New NIH grants fuel research in oral cancer treatment and pain relief

Researchers at the School of Dentistry at UT Health San Antonio, the academic health center of The University of Texas at San Antonio, have been awarded three multi-year grants totaling $6 million from the National Institutes of Health to address treatment and pain management for oral cancer.

The grants propose new targets to stem deadly oral squamous cell carcinoma and novel approaches to treat oral mucositis, massive inflammation and ulcers in the oral cavity that can result from radiotherapy treatment. Also, one of the grants will investigate a new mechanism for reducing oral cancer pain, aimed at providing knowledge for future research to develop drugs for both pain management and cancer treatment.

Taken together, these grants represent new promise in addressing both the treatment and conditions of oral cancer that, unfortunately, is growing more common and carries relatively low survival rates. In so doing, this research could lead to the development of new and transformative therapies."

Kenneth Hargreaves, DDS, PhD, professor and dean of the School of Dentistry, and director of its Center for Pain Therapeutics and Addiction Research

Treating a deadly cancer

There is a big need to develop new therapies to treat oral squamous cell carcinoma, which develops in the lining of the mouth and accounts for more than 95% of oral cancer cases. The condition is ever-increasing with the majority of patients presenting with late-stage disease and a subsequent five-year overall survival rate as low as 38%.

The disease makes up the majority of all head and neck cancers, resulting in 11,000 deaths in the United States each year. Currently, about 200,000 people nationwide are living with the condition.

A two-year, $315,000 grant to principal investigator Cara Gonzales, DDS, PhD, associate professor of comprehensive dentistry at the School of Dentistry, will evaluate the feasibility of targeting TRPC1 (Transient Receptor Potential Canonical 1), a positively charged ion channel located in the cell membrane that regulates the flow of sodium and calcium ions into cells.

Her study will do so using xenograft and syngeneic mouse oral squamous cell carcinoma models. A xenograft mouse model is an experimental tool where human cells or tissues are transplanted into immunodeficient mice to study disease, while a syngeneic mouse model is an immunocompetent mouse with a tumor that originated from a genetically identical mouse strain.

Those studies will determine potential efficacy, toxicities and changes in immune cell populations with TRPC1 "knock-out," or inactivation, and pharmacological inhibition, which refers to the use of a drug or small molecule to suppress or block a specific biological function or action.

"Our overarching hypothesis is that TRPC1 inhibition will selectively kill oral cancer cells while leaving immune cell populations unharmed," Gonzales said. The grant, titled, "Targeting TRPC1: A Novel Approach to Treat Oral Cancer," was awarded in August.

Addressing a painful side-effect

Radiation-induced oral mucositis (RIOM), with its painful inflammation and ulcers, commonly develops in the oral cavity following radiotherapy in head and neck cancer patients, disrupting both the patient's quality of life and cancer treatment. But its mechanisms are not completely understood, which has slowed development of new therapies.

A five-year, $3.1 million grant to principal investigators Shivani Ruparel, PhD, professor of endodontics and deputy director of the Center for Pain Therapeutics and Addiction Research, and Brij B. Singh, PhD, associate dean for research, both with the School of Dentistry, proposes a novel mechanism that investigates the role of calcium, TRPM2 and inflammasome signaling in the pathogenesis of oral mucositis.

TRPM2 (Transient Receptor Potential Melastatin 2), is a calcium-permeable ion channel implicated in oxidative stress and inflammation, both processes involved in RIOM. Inflammasome signaling is a cellular process where multiprotein complexes called inflammasomes are assembled inside a cell to trigger an inflammatory response.

"Our goal is to investigate the role of TRPM2 in the development of RIOM and evaluate the potential of TRPM2 inhibition as a preventive treatment," Singh said of the grant, titled, "TRPM2-Mediated Immune Activation Initiates Radiation-Induced Loss of Oral Function," awarded in June. "We believe this will provide important new insights into new, effective treatment strategies."

Managing oral cancer pain

Pain management is a significant problem for oral cancer patients. But as with mucositis, its mechanisms are not completely understood, impeding development of novel analgesics.

Under a four-year, $2.6 million grant award, principal investigator Ruparel will lead an effort to study the role of truncated TrkBT1 isoform – an alternative version of the Tyrosine Kinase B receptor, known to be associated with conditions including neuropathic pain and injury – in mediating pain at the site of tumor development.

"Given that TrkBT1 is the predominant isoform highly expressed in oral cancers, targeting this receptor signaling can prove to be an effective therapy for cancer-induced pain as well as tumor progression," Ruparel said.

She notes that it often has been very difficult to treat pain from oral cancer with available medications, typically opiates, because of limited effectiveness or rapid development of tolerance.

"This study's relevance lies in its potential to uncover novel therapeutic targets for managing oral cancer-induced pain and improving patients' quality of life," Ruparel said. "By investigating the role of TrkBT1 in both sensory neurons and the tumor microenvironment, the research may pave the way for innovative treatments that address pain and oral tumorigenesis simultaneously."

Titled, "Contribution of Truncated TrkB Isoform in Oral Cancer Pain," the grant was awarded in August.

The three grants fall under or cross the dental school's Center for Regenerative Sciences (Gonzales), Center for Pain Therapeutics and Addiction Research (Ruparel) and both centers (Ruparel/Singh).