Dr. Brian Schmidt and Dr. Igor Spigelman will focus on the therapeutic utility of recently developed synthetic cannabinoids, which work to relieve the chronic inflammation and neuropathic pain symptoms of oral cancer without “getting high.”
Chronic pain affects more than 50 million adults in the U.S. Upwards of 9 out of 10 cancer patients suffer from pain, with oral cancer ranked consistently as one of the most painful cancers. This chronic pain management represents a major socioeconomic and clinical challenge because the side effects of existing treatments—mainly prescribing opioids—greatly limit their effectiveness, especially over time.
Alternatives to opioid treatment are found in synthetic and naturally occurring cannabinoids (CBs) which have demonstrated effectiveness in numerous chronic inflammatory and neuropathic disorders in both human and animal models. However, major impediments to the widespread use of CB-based therapies are their psychotropic side-effects, mediated by the activation of central nervous system (CNS) CB1 receptors (CB1Rs).
In other words, cannabis-based drugs work wonders to alleviate chronic pain for patients, but up until now they have come with undesirable psychotropic side effects—patients “get high.”
“We have developed a novel class of drugs, peripherally-restricted cannabinoids (PRCBs), that are free of central nervous system side effects, for treating chronic pain,” said Igor Spigelman, PhD, professor in the Division of Oral Biology & Medicine, UCLA School of Dentistry. Brian L. Schmidt, DDS, MD, PhD professor in the NYU College of Dentistry Department Oral and Maxillofacial Surgery and director of NYU’s Bluestone Center for Clinical Research and the NYU Oral Cancer Center, added: “With this funding, we propose to broaden our research to determine the antitumor potential of PRCBs, their effectiveness against cancer pain, and also against chemotherapy-induced neuropathic pain.”
The purpose of the five-year, $2,494,784 R01 grant from the National Institutes of Health National Cancer Institute (NIH/NCI) is to test PRCBs for oral cancer and chemotherapy-induced peripheral neuropathy pain reduction. To this end, the research team proposes three specific aims for their investigations:
1. To examine the efficacy of novel PRCBs against the chronic pain symptoms of oral cancer. The team hypothesizes that cancer pain can be alleviated by decreasing sensory fiber activation and by reducing tumor burden. Molecular and clinical assays will be used to quantify the anti-proliferative and apoptotic effects of PRCBs. Other experiments will measure the decrement and restoration of orofacial function following PRCB administration. The team will also study the effectiveness of continuous PRCB administration and the possible development of tolerance to the PRCBs for the relief of cancer pain symptoms.
2. To examine the effects of novel PRCBs on proliferation and apoptosis of human oral carcinoma cell lines. Using state-of-the-art sensors which can monitor the reduction in the cancer tumor’s size or rate of growth in real time, the researchers look to measure the dose-response rates of their synthetic cannabinoids being administered.
3. To determine the effectiveness of PRCBs to suppress or prevent the painful symptoms of chemotherapy-induced peripheral neuropathies (CIPNs) without the psychotropic effects of traditional CB treatment. CIPN is a major side effect of chemotherapeutic agents. The researchers have developed their synthetic cannabinoids which have been shown to suppress CIPN symptoms in male rats via CB1R activation, at doses that produce no CNS side effects, and without development of tolerance to daily dosing. Given potential advantages of PRCBs over brain-penetrant cannabinoids, it is important to test if pretreatment with PRCBs can prevent the development of CIPN.
The research team looks to achieve these aims through the use of innovative and validated operant assays which provide a measure of cerebral processing and orofacial function in mouse oral cancer and rat CIPN models. Gender differences in cancer and CIPN pain sensitivity and their responsiveness to PRCBs will be determined. The researchers note, to their knowledge, that no one has studied gender differences in CBR responsiveness in CIPN. Therefore, putative gender differences in responsiveness to PRCBs in CIPN and their causes must be explored. It is also important to establish dose parameters for continued suppression of CIPN symptoms during continuous PRCB administration. The team will also look at whether PRCBs are more or less effective in reducing oral cancer pain in male versus female mice. While oral cancer pain affects men more often than women, it can be profoundly difficult to relieve in both sexes.
“In order to further characterize PRCBs, we plan to perform pharmacokinetic studies and determine their receptor targets with tissue-specific transgenic mice,” said Dr. Schmidt. “We will be looking at how the synthetic cannabinoid moves through and out of the body, charting the time-course of its absorption, bioavailability, distribution within the tissues, and measuring the body’s ability to effectively metabolize the drug.”
In order to measure potential off-target actions and peripheral side effects of PRCBs, the researchers will use a suite of invasive and non-invasive physiological tools, assessing the potential development of tolerance to PRCBs after chronic administration.
“We are keenly interested to determine if pretreatment with PRCBs may actually prevent oral cancer pain and reduced oral cancer proliferation,” said Dr. Schmidt. “Successful completion of the proposed studies would allow us to translate pre-clinical findings to a clinical trial; thus this work would improve outcomes for cancer patients.”
From a public health perspective, the researchers note that, tragically, approximately half of all oral cancer patients will not be cured with surgery, chemotherapy, or radiation therapy. Oral cancer is the sixth most common cancer in the US; however, in certain regions of the world it is the most common cancer. The intensity of oral cancer pain escalates with disease progression, and terminal patients generally experience debilitating pain during their final months of life. Currently, there is little that can be done for these patients. The global burden of oral cancer pain is enormous.
NIH/NCI Grant: 1R01CA196263 - 01A1 MPI Names: Schmidt, Brian L and Igor Spigelman