# Secondary Chemoprevention of Oral Cancer by Locally Delivered Agents

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $356,255

## Abstract

Approximately 48,330 new cases of oropharyngeal cancer and 9,570 deaths will occur in the US during 2016.
Despite vigilant monitoring and well-recognized risk factors for tumor recurrence over 1/3 of patients previously
treated for oral squamous cell carcinoma (OSCC) develop life-threatening and often fatal recurrent cancers.
Recent cancer-targeted therapies, which were developed to exploit cancers' reliance on overexpressed
pathways and hopefully reduce collateral damage to healthy tissues, were thought to have cancer preventing
potential. Their efficacies, however, become limited by cancer's alternate signaling pathways and
compensatory mechanisms. OSCC is an extremely complex and consistently changing disease. Consequently,
we hypothesize that OSCC secondary chemoprevention needs to be equally dynamic to disrupt its
tumorigenic properties at multiple levels. We have identified three complementary agents [fenretinide (4-HPR),
2-methoxyestradiol (2-ME) & tocilizumab (TOC)] which are capable of multifaceted chemoprevention at the
intracellular, tumor-stroma, and tumor-ECM levels when locally delivered. While these agents have been used
as monotherapy, they have not been combined as chemopreventives, much less in controlled release delivery
formulations. The Specific Aims of this proposal are: 1) Investigate the effect of 4-HPR, 2-ME and TOC on
OSCC gratuitous signaling, intracrine/paracrine growth loops, unlimited replication, and conversion to an
invasive phenotype., 2) Optimize controlled-release local delivery formulations for secondary OSCC
chemoprevention., 3) Evaluate the efficacy and pharmacokinetics of locally delivered 4-HPR, 2-ME and TOC
using an orthotopic OSCC xenograft model. Research methodology will include a variety of biochemical,
molecular and computational analyses (Aim 1), pharmaceutical chemistry technology (Aim 2), and tumor
biology-pathology and pharmacokinetics studies (Aim 3). Anticipated results include: 1) all 3 agents will
suppress inappropriately sustained proliferation, 2) TOC's IL-6R antagonism will suppress IL-6 mediated
intracrine/paracrine signaling and IL-6's Stat3 activation, 3) 4-HPR and 2-ME will induce apoptosis with
additive effects when in combination, 4) 4-HPR will induce keratinocyte differentiation, 5) 4-HPR and 2-ME will
have the greatest signaling inhibition in cells with constitutive Stat3 and NF-κB activation, 6) 4-HPR `s abilities
to bind and block ATP binding on the FAK & Pyk2 signaling kinases and inhibit F-actin organization and 2-
ME's perturbation of microtubules will suppress invasion. It is also anticipated that agent combinations will
provide more extensive chemopreventive responses and that optimal cancer-preventing effects will be
observed during use of 3 agents concurrently both in vitro and in vivo.

## Key facts

- **NIH application ID:** 10147658
- **Project number:** 5R01CA211611-05
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Susan R Mallery
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $356,255
- **Award type:** 5
- **Project period:** 2017-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10147658

## Citation

> US National Institutes of Health, RePORTER application 10147658, Secondary Chemoprevention of Oral Cancer by Locally Delivered Agents (5R01CA211611-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10147658. Licensed CC0.

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