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siRNA-based Gold Nanoparticles as a Therapeutic Enhancer for Triple Negative Breast Cancer (TNBC) Radiotherapy

Award Number: R03CA277216
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/10/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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siRNA-based Gold Nanoparticles as a Therapeutic Enhancer for Triple Negative Breast Cancer (TNBC) Radiotherapy - ABSTRACT Radiation therapy (RT) modulates immunological properties of tumor microenvironment (TME) to stimulate antitumor immune response. However, RT initiates immunosuppressive mechanisms as well and therefore diminishing the effects of RT immuno-stimulation. One of the main RT immunosuppressive modes is exerted by an increase in TGFβ production that in breast cancers (BC) has an additive effect on already high TGFβ levels produced by cancer cells themselves. Triple negative breast cancer (TNBC) in particular, was demonstrated to have higher TGFβ levels compared to other BCs, and this finding correlated with increased tumor grade and invasiveness, and a diminished patient survival. Consequently, RT induced increase in TGFβ within the TME may further potentiate invasiveness and metastatic potential of TNBC. Due to stimulatory aspects of RT immunomodulation, RT has gained interest as a prospective therapeutic enhancer in cancer immunotherapy, such as immune checkpoint blockers, that has shown great potential in improving local control and overall survival in select cancers. Unfortunately, in most forms of BC, including TNBC, response to immunotherapy remains modest. Our long-term goal is to use RT to enhance TNBC response to immunotherapy by taking advantage of RT immunomodulatory potential. Antitumor RT effects, including TME immunomodulation can be improved by using radiosensitizers, such as gold nanoparticles (AuNP). Furthermore, AuNPs can also serve as a drug delivery system by conjugation of small interfering RNAs (siRNAs). In this project we propose to use AuNPs functionally modified by TGFβ siRNA to simultaneously enhance RT immunomodulation and counteract the immunosuppressive effects related to the increased TGFβ production. This approach will enhance RT antitumor effects and create a favorable TME environment for better response to future immunotherapies. This will be tested by the following specific aims: Aim 1: To synthesize and characterize AuNP-siRNATGF?1; Aim 2: To investigate the therapeutic effect of combination of RT and AuNP-siRNATGFβ1 in in vitro and in vivo mouse TNBC model. The proposed studies in determining the potential of AuNPs simultaneously target antitumor and immunomodulatory RT effects will provide critical information for improving TNBC response to immune checkpoint blockers and for designing future RT/ immune checkpoint blockers multimodal TNBC therapies.


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 = $0 )
2026	2024	HENRY FORD HEALTH SYSTEM	1 FORD PL # 5B	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	000	2	12/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $76,225 )
2024	2024	HENRY FORD HEALTH SYSTEM	1 FORD PL	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	000	2	6/19/2024	NON-COMPETING CONTINUATION	$76,225
														Subtotal = $76,225

Issue Date FY: 2023 ( Subtotal = $76,225 )
2023	2023	HENRY FORD HEALTH SYSTEM	1 FORD PL	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	000	1	7/10/2023	NEW	$76,225
														Subtotal = $76,225

Grand Total All Awards = $152,450

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siRNA-based Gold Nanoparticles as a Therapeutic Enhancer for Triple Negative Breast Cancer (TNBC) Radiotherapy

Award Number: R03CA277216

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/10/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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