Oral cancer is a disfiguring disease that makes routine tasks like speaking and eating painful chores. Yet help may be on the way as the National Institute of Dental and Craniofacial Research has awarded a pair of researchers from New York University (NYU) a 3-year, $1.2-million grant to test whether their nonviral gene delivery method can effectively and safely treat oral cancer pain.
“Most of my oral cancer patients have severe pain,” said Brian L. Schmidt, DDS, MD, PhD, professor in the department of oral and maxillofacial surgery at the NYU College of Dentistry and director of NYU’s Bluestone Center for Clinical Research and the NYU Oral Cancer Center. “A recent study revealed that oral cancer pain is often more severe than pain from any other type of cancer.”
Many patients rely on high doses of opioids to manage their pain, though these medications lack anatomical specificity and often include significant unwanted side effects that may add to the patient’s suffering. Gene therapy, the researchers believe, is a promising alternative to opioids for treating cancer pain.
“Our gene therapy will set the stage for a new class of medicines that selectively disrupt nociceptive signaling with fewer off-target effects,” said Seiichi Yamano, DDS, PhD, DMD, associate professor in the department of prosthodontics at the NYU College of Dentistry. “Our long-term goal is to develop an effective and safe treatment for oral cancer pain.”
The researchers have demonstrated that OPRM1, the gene for the µ-opioid receptor, is methylated and down-regulated in oral cancer tumors. They also found that OPRM1 re-expression following viral gene transduction significantly reduced cancer pain in a preclinical model. Expression of the µ-opioid receptor on the cancer led to the secretion of opioids into the cancer microenvironment.
Because of safety concerns and viral transduction inefficiency, Yamano created a pair of novel nonviral hybrid vectors: a cell-permeable peptide combined with a cationic lipid or a cationic polymer. These nonviral vectors have excellent transfection efficiency with little cytotoxicity across a range of cell lines including different types of cancer cells.
“In addition to their transfection efficiency, my nonviral vectors preferentially transfect oral cancer cells compared to normal cells,” said Yamano. “Transfection efficiency using the nonviral vector in oral cancer cells showed eightfold more gene transfer than normal cells and higher expression than that for an adenoviral vector.”
In preliminary work supported by bridge funding, Schmidt and Yamano demonstrated that the nonviral vectors could be used to deliver OPRM1 to oral cancers and reverse cancer pain in the preclinical model.
“Our long-term goal is to develop an effective and safe treatment for oral cancer pain,” said Schmidt. “These studies are a significant step toward that goal. We foresee clinicians directly inoculating our nonviral vector into oral cancers.”
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