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Inhibiting mitochondrial complex I to improve cetuximab efficacy in oral cancer

Award Number: R01DE033691
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Inhibiting mitochondrial complex I to improve cetuximab efficacy in oral cancer - PROJECT SUMMARY Oral squamous cell carcinoma (OSCC) is the most common type of head and neck cancer. Most patients with OSCC are diagnosed at advanced stages and have significant mortality and recurrence rates. In addition to PD- 1-based immunotherapy, cetuximab (CTX) is the only FDA-approved anti-epidermal growth factor receptor (EGFR) monoclonal antibody to treat this disease. However, only a small proportion of OSCC patients benefit from CTX monotherapy or CTX-based combination therapies, and most of them eventually develop resistance. These clinical challenges underscore the need to develop safer and more effective treatment strategies to improve the efficacy of CTX therapy in OSCC. Through an unbiased genome-wide CRISPR/Cas9 knockout screening, we have identified TNF-mediated pro-survival pathway as the dominant driver of reduced CTX efficacy in OSCC cells. Strikingly, IACS-010759 (IACS), an orally bioavailable mitochondrial complex I inhibitor, redirects TNF signaling from cell survival to gasdermin D (GSDMD)-mediated pyroptosis in CTX-treated OSCC cells via a reactive oxygen species (ROS)-dependent mechanism. Our pilot studies in a human EGFR (hEGFR)- expressing murine oral cancer model further demonstrated that CD8+ T cell-mediated anti-tumor immunity is essential for CTX/IACS-induced remission of GSDMD+ oral tumors. Based on these novel and significant findings, we formulated our central hypothesis that the therapeutic efficacy of CTX/IACS combination is not only due to its ability to suppress tumor growth, but also critically depends on the interplay between therapy-induced pyroptotic tumor cells and the host immune system, leading to a durable and more effective elimination of OSCC. This mechanism-driven project will integrate unbiased molecular and immunological technologies and multiple preclinical models to advance our understanding of the molecular and immunological mechanisms, and to develop an improved CTX/IACS combination therapy to facilitate clinical translation. To achieve these goals, we will elucidate the mechanisms by which IACS is synergistic with CTX against OSCC by inducing NLRP3 inflammasome-dependent pyroptosis (Aim 1) and define the immunomodulatory mechanisms and effects associated with OSCC cell pyroptosis induced by the combination of CTX/IACS (Aim 2). We will also evaluate an improved CTX/IACS combination therapy designed with tumor-targeting nanotechnology to maximize efficacy while minimizing toxicity to facilitate clinical translation (Aim 3). Results of this project should provide us with preclinical data for the translational development of a Phase 1 clinical trial using this novel combination strategy to preferentially target EGFR-overexpressing OSCC.


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 = $378,951 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Oral Diseases and Disorders Research	001	2	5/7/2025	NON-COMPETING CONTINUATION	$37,895
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Oral Diseases and Disorders Research	000	2	4/16/2025	NON-COMPETING CONTINUATION	$341,056
														Subtotal = $378,951

Issue Date FY: 2024 ( Subtotal = $386,463 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Oral Diseases and Disorders Research	000	1	2/22/2024	NEW	$386,463
														Subtotal = $386,463

Grand Total All Awards = $765,414

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Inhibiting mitochondrial complex I to improve cetuximab efficacy in oral cancer

Award Number: R01DE033691

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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