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Development of a novel therapy targeting the tumor microenvironment in inflammatory breast cancer

Award Number: R01CA258523
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Development of a novel therapy targeting the tumor microenvironment in inflammatory breast cancer - PROJECT SUMMARY Despite great promise, immune checkpoint inhibitors (ICIs) have had only modest impact on breast cancer patients’ survival. Mechanistic studies into the interplay between the immune system and the tumor cells identified the tumor microenvironment (TME) as the critical factor in dictating the impact of ICIs on tumor progression. Clinical advancements in ICI efficacy will require combinations with agents that can induce a broad shift in the microenvironmental milieu, which may prove especially important for highly aggressive tumors. Inflammatory breast cancer (IBC) is a rare and highly lethal breast cancer with few therapeutic options. In phase II clinical trial for triple-negative IBC patients, we found that anti-EGFR antibody panitumumab (PmAb) combined with preoperative chemotherapy led to a high treatment response. We further found that in IBC models, PmAb reduced the expression of immunosuppressive chemokines and led to increased infiltration of cytotoxic T cells; suggesting a broad shift from an immunosuppressive to immunoreactive TME. Building on these preliminary findings, we propose to determine the mechanism by which EGFR promotes the expression of immunosuppressive chemokines and if, in turn, this effect is responsible for the observed immunosuppressive TME in IBC. While EGFR inhibition has been examined as a way to target tumor cell proliferation and survival, to our knowledge, no other group has examined EGFR as a modulator of the TME in IBC. We propose 3 aims: Aim 1: Determine the mechanism by which the EGFR pathway modulates the TME in IBC. We hypothesize that the EGFR pathway induces an immunosuppressive TME in IBC through EGR1-regulated expression of immunosuppressive chemokines. We will test this hypothesis via in vitro assays and our novel humanized IBC immunocompetent mouse model. Aim 2: Evaluate the combination of immunotherapy with EGFR inhibition in IBC. We hypothesize that EGFR-targeted therapy will enhance the efficacy of immunotherapy in IBC by shifting the TME from an immunosuppressive to an immunoreactive phenotype. We will test the efficacy of targeting EGFR and inhibiting immune checkpoints in combination using the novel IBC humanized mouse model and triple-negative breast cancer immunocompetent mouse models with intrinsic and acquired resistance to ICIs. Aim 3: Determine the clinical relevance of EGFR-modulated TME changes in IBC. We hypothesize that reduced expression of EGR1 and its likely transcriptional targets correlates with TME immunoreactive status and predicts IBC patient response to PmAb-based therapies. We will assess the clinical relevance of our pathway using an IBC genomic dataset and multiplexed immunostaining on an IBC tissue microarray and IBC tissues from an ongoing PmAb clinical trial. Upon completion, we expect to identify TME changes that predict patient response to EGFR-targeted therapy and establish a novel EGFR-based combination therapy with ICIs for patients with IBC. Beyond IBC, our research will broaden our understanding of how we can modulate the TME as a potential therapeutic approach.


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 = $1,309,379 )
2025	2025	UNIVERSITY OF HAWAII	2425 CAMPUS RD SINCLAIR RM 1	HONOLULU	HI	96822	HONOLULU	USA	Cancer Treatment Research	003	4	9/26/2025	EXTENSION WITH OR WITHOUT FUNDS	$206,580
2025	2025	UNIVERSITY OF HAWAII	2425 CAMPUS RD SINCLAIR RM 1	HONOLULU	HI	96822	HONOLULU	USA	Cancer Treatment Research	002	4	9/10/2025	EXTENSION WITH OR WITHOUT FUNDS	$1,102,799
2025	2023	UNIVERSITY OF HAWAII	2425 CAMPUS RD SINCLAIR RM 1	HONOLULU	HI	96822	HONOLULU	USA	Cancer Treatment Research	001	2	1/15/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$321,897
2025	2022	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	1	1/15/2025	NEW	-$321,897
														Subtotal = $1,309,379

Issue Date FY: 2024 ( Subtotal = $734,453 )
2024	2024	UNIVERSITY OF HAWAII	2425 CAMPUS RD SINCLAIR RM 1	HONOLULU	HI	96822	HONOLULU	USA	Cancer Treatment Research	001	3	8/16/2024	SUPPLEMENT FOR EXPANSION	$192,495
2024	2024	UNIVERSITY OF HAWAII	2425 CAMPUS RD SINCLAIR RM 1	HONOLULU	HI	96822	HONOLULU	USA	Cancer Treatment Research	000	3	8/15/2024	NON-COMPETING CONTINUATION	$541,958
														Subtotal = $734,453

Issue Date FY: 2023 ( Subtotal = $581,465 )
2023	2023	UNIVERSITY OF HAWAII	2425 CAMPUS RD SINCLAIR RM 1	HONOLULU	HI	96822	HONOLULU	USA	Cancer Treatment Research	001	2	9/18/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$581,465
2023	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	1	9/18/2023	NEW	$0
														Subtotal = $581,465

Issue Date FY: 2022 ( Subtotal = $536,764 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	1	2/28/2022	NEW	$536,764
														Subtotal = $536,764

Grand Total All Awards = $3,162,061

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Development of a novel therapy targeting the tumor microenvironment in inflammatory breast cancer

Award Number: R01CA258523

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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