Researchers are edging closer to understanding an intracellular mechanism that might prove to be an effective target for treating oral cancer pain and inflammation without the side effects and risks of opioids or non-steroidal anti-inflammatory drugs (NSAIDs).
In late January, the NIH awarded $3.7 million to a pair of investigators to help fund their groundbreaking work in better understanding and potentially developing treatments for oral cancer pain, based on findings that some pain signals originate from within nerve cells rather than exclusively from surface receptors.
Current pain medications, notably opioids and NSAIDs, can only target and quiet pain receptors on their outer surface. By targeting pain receptors that migrate from the surface to within endosomes, the researchers hope to develop more potent and longer-lasting pain medications.
New York University's Brian Schmidt, DDS, MD, PhD, together with Nigel Bunnett, PhD, at Columbia University's Departments of Surgery and Pharmacology, received the grant from The National Institute of Dental and Craniofacial Research. Schmidt is Director of the Bluestone Center for Clinical Research at NYU's College of Dentistry, while Bunnett is Vice Chair of Dental Surgery and Pharmacology at Columbia.
Schmidt is a clinical research scientist and surgical oncologist specializing in neuronal mechanisms of cancer pain, while Bunnett is an internationally recognized expert on cellular mechanisms of pain, itching, and neurogenic inflammation, notably G protein-coupled receptors and transient receptor potential ion channels.
The 5-year grant will be used to identify proteases-enzymes that catalyze the breakdown of proteins-and neuronal signaling pathways that initiate and sustain oral cancer pain from inside of nerve cells.
In a landmark study, researchers led by Bunnett demonstrated that tryptase-a degradatory enzyme involved in triggering inflammation-activates a new class of receptor called protease-activated receptor, or PAR2 (Nature Med 2000;6:151-158).PAR2 is a G protein-coupled receptor (GPCR) believed to be a key signaling receptor and major mediator of neurogenic inflammation and pain.
GPCRs control many physiological processes in the body and are thought to be cell surface sensors of extracellular signals, including sensing and transmitting pain signals. They are targeted by about one-third of all therapeutic medications. The researchers believe that excessive proteases present in oral cancer react with the PAR2 enzyme in cancer cells, sending pain signals to the brain.
Subsequent research has demonstrated the role of PAR2 and TRPV, a cell membrane ion channel called a capsaicin receptor, in neurogenic inflammation and pain.
More recently, Bunnett discovered that that, during the pain signaling process, PAR2 is internalized within endosomes. The researchers wondered if proteases, found at high levels in oral cancers, might induce pain by activating PAR2 on oral nociceptors and whether manipulating the protease/PAR2 axis might provide a new approach to pain relief.
"In preclinical models, we have found that blocking PAR2 relieves pain 100 percent of the time," Schmidt told Oncology Times. "This research may lay the foundation for development of a new class of drugs to treat cancer pain and chronic pain without opioids."
New Paradigm
In an animal study published last May, the investigators reported that a neurotransmitter called substance P neurokinin 1 receptor (NK1R) sends pain and inflammation signals for long periods from endosomes (Sci Trans Med 2017;9:392 eaal3447). These cause sustained excitation of spinal neurons and pain transmission. However, they found specific antagonism of the NK1R in endosomes with membrane-anchored drug conjugates provides more effective and sustained pain relief than conventional plasma membrane-targeted antagonists.
They attached these to special molecules called cholestanols to transport them across the surface membrane and target endosomes. Pharmacological and genetic endocytosis inhibitors were used to prevent sustained SP-induced excitation of neurons in spinal cord slices, both in vitro and in vivo. Disruption of the cell coating protein clathrin, the GTPase enzyme dynamin, and the intracellular protein [beta]-arrestin blocked SP-induced NK1R endocytosis, preventing activation and transportation of pain signals.
Most clinical trials of compounds targeting receptors like NK1R have not succeeded, likely because they failed to penetrate the cell surface to reach endosome-mediated pain signaling, said Schmidt.
"Of all of the receptors we have studied, PAR is the only one we have found that can completely relieve pain. Bunnett's work has challenged dogma within the field and refined our understanding of how proteases signal on the cell surface and within intracellular compartments."
Moving Forward
The investigators are now trying to identify tumor-generated proteases, as well as other pain signaling pathway(s) from the surface of nerve cells to the endosomes within. Schmidt will use pain severity data gathered from his patients along with oral cancer tissue obtained during surgical resection, looking for cellular origins of the proteases.
Bunnett will use high-resolution imaging and molecular probes on patient tumors to track the GPCR intracellularly after cell surface activation.
"We think that modification of many existing compounds, as we did with NK1R inhibitors, may have the potential to enhance the effectiveness of many different classes of medications," he noted.
"Previous efforts to develop more effective analgesics have been hampered by our limited understanding of the mechanisms that allow nerves to sense and transmit pain signals. From these experiments, we have demonstrated that designing NK1R inhibitors that are capable of reaching the endosomal network within nerve cells may provide much longer-lasting pain relief than currently available analgesics."
Schmidt said that he is optimistic about the approach.
"I would say that testing in humans is not that far off," he said. "These days it is much easier to get something to the clinical trial stage than in the past. Also, one thing about studying oral cancer pain is that promising drugs can easily be delivered. I can inject a drug directly into a cancer in the mouth; it's far easier than trying to treat pancreatic cancer or colorectal cancer, for example."
Kurt Samson is a contributing writer.