Wednesday, October 1, 2025 10/1/2025

Developing a novel combination immunotherapy for triple-negative breast cancer

Award Number: R01CA278056
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/18/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Developing a novel combination immunotherapy for triple-negative breast cancer - PROJECT SUMMARY Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and has a very poor prognosis due to its tendency to metastasize and relapse. Immune checkpoint blockade (immunotherapy) plus chemotherapy is the first-line treatment for metastatic TNBC, but the tumor responses are limited and not durable. Additionally, the lack of robust predictive biomarkers of response remains a limiting factor in maximizing the efficacy of immunotherapy. Therefore, there is an urgent need to develop a more effective immunotherapy combination and establish novel biomarkers to identify TNBC patients who will benefit from this treatment. Because the tumor microenvironment (TME) critically influences TNBC response to immunotherapy, we set out to identify mechanisms that broadly mediate the immune response in TNBC. Our preliminary studies showed that the c-Jun N-terminal kinase (JNK) pathway acts as a TME master switch in promoting a persistent immunosuppressive TME in TNBC. Building on this evidence, our central hypothesis is that JNK inhibitors (JNKi) synergize with immunotherapy by converting the TNBC TME from an immunosuppressive to an immunoactive state. Our hypothesis will be tested through 3 specific aims: Aim 1) Determine how JNK regulates the immunosuppressive TME and aggressiveness in TNBC; Aim 2) Establish JNK signaling-related biomarkers of the immunosuppressive status of the TNBC TME; and Aim 3) Develop an optimal JNKi-immunotherapy combination for TNBC. Completing these aims will provide a robust scientific framework for developing effective therapeutic strategies for TNBC. The experimental approach will be as follows: In Aim 1, we will investigate how JNK promotes TNBC aggressiveness by immunologically modulating the TME using clinically relevant immunocompetent syngeneic TNBC mouse models with well-defined immune TMEs. We will also identify molecules responsible for JNK’s immunological modulation of the TME. In Aim 2, we will establish novel JNK signaling-related biomarkers reflecting the immunosuppressive status of the TNBC TME using patient samples. In Aim 3, we will test whether JNKi synergize with immunotherapy in TNBC by promoting an immunoactive TME, using clinically relevant immunocompetent syngeneic TNBC mouse models and our established patient-derived xenografts of TNBC molecular subtypes (sensitive or resistant to immunotherapy) in humanized mouse models. We expect to 1) generate sufficient preclinical data to support the development of an effective JNKi-immunotherapy combination for patients with TNBC and 2) establish biomarkers of the immunosuppressive status of the TNBC TME. The proposed research is significant because it will fundamentally advance our understanding of mechanisms by which cancers promote suppression of the response to immunotherapy and may lead to the development of a novel combination immunotherapy that improves the survival of TNBC patients.


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: 2025 ( Subtotal = $650,749 )
2025	2025	UNIVERSITY OF HAWAII	2425 CAMPUS RD SINCLAIR RM 1	HONOLULU	HI	96822	HONOLULU	USA	Cancer Treatment Research	000	3	8/27/2025	NON-COMPETING CONTINUATION	$650,749
														Subtotal = $650,749

Issue Date FY: 2024 ( Subtotal = $618,212 )
2024	2024	UNIVERSITY OF HAWAII	2425 CAMPUS RD SINCLAIR RM 1	HONOLULU	HI	96822	HONOLULU	USA	Cancer Treatment Research	000	2	8/16/2024	NON-COMPETING CONTINUATION	$618,212
														Subtotal = $618,212

Issue Date FY: 2023 ( Subtotal = $664,874 )
2023	2023	UNIVERSITY OF HAWAII	2425 CAMPUS RD SINCLAIR RM 1	HONOLULU	HI	96822	HONOLULU	USA	Cancer Treatment Research	000	1	9/18/2023	NEW	$664,874
														Subtotal = $664,874

Grand Total All Awards = $1,933,835

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Developing a novel combination immunotherapy for triple-negative breast cancer

Award Number: R01CA278056

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/18/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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