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Rewired Golgi secretion creates a therapeutic vulnerability in chromosome 3q-amplified NSCLC.

Award Number: R01CA316689
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Rewired Golgi secretion creates a therapeutic vulnerability in chromosome 3q-amplified NSCLC. - Abstract Chromosome 3q amplification occurs in more than half of non-small cell lung cancers (NSCLC). Although several oncogenic drivers within this amplicon have been identified, effective therapeutic strategies remain lacking. Emerging evidence indicates that dysregulated Golgi-mediated secretion is a hallmark of epithelial cancers. Cancer cells depend on secreted proteins to support tumor growth, metastasis, and remodeling of the tumor microenvironment; however, efforts to target individual secreted factors have been largely unsuccessful due to functional redundancy, underscoring the need to target the secretory pathway itself. Among the Golgi-associated genes within the 3q amplicon, we identified phospholipase D1 (PLD1) as a promising therapeutic target. Our preliminary studies demonstrate that PLD1 is required for the growth of 3q-amplified NSCLC by promoting oncogenic secretion but is dispensable in 3q-diploid NSCLC and normal bronchial epithelial cells. We further found that transferrin receptor 1 (TfR1) is amplified and highly expressed in 3q-amplified NSCLC, making it an attractive target for antibody–drug conjugate (ADC)-based therapy. In this project, we will define the mechanisms by which PLD1 promotes NSCLC progression and tumor microenvironment remodeling through oncogenic secretion and evaluate the therapeutic efficacy of PLD1 inhibitors and TfR1-targeted ADC formulations, alone or in combination with immune checkpoint blockade, in preclinical mouse models. These studies require mouse models to assess tumor progression, immune responses, metastatic dissemination, and treatment efficacy in a physiologically relevant in vivo setting. Collectively, this work will establish PLD1-driven secretion as a therapeutic vulnerability and provide a foundation for developing new targeted therapies for 3q-amplified NSCLC.


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 = $635,948 )
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	7/23/2026	NEW	$635,948
														Subtotal = $635,948

Grand Total All Awards = $635,948

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Rewired Golgi secretion creates a therapeutic vulnerability in chromosome 3q-amplified NSCLC.

Award Number: R01CA316689

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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