Evaluation of CYP24 as a Target for Enhancing Vitamin D

描述（由申请人提供）：维生素D信号通路是癌症治疗的重要靶点。在体外和体内，骨化三醇（1，25二羟基胆钙化醇）具有抗增殖作用，并增强细胞毒性药物（例如紫杉烷类、铂类似物、蒽二酮类）的抗肿瘤作用。大剂量地塞米松（Dex）可增强抗肿瘤作用并减弱骨化三醇诱导的高钙血症。在晚期和早期前列腺癌男性患者中给予高剂量骨化三醇+ Dex以及与紫杉烷类或铂类似物的联合治疗是安全的，并且已观察到抗肿瘤作用的明确证据。临床前数据表明，抗肿瘤作用取决于骨化三醇的高暴露量，这可能受到以下因素的限制：[1]口服给药后的表观“饱和吸收”，这可能取决于CYP 24对骨化三醇粘膜和肝脏代谢的诱导，CYP 24是骨化三醇催化剂中最具活性的酶[2]通过CYP 24对骨化三醇的瘤内催化。我们已经证明，酮康唑，一种CYP 24的抑制剂，在临床前模型中增强骨化三醇的抗肿瘤作用并降低CYP 24活性。在我们的高剂量骨化三醇的临床试验中，我们证明了外周血单核细胞中GYP 24活性的诱导。我们假设口服钙三醇+酮康唑可能会通过抑制钙三醇氧化分解代谢而促进更高的全身和瘤内暴露。因此，我们建议：SA1：评价递增剂量的口服骨化三醇QDx 3，第1、2、3天每周一次联合口服，高剂量（400 mg TID）酮康唑+生理替代剂量的地塞米松（0.5 mg BID），以确定（a）口服骨化三醇+酮康唑/地塞米松的最大耐受剂量（MTD）（B）骨化三醇+/-酮康唑/地塞米松的药代动力学（c）骨化三醇/地塞米松的安全性和毒性。酮康唑/Dex（d）酮康唑/Dex对PBMC CYP 24水平的影响（e）以确定VDR的调节，VDR是治疗前后PBMC中骨化三醇作用的标志物。SA2：a）酮康唑和更特异性的CYP 24抑制剂对骨化三醇催化剂、维生素D受体表达、细胞凋亡标志物表达的作用，在前列腺癌、胰腺癌和肺癌模型中，体外对肿瘤细胞的这些作用的调节与体内显著的抗肿瘤反应之间是否存在关系

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