Basic science observations in the laboratory of Co-Investigator David Weber have demonstrated that S100B is a Ca2+binding protein that also binds to wild type (wt) p53 in primary melanoma cells. When targeted downregulation of S100B is accomplished by siRNA, recovery of p53 function ensues, with induction of apoptosis. This suggests the hypothesis that small molecules directed at the interaction of S100B and p53 might have clinical value in melanoma patients with wt p53 and expression of S100B. Co- Investigator Weber engaged collaborators to conduct a computer assisted drug discovery screen based on the known structure of S100B which defined that pentamidine, a clinically available FDA approved agent for treatment of protozoal infections could potently disrupt the p53-S100B interaction. The current Quick Trials application therefore seeks to partner the laboratory expertise of Co-Investigator Weber with the clinical experience of Principal Investigator Edward Sausville to conduct a phase II clinical trial in which patients with metastatic and/ or refractory malignant melanoma who are shown to express wtp53 and detectable S100B in their tumor cells will be treated with a well tolerated, outpatient regimen of pentamidine (days 1-5 for two of four weeks) for two cycles, followed by clinical reassessment. The primary endpoint will be to determine the response rate of relapsed and/or refractory melanoma that has previously been defined to express detectable S100B and to have wtp53, using RECIST criteria. The second goal of the application is to follow the effect of pentamidine on p21 expression in tumors, as a marker of p53 transactivator function, and S100B levels in tumor (also reflecting transactivation by p53) and in serum, as correlative indicators of drug effect on this pro-apoptotic pathway. Correlative science will benefit from the enormous expertise and established background of the Weber laboratory in S100B assays and expression systems.
The result of this clinical study will be important scientifically, as it will allow a clinical test with a readily available drug of an important therapeutic goal in oncology, namely """"""""re- awakening"""""""" of p53 function with a readily available drug molecule. From a clinical and patient perspective, patients with advanced melanoma have essentially no consistently useful chemotherapeutic approaches, and so the documentation of clinical utility would provide options heretofore not available to these patients.
