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NYU College of Dentistry clinician-scientists Seiichi Yamano and Brian Schmidt have set out to develop a new class of medicines using gene therapy to effectively and safely treat oral cancer pain.
The National Institute of Dental and Craniofacial Research (NIDCR), part of the National Institutes of Health (NIH), has awarded the researchers a five-year, $2.9 million grant (R01DE029694) to test whether nonviral co-delivery of DNA and RNA will safely alleviate oral cancer pain.
Patients with oral cancer often suffer from severe pain. These patients may find it difficult to eat, drink or even talk. The opioid medications used to treat oral cancer pain become less effective as patients develop drug tolerance, and cause numerous debilitating side effects.
Gene therapy offers an alternative to opioids for the treatment of cancer pain by reversing cancer-induced epigenetic changes. This approach selectively disrupts pain signaling without the side effects of opioids.
“Complete elimination of cancer pain in a patient is exceptionally challenging because there are multiple and redundant pain-signaling mechanisms and pathways,” explained Schmidt, who is a professor in the Department of Oral and Maxillofacial Surgery at NYU College of Dentistry as well as the director of NYU’s Bluestone Center for Clinical Research and the NYU Oral Cancer Center.
As a strategy to obstruct these multiple and varied pathways, Yamano and Schmidt created two nonviral vectors that can efficiently deliver DNA and RNA to cells (transfection) with no toxicity: a cell-permeable peptide combined with a cationic lipid for DNA, and a lipopolymer for RNA. They hypothesize that the combination of OPRM1 (mu opioid receptor gene) re-expression and F2RL1 (gene for protease-activated receptor-2, or PAR2) downregulation in the cancer could eliminate cancer pain.
In preliminary studies, Yamano and Schmidt demonstrated that nonviral transfection with OPRM1 DNA led to re-expression of the mu opioid receptor and partial reduction of pain in preclinical cancer models. PAR2 was found to be elevated in certain neurons that supply the cancer with nerves and drive pain. Knockdown of the F2RL1 gene partially attenuated pain.
In their newly funded NIH grant, the researchers will test whether the combination of OPRM1 re-expression and F2RL1downregulation in the cancer can go beyond reducing cancer pain to eliminate it.
“Our approach is innovative because delivering DNA and RNA into a cancer with nonviral vectors for the management of pain has not been done before,” said Yamano, an associate professor of prosthodontics at NYU College of Dentistry. “If we are successful, the knowledge generated through this research could set the stage for a clinical trial and ultimately lead to the development of novel non-opioid medicines for cancer pain.”
Yamano and Schmidt have collaborated on this work over the past decade; their efforts have been supported by three previous NIH-funded grants.
(Source: NYU College of Dentistry)