Development of Drugs That Target Prostate Cancer

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We are attempting to develop novel agents that alter the biology of the cancer. In order to accomplish this goal, we have initiated a collaboration with a unique computational chemistry company to design compounds that abrogate key molecular targets in the development, progression and metastasis of cancer. These studies are just being initiated but could provide valuable new agents.A successful drug development program requires a complete understanding of the clinical pharmacology of the agent(s) being evaluated. One of our interests is to utilize pharmacokinetic/pharmacodynamic concepts in the development of novel anticancer agents. This has led to attempts to optimize therapy through characterizing the pharmacogenetics of patients and appreciates for potential drug interactions. Agents that we have recently been involved with include: MS275, UCN01, perifosine, OSI774, depsipeptide, 17-DMAG, COL3, flavopiridol, phenylbutyrate, PSC833 and phenylacetate.We have found that ketoconazole exerts a cystostatic effect on panel of human prostate cancer cell lines, with IC50 values of 5 ug/mL, 12 ug/mL and 25 ug/mL for LNCaP, PC3/PC3M, and DU145 cells, respectively. This resistance was associated with a lesser degree of Raf-1 and Bcl-2 phosphorylation. Combinations of microtubule-active drugs with ketoconazole were beneficial in DU145 cancer cells. Furthermore, ketoconazole blocked the recovery of all the prostate cancer cell lines following 24 h-pulse treatment.To build on the preclinical observations above, we initiated a Phase I trial of ketoconazole plus weekly docetaxel in patients with AIPC. The primary objective of this study is to determine the side effect profile and determine the MTD. In recognition oof possible drug-drug interations, starting doses of 5 mg/m2 and 1200 mg/d were used for docetaxel and ketoconazole, respectively. Significant hepatotoxicity was noted with a docetaxel dose of 10 mg/m2. We have therefore modified the dosing regimen to 600 mg/d of ketoconazole and 10 mg/m2 of docetaxel. A total of 22 patients have been treated with this combination to date and pharmacokinetic analyses are currently ongoing.