[R03] Chemoprevention of head and neck cancer using combination of natural compounds
Ente: National Institute of Dental and Craniofacial Research
Scadenza: 2028-07-31
Importo max: 295.000 EUR
Paese: US
Descrizione
PROJECT SUMMARY
Head and neck squamous cell carcinoma (HNSCC) is a devastating disease with significant morbidity and
mortality; 72,680 projected new cases and 16,680 deaths in the US in 2025. Delaying and preventing the
progression of premalignant lesions to invasive cancer by chemoprevention can save thousands of lives;
currently no such treatment regimen is available. An effective chemoprevention method implemented before
invasive cancer develops is warranted to reduce the incidence of HNSCC. This research will investigate the use
of diet-derived natural compounds EGCG and resveratrol as a novel combination for chemoprevention of this
deadly cancer. Carcinogenesis initiates with an irreversible genetic mutation caused by endogenously-derived
or carcinogen-induced oxidative stress when physiological repair mechanisms fail. The transcription factor NRF-
2 is activated in response to oxidative stress and essential for detoxifying carcinogens and carcinogen-induced
oxidative stress, thus compounds capable of activating this pathway are suitable for chemoprevention. The
combination of EGCG and resveratrol demonstrates activation of genes associated with xenobiotic metabolism
and antioxidant defense against oxidative stress. In this proposal, we will develop the combination of resveratrol
and EGCG as a regimen for the chemoprevention of HNSCC. Our previously published data demonstrates that
the combination of EGCG and resveratrol induces synergistic apoptosis and more effectively inhibits HNSCC
xenografts in nude mice that any single agent by inhibiting the AKT-mTOR pathway. More importantly, the
combination also significantly inhibits 4NQO-induced oral carcinogenesis in mice. This proposal will test the
ability of the combination of EGCG and resveratrol to prevent or delay the development and progression of oral
lesions in carcinogen-induced oral cancer models in a GDF15-dependent manner and uncover the cell signaling
mechanism(s) of action for this agent. We hypothesize that the combination of EGCG and resveratrol induces
chemopreventive effect by activating the antioxidant and the xenobiotic metabolism pathways and by
upregulating the expression of GDF15. Two specific aims are proposed. Aim 1: Demonstrate the molecular
pathway for chemoprevention of HNSCC by EGCG and resveratrol. We will study the role of the NRF2-
mediated oxidative stress pathway that ameliorates carcinogen-induced oxidative stress and mutagenicity. Aim
2: Explore the role of GDF15 in 4-NQO-induced oral carcinogenesis and chemoprevention by the
combination of resveratrol and EGCG. 4-NQO-induced oral cancer in mice will evaluate the role of GDF15 in
oral carcinogenesis and the prevention or delay in oral carcinogenesis with the administration of EGCG and
resveratrol. The outcome of the in vivo studies will confirm the chemoprevention effects of the combination of
EGCG and resveratrol in HNSCC and will pave the way for further clinical development of this novel combination.
Istituzione: MARSHALL UNIVERSITY
PI: A.R.M. Ruhul Amin
Progetto: 1R03DE036365-01
Settori: National Institute of Dental and Craniofacial Research
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