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HER3-PHF8 signaling axis in triple-negative breast cancer progression

Award Number: R01CA266269
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/23/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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HER3-PHF8 signaling axis in triple-negative breast cancer progression - Triple-negative breast cancer (TNBC) is defined as a breast cancer (BC) subtype lack of estrogen receptor (ER) and progesterone receptor (PR) expression and HER2 amplification/overexpression. It represents a significant clinical challenge because the patients with TNBC have a poor prognosis and account for a disproportionate number of BC deaths. Although targeted therapies, including PARP inhibitors and a Trop-2-directed antibody (Ab)-drug conjugate as well as immunotherapy (anti-PD-1/PD-L1 Abs) have been approved to treat advanced/metastatic TNBC, chemotherapy currently remains the mainstay for a large part of TNBC patients and initially effective. However, drug resistance and tumor recurrence frequently occur, suggesting that TNBC is highly heterogenerous and it is in urgent need to develop more effective molecular- based therapies for this aggressive disease. We recently discovered an elevated expression of HER3 (or erbB3) in about half of the TNBC clinical samples and cell lines examined. Bioimformatics analyses of TCGA datasets revealed that high erbB3 expression significantly associated with poorer outcomes in TNBC patients, especially those with the subtypes of Basal-like 1 (BL1), Luminal-Androgen receptor (LAR), or Basal-like 2 (BL2). We then identified PHF8 (PHD finger protein 8, or KDM7B, a histone lysine demethylase) as one of the most downregulated epigenetic modifiers upon silencing of erbB3 in a BL2-TNBC cell line. The positive correlation of erbB3 and PHF8 was further supported via analysis of BC clinical samples and cell lines. Moreover, studies with gain-of-function and loss-of-function approaches indicated that PHF8 played a crucial role in HER3-mediated promotion of BL1/2-TNBC cell growth, migration, and invasion. Thus, we hypothesize that PHF8 functions as a key downstream mediator of HER3 signaling in BL1/2-TNBC progression and metastasis; and inhibition of HER3 or PHF8 will significantly enhance the efficacy of chemotherapy against TNBC. We intend to define the molecular basis of HER3 signaling-mediated upregulation of PHF8 in TNBC and subsequent tumor progression and metastasis, and to determine the therapeutic potential of inactivation of HER3 or PHF8 in combination with chemotherapy against TNBC.


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 = $404,942 )
2025	2025	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER NEW ORLEANS	433 BOLIVAR ST RM 619	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Treatment Research	000	3	11/15/2024	NON-COMPETING CONTINUATION	$364,448
2025	2025	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER NEW ORLEANS	433 BOLIVAR ST RM 619	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Treatment Research	001	3	6/4/2025	NON-COMPETING CONTINUATION	$40,494
														Subtotal = $404,942

Issue Date FY: 2024 ( Subtotal = $390,376 )
2024	2024	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER NEW ORLEANS	433 BOLIVAR ST RM 619	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Treatment Research	001	2	4/18/2024	NON-COMPETING CONTINUATION	$20,547
2024	2024	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER-NEW ORLEANS	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Treatment Research	000	2	11/28/2023	NON-COMPETING CONTINUATION	$369,829
														Subtotal = $390,376

Issue Date FY: 2023 ( Subtotal = $416,723 )
2023	2023	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER-NEW ORLEANS	433 BOLIVAR ST STE 815	NEW ORLEANS	LA	70112	ORLEANS	USA	Cancer Treatment Research	000	1	12/23/2022	NEW	$416,723
														Subtotal = $416,723

Grand Total All Awards = $1,212,041

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HER3-PHF8 signaling axis in triple-negative breast cancer progression

Award Number: R01CA266269

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/23/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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