SRIN009, a cannabidiol formulation to treat chemotherapy-induced neuropathic pain

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating adverse effect experienced by up to 75% of patients receiving certain chemotherapy regimens. Common sensory symptoms include pain, paresthesia, dysesthesia, and hypersensitivity to touch and temperature. CIPN is a major cause of dose reduction or early cessation of cancer treatment, which may increase recurrence risk and reduce survival. Chemotherapeutic agents disrupt cytoskeletal and mitochondrial function, DNA synthesis, and promote inflammatory cell death; inflammation is a prominent contributor to CIPN. There are currently no FDA-approved therapies for prevention or treatment of CIPN. Although opioids have been used for pain for decades, their utility in CIPN is limited by questionable efficacy and well-known adverse effects. Cannabidiol (CBD), a non-psychoactive and non-addictive phytocannabinoid, has anti-inflammatory and neuroprotective activity in preclinical cell-based and rodent studies and is widely used by patients because of its perceived therapeutic benefit. Our laboratory was the first to describe protective effects of CBD in rodent models of CIPN and has subsequently demonstrated anti-neuropathic effects of CBD across multiple animal models. However, three barriers must be addressed before CBD can be advanced as a pharmacotherapy for CIPN: poor water solubility and bioavailability; an incomplete understanding of disease- and symptom-specific mechanisms; and the critical need to establish that prophylactic CBD does not diminish the anti-neoplastic efficacy of chemotherapy. To address these barriers, we developed two nanoemulsion formulations of CBD, SRIN-009, with and without terpenes. In well-defined preclinical BRAFV600E melanoma and non-small-cell lung cancer models, SRIN-009 did not diminish the in vivo anti-tumor efficacy of dacarbazine or carboplatin. CBD also did not reduce the anti-neoplastic effects of paclitaxel in two breast-cancer cell lines in vitro. Tumor-bearing rodent models are essential because they allow simultaneous assessment of chemotherapy-induced sensory neuropathy, systemic inflammatory and neuroimmune responses, drug exposure, and anti-tumor efficacy within an intact organism. These integrated outcomes cannot be adequately modeled using cell culture or other non-animal approaches alone. We hypothesize that SRIN-009 will prevent CIPN by minimizing chemotherapy-associated neurotoxicity and inflammation without compromising anti-cancer treatment efficacy, thereby improving patients’ ability to complete prescribed chemotherapy. The aims of this R01 proposal are to: (1) determine the SRIN-009 formulation that provides optimal therapeutic efficacy against CIPN; (2) define anti-inflammatory mechanisms underlying SRIN-009-mediated prevention of CIPN; and (3) evaluate compatibility of SRIN-009 with targeted-pathway and immune-checkpoint inhibitors to establish its safety for use in cancer patients.