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）具有抗增殖和增强细胞毒性药物（如紫杉烷、铂类似物、蒽二酮）的抗肿瘤作用。大剂量地塞米松（Dex）增强抗肿瘤作用，减弱骨化三醇引起的高钙血症。在晚期和早期前列腺癌患者中使用高剂量骨化三醇+右美托咪唑以及与紫杉烷或铂类似物联合治疗是安全的，并且已经看到了抗肿瘤作用的明确证据。临床前数据表明，抗肿瘤作用依赖于高剂量暴露于骨化三醇，这可能受到以下因素的限制：[1]口服后明显的“饱和吸收”，这可能依赖于CYP24诱导骨化三醇的粘膜和肝脏代谢，CYP24是骨化三醇分解代谢中最活跃的酶；[2]CYP24在肿瘤内分解骨化三醇。我们在临床前模型中发现，酮康唑（一种CYP24抑制剂）可以增强骨化三醇的抗肿瘤作用，降低CYP24的活性。在我们高剂量骨化三醇的临床试验中，我们证明了在外周血单核细胞中诱导GYP 24活性。我们假设口服骨化三醇+酮康唑可能通过抑制骨化三醇氧化分解代谢而促进更高的全身和肿瘤内暴露。因此，我们建议：评估升级剂量的口服骨化三醇QDx3 D1, 2、3周结合口服,高剂量(400毫克TID)酮康唑+生理替代剂量的敏捷(0.5毫克)晚期癌症患者确定(a)最大耐受剂量(MTD)的口服骨化三醇+酮康唑/敏捷(b)药物动力学的骨化三醇+ / -酮康唑/敏捷(c)的安全性和毒性骨化三醇酮康唑/敏捷(d)酮康唑/敏捷对PBMC CYP24水平(e)来确定船舶的调制,骨化三醇在治疗前后PBMC中的作用。SA2：通过检测酮康唑和更多特异性CYP24抑制剂对骨化三醇分解代谢、维生素D受体表达、凋亡标志物表达的影响，确定骨化三醇信号通路在体外和体内的调节作用：a)在前列腺、胰腺癌和肺癌模型中，这些作用在体外对肿瘤细胞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