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Targeting oncogenic pathways for chemoprevention of head and neck cancer by FLLL12

Award Number: R15DE032063
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: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Targeting oncogenic pathways for chemoprevention of head and neck cancer by FLLL12 - PROJECT SUMMARY The delay or prevent the progression of premalignant lesions to invasive cancer by chemoprevention of squamous cell carcinoma of head and neck (SCCHN) is a devastating disease with significant morbidity and mortality. This research will investigate the use of FLLL12, a compound structurally related to the natural compound curcumin, as a novel compound for chemoprevention of this deadly cancer; FLLL12 demonstrates a cell signaling profile of binding to Janus kinase (JAK)2 and inhibition of the phosphorylation of STAT3. In addition, FLLL12 inhibits EGFR and AKT transcripts resulting in inhibition of EGFR/AKT-mTOR signaling. These signaling pathways confer cells with the ability to acquire the advantage of unlimited growth and resistance to cell death - two hallmarks of carcinogenesis. An effective chemoprevention method implemented before an invasive cancer develops is needed to reduce the incidence of SCCHN; however, currently no such treatment regimen is available. Thus, the identification of new compounds effective in preventing SCCHN carcinogenesis is warranted. In this proposal, we will develop FLLL12 as a therapeutic agent for the chemoprevention of SCCHN. Our preliminary data demonstrate that FLLL12 has IC50 values in a highly selective range (<1 µM against most SCCHN cell lines and 0.35 µM against a premalignant oral cancer cell line). Pharmacokinetic studies reveal that a pharmacologically relevant concentration is achievable in mice. FLLL12 also effectively inhibits tumor growth in a xenograft model of SCCHN. This proposal will test the ability of FLLL12 to prevent or delay the progression of premalignant lesions to SCCHN in a carcinogen-induced oral cancer model in a mouse model and uncover the cell signaling mechanism(s) of action for this agent. We hypothesize that FLLL12 regulates JAK-STAT3 and EGFR/AKT-mTOR survival pathways to reverse and/or slow the progression of premalignant lesions to a squamous cell cancer. Three specific aims are proposed. Aim 1: Evaluate the JAK-STAT3 pathway as a direct target of FLLL12. We will test the prediction that FLLL12 interacts with JAK2 and inhibits JAK-STAT3 pathway to mediate the chemoprevention effects of this compound. A cell free system, in vitro kinase assays, reporter assays and a constitutively active STAT3 plasmid will be used. Aim 2: Define the mechanism of regulation of the EGFR-AKT pathway by FLLL12. By employing promoter deletion-mutation, we will identify transcription factor(s) that inhibit EGFR and AKT transcripts. Aim 3: Analyze the in vivo efficacy of FLLL12 as a chemoprevention agent in a carcinogen-induced oral carcinogenesis model. A 4NQO-induced oral cancer mouse model will evaluate the prevention or delay in oral carcinogenesis with administration of FLLL12. The outcome of the in vivo studies will confirm the chemoprevention effects of FLLL12 in SCCHN. Importantly, this R15 award will provide a stimulating training opportunity for undergraduate and graduate students to participate actively in the research and discovery process to improve our understanding of the signal transduction pathways involved in cancer biology.


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 = $0 )
2026	2023	MARSHALL UNIVERSITY RESEARCH CORPORATION	1 JOHN MARSHALL DR	HUNTINGTON	WV	25755	CABELL	USA	Oral Diseases and Disorders Research	000	1	7/29/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	MARSHALL UNIVERSITY RESEARCH CORPORATION	1 JOHN MARSHALL DR	HUNTINGTON	WV	25755	CABELL	USA	Oral Diseases and Disorders Research	000	1	6/20/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $444,000 )
2023	2023	MARSHALL UNIVERSITY RESEARCH CORPORATION	ONE JOHN MARSHALL DRIVE	HUNTINGTON	WV	25755	CABELL	USA	Oral Diseases and Disorders Research	000	1	7/25/2023	NEW	$444,000
														Subtotal = $444,000

Grand Total All Awards = $444,000

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Targeting oncogenic pathways for chemoprevention of head and neck cancer by FLLL12

Award Number: R15DE032063

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: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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