The National Institute of Dental and Craniofacial Research (NIDCR), part of the National Institutes of Health (NIH), has awarded Drs. Brian Schmidt and Seiichi Yamano a $1.2M (3-year) grant to test whether their non-viral gene delivery method can effectively and safely treat oral cancer pain.
Quality of life for oral cancer patients can be dismal.
"Most of my oral cancer patients have severe pain," says Brian L. Schmidt, DDS, MD, PhD, professor in the Department of Oral and Maxillofacial Surgery at New York University College of Dentistry (NYU Dentistry) and director of NYU's Bluestone Center for Clinical Research and of 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."
Due to their severe pain, oral cancer patients have difficulty eating, drinking, or talking, leaving doctors with little or no choice other than to prescribe high doses of opioid medications.
"The clinical challenge of treating oral cancer pain is then compounded by the off-target effects produced by pharmacological agents which lack anatomical specificity," notes Dr. Schmidt, "since high opioid doses generate unwanted side effects that create additional unintended suffering for the patient."
"Gene therapy is emerging as an exciting alternative to opioids for the treatment of cancer pain," says Seiichi Yamano, DDS, PhD, DMD, MMSc, associate professor in the Department of Prosthodontics at NYU Dentistry. "We seek to alleviate oral cancer pain by reversing epigenetic changes. Our gene therapy method will set the stage for a new class of medicines that selectively disrupt nociceptive signaling with fewer off-target effects. Our long-term goal is to develop an effective and safe treatment for oral cancer pain."
Dr. Schmidt's research team demonstrated that OPRM1 (the gene for the μ-opioid receptor) is methylated and down regulated in oral cancer tumors. They also demonstrated 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, Dr. Yamano created two novel nonviral hybrid vectors: a cell-permeable peptide (CPP) combined with either a cationic lipid (CPP/lipid) or a cationic polymer (CPP/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 non-viral vectors preferentially transfect oral cancer cells compared to normal cells," says Dr. Yamano. "Transfection efficiency using the nonviral vector in oral cancer cells showed eight-fold more gene transfer than normal cells and higher expression than that for an adenoviral vector."
In preliminary work funded by a High Priority, Short-Term Project Award (R56DE025393) from the NIDCR, Dr. Schmidt and Dr. Yamano demonstrated that the nonviral vectors could be used to deliver OPRM1 to oral cancers and reverse cancer pain in the preclinical model.
"Dr. Yamano and I collaborated over the last five years in preparation for the work described in this current grant," notes Dr. Schmidt. "I found that delivery of the OPRM1 gene into the cancer reversed cancer pain. I just needed a safe method to deliver the gene. Dr. Yamano's non-viral method is ideal. Our previously awarded bridge funding allowed us to develop preliminary data for the application. Our long-term goal is to develop an effective and safe treatment for oral cancer pain. These studies are a significant step toward that goal. We foresee clinicians directly inoculating our non-viral vector into oral cancers."