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Tumor cell -TAM Paracrine Signaling in Breast Cancer

Award Number: R01CA269508
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/13/2023
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Tumor cell -TAM Paracrine Signaling in Breast Cancer - ABSTRACT Immune checkpoint inhibitors are FDA approved for metastatic triple negative breast cancer (TNBC) and work well for patients with high levels of tumor infiltrating lymphocytes (TIL), but for the majority of BC patients, these agents are ineffective. Continued research is needed to elucidate the interplay between tumor cells and the diverse immune cell populations within the primary TME, and how this interaction shapes tumor biology. Tumor- associated macrophages (TAM) represent one of the most abundant immune components in BC TME and exhibit a robust and unique influence on the disease. High levels of TAM infiltration are associated with poor prognosis in BC. TAMs play a critical role in a wide range of pro-tumorigenic, pro-metastatic activities including tumor angiogenesis, extracellular matrix (ECM) remodeling, immunosuppression, and chemoresistance. How to surmount TAM infiltration and function in order to activate a potent anti-tumorigenic and anti-metastatic response represents a gap in knowledge for the BC field. TAMs most closely resemble M2-polarized type macrophages and exhibit some overlapping functions between the categories. TAMs are a highly heterogeneic, plastic cell population endowed with tumor-promoting functionality measured by the overall abundance of M2 vs M1 markers. TAM polarization and immunosuppressive capacities are dependent upon where these cells are located and what signals are received within the TME. Whereas M2-like polarization is considered pro-tumorigenic, M1- like polarization is associated with inflammatory, anti-tumor effects and improved prognosis. Tumor cells generate paracrine signals that recruit and regulate TAM function. In turn, TAMs produce signals that affect the metastatic potential of tumor cells. Given the clear pro-tumor and metastatic roles of TAMs, it seems evident that identifying ways to abrogate pro-tumorigenic M2-like responses and promote anti-tumorigenic M1-like responses in BC will be clinically advantageous. However, effective strategies remain elusive. Our proposal introduces a new strategy to target a kinase called HUNK that has the potential to be more advantageous than strategies that directly target TAMs. Targeting HUNK will have a multifaceted effect by not only halting pro-tumor/metastatic tumor intrinsic signaling but also fundamentally changing the “feed forward” paracrine loop between tumor cells and TAMs.


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 = $447,481 )
2026	2026	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	000	4	2/26/2026	NON-COMPETING CONTINUATION	$447,481
														Subtotal = $447,481

Issue Date FY: 2025 ( Subtotal = $447,481 )
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	000	3	2/17/2025	NON-COMPETING CONTINUATION	$402,733
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	001	3	5/22/2025	NON-COMPETING CONTINUATION	$44,748
														Subtotal = $447,481

Issue Date FY: 2024 ( Subtotal = $430,489 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	000	2	2/22/2024	NON-COMPETING CONTINUATION	$407,831
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	001	2	4/18/2024	NON-COMPETING CONTINUATION	$22,658
														Subtotal = $430,489

Issue Date FY: 2023 ( Subtotal = $456,441 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	000	1	3/13/2023	NEW	$456,441
														Subtotal = $456,441

Grand Total All Awards = $1,781,892

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Tumor cell -TAM Paracrine Signaling in Breast Cancer

Award Number: R01CA269508

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/13/2023

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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