Grant R21CA180997

The pathophysiology and palliation of the paclitaxel-induced acute pain syndrome

DESCRIPTION (provided by applicant): Paclitaxel is one of the most commonly prescribed cancer drugs and serves an important role in the treatment of a variety of malignancies. The paclitaxel-induced acute pain syndrome (PIAPS) occurs after paclitaxel administration. Its seminal feature is refractory, untreatable pain. Even opioids are ineffective. Although PIAPS typically remits by day 7, patients suffer from refractory pain one-third of their time on chemotherapy. Our group was the first to prospectively characterize this syndrome from a clinical standpoint, but the pathophysiology of this syndrome remains unknown and remarkably understudied. We hypothesize that the atypical protein kinase C (PKC) isoenzymes, PKC iota and zeta, are key mediators of the PIAPS and that the gold compound auranofin, an inhibitor of of PKC iotal and zeta, prevents or palliates this syndrome. Indeed, 1) the PKC family has been implicated in a host of other musculoskeletal pain syndromes; 2) our preclinical data demonstrate that paclitaxel results in PKC iota activation; and 3) our preclinical and clinical dat also show that auranofin, a drug used to treat autoimmune arthritis, inhibits PKC iota and zeta. Hence, we propose the following specific aims: 1) To measure quantitatively the mRNA expression of PKC iota and zeta in the muscle of patients before and after paclitaxel administration and to determine whether PKC iota or zeta overexpression are associated with the development of the PIAPS (as assessed by patients' completion of the Brief Pain Inventory). 2) To conduct a pilot, randomized controlled trial to test whether auranofin prevents or palliates the PIAPS. Thirty patients (15 per arm) will be randomly assigned to either auranofin (one 6 mg dose) the day after paclitaxel versus placebo. Daily pain scores (Brief Pain Inventory) will be compared between auranofin- and placebo-exposed arms. These two independent but integrated aims -- which include two independent groups of patients for each aim -- will provide long-overdue insight into the pathophysiology of the PIAPS and will potentially position us to mount a future, definitive randomized controlled trial with auranofin to prevent or palliate the PIAPS.