Project Description Narrative:
Cancer is a major public health concern and the second leading cause of mortality and morbidity in the United States. In 2022, Wisconsin was ranked 12th in the nation for cancer incidence. Almost 300,000 people in Wisconsin are living with a cancer diagnosis, and projections suggest 37,640 new cancer cases and 11,670 cancer-related deaths in 2023. Cancer incidence is higher in males than females in Wisconsin, and cancer rates increase significantly with age. With a high mortality rate, survival becomes a key goal in cancer treatment and the prevalence of cancer therapy-related adverse effects is often underappreciated.
The common neurological complication of anticancer therapy is chemotherapy-induced peripheral neuropathy (CIPN). This disorder is associated with sensory symptoms such as allodynia, hyperalgesia, dysesthesia, and unprovoked sensations of burning or shooting-like pain in the lower extremities and hands. CIPN affects around 60% of patients undergoing chemotherapy, and chronic symptoms can develop in 30-40% of cancer survivors. The severity of CIPN-related pain can lead to dosage reductions, switching to less effective therapies, or even discontinuation of treatment negatively impacting overall therapy outcomes. Conventional neuropathic pain treatments, including antiepileptic agents, antidepressants, and opioids, exhibit limited efficacy and often come with systemic interactions and side effects. There exists an unmet need to explore new molecular targets that could help ease the symptoms of painful neuropathy associated with cancer treatment.
Recent studies indicate that systemic inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4) cation channel or global knockout of TRPV4 demonstrates significant improvement in alleviating the painful neuropathy induced by chemotherapeutic agents. TRPV4 is expressed in various tissues where it plays a critical role in normal functioning, contributing to the perceiving and processing of various sensory modalities, regulation of cardiovascular, respiratory, and renal function, etc. This underscores the necessity of identifying a specific site for targeting TRPV4 to effectively treat painful CIPN. Skin epidermal cells play a vital role in detecting, modulating, and transmitting sensory information to the dorsal root ganglia (DRG), which serves as a crucial relay point for sensory signals from the skin to the central nervous system. Recent studies indicate that keratinocytes, which comprise more than 95 % of skin epidermal cells, play a critical role in mediating normal touch and thermal sensation and contribute to the processing of pain stimuli. The research team’s preliminary data reveal: 1) Keratinocytes significantly contribute to chemotherapy-induced mechanical hypersensitivity; 2) Keratinocytes exhibit tenfold higher TRPV4 expression than DRG neurons; 3) Chemotherapy treatment increases TRPV4 expression in keratinocytes but not in DRG neurons; 4) Chemotherapy sensitizes mouse and human keratinocytes to mechanical stimuli and TRPV4 agonists.
Their central hypothesis of the present proposal is that TRPV4 expressed in the keratinocytes contributes to chemotherapy-induced neuropathic mechanical and thermal pain. Validating the role of epidermal TRPV4 in CIPN will create opportunities for developing new topical anesthetics with localized relief and easy application, as well as potential synergies with other pain-related management interventions that could lead to reducing systemic medication doses and side effects. Additionally, this research will guide the trajectory of future studies, providing preliminary data for extramural funding opportunities.