Evaluation of CYP24 as a Target for Enhancing Vitamin D*

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DESCRIPTION (provided by applicant): Vitamin D signaling pathways are important targets in cancer therapeutics. In vitro and in vivo calcitriol (1,25 dihydroxycholcalciferol) is antiproliferative and potentiates the antitumor effects of cytotoxic agents (e.g. taxanes, platinum analogues, antracenediones). High dose dexamethasone (Dex) potentiates the antitumor effects and blunts calcitriol-induced hypercalcemia. Administration of high doses of calcitriol + Dex in men with advanced and early prostate cancer as well as combination therapy with taxanes or platinum analogues is safe and clear evidence of antitumor effects have been seen. Preclinical data indicate that antitumor effects depend on high exposure to calcitriol which may be limited by: [1] apparent "saturable absorption" following oral administration, which may depend on induction of mucosal and hepatic metabolism of calcitriol by CYP24, the enzyme most active in calcitriol catabolism [2] intratumor catabolism of calcitriol by CYP24. We have shown that ketoconazole, an inhibitor of CYP24, enhances the anti-tumor effects of calcitriol and decreases CYP24 activity in preclinical models. In our clinical trials of high dose calcitriol we demonstrated induction of GYP 24 activity in peripheral blood monocytes. We hypothesize that oral administration of calcitriol + ketoconazole may facilitate higher systemic and intratumoral exposure through inhibition calcitriol oxidative catabolism. Therefore, we propose: SA1: Evaluate escalating doses of oral calcitriol QDx3, D1,2,3 weekly in combination with oral, high dose (400mg TID) ketoconazole + physiologic replacement doses of dex (0.5mg BID) in patients with advanced cancer to determine the (a) maximum tolerated dose (MTD) of oral calcitriol + ketoconazole/Dex (b) pharmacokinetics of calcitriol +/- ketoconazole/dex (c) safety and toxicity of calcitriol/ketoconazole/Dex (d) effect of ketoconazole/Dex on PBMC CYP24 levels (e) to determine modulation of VDR, a marker of calcitriol effect in PBMC before and after therapy. SA2: Determine the modulation of calcitriol signaling pathways in vitro and in vivo by examining the: a) effect of ketoconazole and more specific CYP24 inhibitors on calcitriol catabolism, vitamin D receptor expression, expression of apoptosis markers whether a relationship exists between modulation of these effects in vitro on tumor cells and a significant antitumor response in vivo in prostate, pancreatic and lung cancer models