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Distinct contributions of mesenchymal cell niches in the therapeutic potential of the hedgehog pathway in triple negative breast cancer

Award Number: SC1GM131967
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Distinct contributions of mesenchymal cell niches in the therapeutic potential of the hedgehog pathway in triple negative breast cancer - Recent studies show that Hedgehog (Hh) signaling correlates with tumor expansion and reduced survival rates in triple negative breast cancer (TNBC) patients, suggesting a potential therapeutic value for Hh inhibitors. Several studies have highlighted mesenchymal cells as potential targets in the tumorigenicity of Hh signaling, yet their diagnostic value and influence in the therapeutic response of Hh inhibitors have not been established. A main limitation is the lack of models that capture distinct contributions of mesenchymal cell sub-types in the growth response to Hh inhibitors. Inhibition of Hh signaling can lead to tumor expansion or suppression; a bi- modal growth mechanism that can negatively impact the therapeutic outcome in tumors treated with Hh inhibitors. Our studies and preliminary data support the influence of mesenchymal cell sub-types in the tumorigenic potential of Hh signaling. Our evaluation of individual contributions of fibroblasts and mesenchymal stem cells suggest that changes in the composition of the mesenchymal niche influence tumorigenic signals of the Hh pathway and response to Hh inhibitors. Our long-term goal is to provide biomimetic and multi-cell type in vitro models that enable the identification of new targets in clinically challenged endocrine tumors. Our overall goal is to validate an in vitro model for prediction of therapeutic efficacy and identify oncogenic cues associated to the composition of the stroma that can be used as oncogenic markers and targets to improve therapeutic response to Hh inhibitors. Our central hypothesis is that the oncogenicity of Hh signaling is regulated by the composition of the adjacent stroma. Our hypothesis has been formulated based on previous studies and our preliminary data supporting distinct contributions of mesenchymal cell sub-types in the response of tumor cells to Hh signaling. Our rationale is that the evaluation of the interplay between the mesenchymal and immune cell niches in the sensitivity of tumors to Hh inhibitors will be valuable towards understanding tumor transitions to therapeutic resistance driven by the stroma. The following aims are proposed: Aim 1- Model paracrine Hh signaling contribution to stemness and resistance to therapy, Aim 2- In vivo validation of a Hh paracrine model through evaluation of response to Hh inhibition, and Aim 3- Impact of immune cells in the oncogenicity of Hh paracrine signaling. These aims will support recapitulation of in vivo observations in our in vitro models and confirm the influence of the mesenchymal cell niche in the tumorigenicity of Hh signaling. This contribution is significant as it will provide new biological insights into the modulation of tumor cell behavior in response to shifts in the stromal niche and establish the therapeutic value of stromal cell components in Hh signaling. The technology is innovative because it provides with a simple and customizable culture model in which to evaluate tumor transitions towards a more aggressive state and the impact of immune cells in Hh paracrine signaling.


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: 2023 ( Subtotal = $527,147 )
2023	2023	UNIVERSITY OF PUERTO RICO	259 BLVD ALFONSO VALDES	MAYAGUEZ	PR	00680	MAYAGUEZ	USA	Biomedical Research and Research Training	001	4	7/27/2023	SUPPLEMENT FOR EXPANSION	$152,147
2023	2023	UNIVERSITY OF PUERTO RICO	259 BLVD ALFONSO VALDES	MAYAGUEZ	PR	00680	MAYAGUEZ	USA	Biomedical Research and Research Training	000	4	7/24/2023	NON-COMPETING CONTINUATION	$375,000
														Subtotal = $527,147

Issue Date FY: 2022 ( Subtotal = $520,147 )
2022	2022	UNIVERSITY OF PUERTO RICO	259 BLVD ALFONSO VALDES	MAYAGUEZ	PR	00680	MAYAGUEZ	USA	Biomedical Research and Research Training	001	3	9/1/2022	SUPPLEMENT FOR EXPANSION	$152,147
2022	2022	UNIVERSITY OF PUERTO RICO	259 BLVD ALFONSO VALDES	MAYAGUEZ	PR	00680	MAYAGUEZ	USA	Biomedical Research and Research Training	000	3	7/15/2022	NON-COMPETING CONTINUATION	$368,000
														Subtotal = $520,147

Issue Date FY: 2021 ( Subtotal = $332,500 )
2021	2021	UNIVERSITY OF PUERTO RICO	259 BLVD ALFONSO VALDES	MAYAGUEZ	PR	00680	MAYAGUEZ	USA	Biomedical Research and Research Training	000	2	7/30/2021	NON-COMPETING CONTINUATION	$332,500
														Subtotal = $332,500

Issue Date FY: 2020 ( Subtotal = $322,645 )
2020	2020	UNIVERSITY OF PUERTO RICO	259 BLVD ALFONSO VALDES	MAYAGUEZ	PR	00680	MAYAGUEZ	USA	Biomedical Research and Research Training	000	1	6/18/2020	NEW	$322,645
														Subtotal = $322,645

Grand Total All Awards = $1,702,439

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Distinct contributions of mesenchymal cell niches in the therapeutic potential of the hedgehog pathway in triple negative breast cancer

Award Number: SC1GM131967

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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