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.

Grant Number: 1R15DE032063-01A1
NIH Institute/Center: NIH
Principal Investigator: A.R.M. Amin