNA- silencing, to enhance anti-tumor immune responses in STS. The study aims to elucidate the interplay between Abemaciclib, circular RNAs (circRNAs), and immune responses in STS using newly developed immunocompetent mouse models. The research is structured around three specific aims: Aim 1 explores how circCsnk1g3 limits Abemaciclib-triggered interferon and inflammatory responses. Abemaciclib and circCsnk1g3 exhibit opposing effects on these responses in sarcoma cells, and the study aims to uncover the shared signaling pathway impacted by both. Experimental approaches include treating with Abemaciclib, manipulating circCsnk1g3 expression, and assessing the RIG-I/MDA5/MAVS pathway through co-immunoprecipitation assays and downstream effector evaluation. Aim 2 investigates whether circCsnk1g3 silencing enhances Abemaciclib's anti-tumor effects and shapes the tumor microenvironment (TME). The study hypothesizes that circCsnk1g3 targeting could serve as a therapeutic adjuvant to boost Abemaciclib-induced anti-tumor immune responses. Advanced techniques such as single-cell RNA-sequencing and flow cytometry will be employed to comprehensively assess tumor immune composition, including sub-types of tumor-associated macrophages (TAMs) and T cells. Aim 3 assesses the functional role of circCdyl in regulating TAM inflammatory responses. TAMs express higher levels of circCdyl and RIG-I than sarcoma cells, and the study aims to determine the impact of circCdyl on TAM activation and anti-tumor effects. Intervention with circCdyl expression in bone marrow- derived macrophages (BMDM) will be conducted, and in vivo experiments will assess the influence of circCdyl- manipulated BMDM on tumor growth. Overall, this research aims to deepen our understanding of the mechanisms underlying the potential synergy between Abemaciclib and circRNA-silencing in STS, with a focus on immune responses and the tumor microenvironment content.


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 = $567,059 )
2026	2026	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	2	2/26/2026	NON-COMPETING CONTINUATION	$567,059
														Subtotal = $567,059

Issue Date FY: 2025 ( Subtotal = $567,059 )
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	1	3/17/2025	NEW	$567,059
														Subtotal = $567,059

Grand Total All Awards = $1,134,118

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Endogenous Circular RNAs limit abemaciclib anti tumor immune responses

Award Number: R01CA295834

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/17/2025

PERIOD OF PERFORMANCE END DATE: 02/28/2030

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