The School of Dentistry at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) earned the first National Institutes of Health grant under its new Center for Pain Therapeutics and Addiction Research, addressing pain in patients with head and neck carcinoma.
The nearly $600,000 grant by the NIH's National Institute of Dental and Craniofacial Research will address this critical pain issue that significantly impairs quality of life. Many head and neck carcinoma patients require opiate pain management, but tolerance develops quickly, requiring new pain relief approaches.
"It is often very difficult to treat pain from oral cancer with available medications due to limited effectiveness or rapid development of tolerance," said Shivani Ruparel, PhD, associate professor of endodontics at the UT Health San Antonio School of Dentistry, and the grant's recipient and principal investigator.
We propose a novel mechanism of oral cancer pain that will provide knowledge for future research at developing drugs for not only pain management but also cancer treatment."
Shivani Ruparel, Associate Professor, San Antonio School of Dentistry, The University of Texas Health Science Center at San Antonio
The Center for Pain Therapeutics and Addiction Research, started in June this year, represents a transformative multidisciplinary approach to decrease pain and addiction. It focuses on both the mechanisms of pain and therapies to reduce or block its transmission, whether oral-facial or other regions of the body.
Therapies include novel, non-addictive medications, diet/nutritional modification and alternative therapies.
"This important NIH grant will support the groundbreaking research of Dr. Shivani Ruparel who is leading efforts towards novel mechanisms of orofacial pain and its treatment," said Kenneth M. Hargreaves, DDS, PhD, professor of endodontics at the UT Health San Antonio School of Dentistry and inaugural director of its Center for Pain Therapeutics and Addiction Research. "By expanding our knowledge of pain biology, we can leverage these findings into tomorrow's new medications."
Targeting oral pain mechanisms
Pain is the No. 1 symptom of oral cancer patients that makes them go to the doctor. They experience pain as soon as a tumor develops in the oral cavity, and it increases as the tumor progresses. Therefore, these patients go through pain throughout the course of the disease that adds so much more to the burden of having cancer.
Unfortunately, pain management in these patients is not adequate because of limited treatment options available. This new study seeks to better understand the mechanisms of oral cancer pain to develop novel analgesics.
Tyrosine kinase receptors, a group of proteins found on the surface of cells important in many cell functions, have gained attention due to the emergence of small-molecule inhibitors for cancer treatment. Brain-derived neurotrophic factor, a protein vital for cognitive performance, together with its tyrosine kinase receptor are known to be overexpressed in oral tumors and implicated in cancer progression.
Ruparel's team of researchers for the first time demonstrated that this pathway not only promotes tumor progression but also drives pain produced from the tumor at the very site of tumor growth. They have shown that brain-derived neurotrophic factor released from oral squamous cell carcinoma cells influences pain transmission, which can be reversed by inhibiting its receptor locally.
This indicates that this receptor potentially can be targeted to treat oral cancer pain without causing side effects typically observed with centrally acting drugs such as opioids.
Their preliminary data suggests that the truncated receptor is a predominant isoform or protein type in trigeminal sensory neurons that send pain signals for the head and face, as well as in oral squamous cell carcinoma cells, and is involved in oral cancer pain regulation.
Accordingly, the researchers aim to investigate the receptor's role in sensory neurons and its impact on pain behaviors, neuronal plasticity and gene expression. And they will examine whether that receptor derived from oral squamous cell carcinoma cells regulates pain-associated changes in the tumor microenvironment by assessing immune cell profiles, transcriptomic changes and single-cell analysis in tongue tumors.
"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.
"Specifically, we propose to study the role of the truncated tyrosine kinase receptor isoform of the brain-derived neurotrophic factor in mediating pain at the site of tumor development," she said. "Given that this isoform contributes to tumor progression, targeting this receptor signaling can prove to be effective therapy for cancer-induced pain as well as tumor progression."
The research has broad implications.
"Dr. Shivani Ruparel's research addresses the critical need of pain management for those suffering from oral cancer," said Peter M. Loomer, DDS, PhD, MBA, professor and dean of the UT Health San Antonio School of Dentistry. "Oral cancer is a significant health issue in South Texas, and Dr. Ruparel works towards improving the quality of life of those suffering from this devastating disease."
Triptans better at relieving migraine pain than recently marketed and more expensive drugs