Project Summary:
Cancer is the leading cause of death in Wisconsin, with rates exceeding national averages. Age and obesity influence the incidence of cancer, both of which are increasing in Wisconsin. As the population ages, cancer incidence in Wisconsin is projected to increase 70% by 2050 from 2024. Breast cancer is the most common cancer among women in Wisconsin, and the incidence of lung cancer is higher in Wisconsin than the national average. Chemotherapy remains the frontline treatment for most cancers and the chemotherapeutic drug paclitaxel (PTX) is the primary therapeutic intervention for breast, lung, and ovarian cancers. PTX inhibits cancer progression by stabilizing microtubules. Despite its clinical effectiveness, PTX causes severe side effects by its actions on healthy non-cancerous tissues. Chief among these is chemotherapy-induced peripheral neuropathy (CIPN), which affects 60-70% of patients treated with PTX and is characterized by painful sensory symptoms such as hypersensitivity evoked by touch, heat or cooling, dysesthesia (pins and needles sensations), and spontaneous burning or shooting pain. These debilitating symptoms often force patients to reduce their chemotherapy dosage, pursue less-effective therapies, or discontinue treatment altogether.
There is currently no FDA-approved treatment for managing CIPN. Current treatments for CIPN, including opioids, antidepressants, and anti-seizure medications, offer limited relief, and come with their own harmful side effects. New molecular targets for treating CIPN-related pain are critically needed.
This project’s research team hypothesizes that PTX treatment induces touch hypersensitivity by upregulating keratinocyte ADORA2B, which then sensitizes PIEZO1. Establishing a role of epidermal ADORA2B in CIPN will create opportunities to develop new topical analgesics that provide localized relief and easy application, avoid the side effects that occur with systemic drugs, and allow synergy with other pain-related management interventions. This would in turn dramatically reduce systemic medication doses and side effects. Their research will guide the trajectory of future studies, provide preliminary data for large scale extramural funding opportunities, and ultimately could lead to improved therapies for CIPN.