Inhibition of hedgehog signaling as a therapeutic strategy for oscc

Rowan University School of Osteopathic Medicine received a $616,000 Project Grant award from the National Institute of Dental and Craniofacial Research (NIDCR) under the Oral Diseases and Disorders Research program (CFDA 93.121), effective August 1, 2025, through July 31, 2029. The award supports basic and translational research investigating hedgehog (HH) signaling inhibition as a therapeutic strategy for oral squamous cell carcinoma (OSCC), which represents over 90% of oral cancer cases and accounts for approximately 12,000 deaths annually in the United States.

The research initiative encompasses three primary aims: (1) evaluating how the HH pathway inhibitor sonidegib reduces OSCC cell viability through gene and protein analyses, assessing mechanisms including cell proliferation, inflammation, oxidative stress, and apoptosis; (2) determining how sonidegib decreases OSCC cell migration using motility assays and evaluation of motility markers such as podoplanin, MMP-2, and MMP-9; and (3) investigating the synergistic effects of combining sonidegib with FDA-approved therapies. The research utilizes recently derived OSCC patient-derived cell lines adapted to in vitro cultures, representing current disease characteristics and providing innovative preclinical models for advancing prevention and treatment strategies for oral and craniofacial disease.

Abstract

Oral cancer is a global health crisis. Within the united states alone, an estimated 58,000 oral cancer cases and over 12,000 related deaths are projected for 2024. More than 90% of oral cancers are oral squamous cell carcinoma (oscc). Current treatments have challenges, and more effective treatments are required. Growing evidence suggests hedgehog (HH) signaling as one of the key drivers of oscc progression and metastasis. HH signaling induces the expression of genes that promote cancer, including those involved in cell proliferation and migration. HH pathway inhibition (HPI) drugs have been FDA-approved or under clinical trial for treating various cancers. However, the therapeutic potential of HPI drugs against oscc is not clearly elucidated. We hypothesize HPI could serve as a therapeutic strategy for oscc. To test this hypothesis, we evaluated the effects of the HPI drug sonidegib on the viability of oscc cells, which were recently derived from oscc cancer patient tissue and adapted to in vitro cultures. Our innovative research design includes oscc cells representing current disease characteristics. Our preliminary data show that sonidegib significantly reduces oscc cell viability. Thus, our first aim investigates how sonidegib decreases oscc cell viability. We will employ imaging and viability assays, as well as gene and protein analyses, to evaluate the effects of sonidegib on oscc cells. We will specifically assess reductions in cell proliferation, inflammation, oxidative stress, and apoptosis inhibition. Additionally, sonidegib can reduce the expression of motility markers, including podoplanin, MMP-2, and MMP-9. We hypothesize that sonidegib can inhibit oscc cell migration. In our second aim, we will utilize motility assays to determine how sonidegib decreases oscc cell migration. Our third aim focuses on determining the synergistic effects of pairing sonidegib with FDA-approved drugs currently in trials for oscc but not targeting HH signaling. We hypothesize that these combination therapies will exert a greater inhibitory effect on oscc growth and motility compared to individual HPI treatment. We will evaluate cytotoxic, cytostatic and migratory markers from aim 1 and aim 2 to quantify the synergistic effects. We will employ RNA-SEQ to identify key driver genes to further understand the mechanism of action of sonidegib on oscc cells, both alone and in combination with other drugs. The implications of our research are significant: by targeting a major pathway involved in oscc, we aim to improve treatment outcomes and the quality of life for oscc patients. We focus on orally available drugs to offer convenient administration and pharmacokinetics to offer expedite relief to those suffering from oscc. Together, our work will alleviate the burden of this devastating disease and pave the way for more effective oscc treatments. Additionally, the proposal will serve as an excellent platform for training undergraduate and graduate students at rowan university in oral cancer research and cancer drug discovery development utilizing various molecular biology techniques and bioinformatics.