Biological Effects of Calcitriol in Pancreatic Cancer

描述(申请人提供)：自吉西他滨被批准以来的11年中，晚期胰腺癌患者的总体存活率基本保持不变。奥沙利铂、贝伐单抗或西妥昔单抗最近未能提高存活率，促使NCI的GI癌症指导委员会呼吁研究人员评估新的治疗方法，以寻找这种疾病的新靶点。有挑衅性的证据表明，维生素D途径可能是这样的目标之一。维生素D受体(VDR)在绝大多数人胰腺癌中过表达，暴露于维生素D可通过基质金属蛋白酶、E-钙粘蛋白和2-连环蛋白等关键致病机制降低体外细胞增殖率。维生素D水平最高的人患胰腺癌的几率低20%-40%。以前在这种疾病中每天服用维生素D类似物的尝试因剂量限制性高钙血症的发展而受到限制。DN-101是骨化三醇的专利配方，每周给药一次，而不是每天一次。其提高的生物利用度使治疗性血浆浓度得以实现，而不会出现相关的高钙血症。DN-101增强吉西他滨对胰腺癌细胞株和异种移植瘤的细胞毒作用。自从最初提交这笔赠款以来，主要研究人员和赞助商已经完成了设计，并开始在晚期疾病患者中启动一项4组随机、安慰剂对照的IIB期研究，以评估吉西他滨+安慰剂；吉西他滨+DN-101；吉西他滨、厄洛替尼和安慰剂；以及吉西他滨、厄洛替尼和DN-101。该试验的主要临床终点将是6个月存活率。这项研究将有90%的能力在任何一个研究治疗组中检测到真实的6个月存活率&50%。修订后的R21将支持肿瘤和血液的生物学相关性研究，以阐明(S)DN-101可能增强系统治疗疗效的途径。我们的两个具体目标是：1)确定肿瘤和/或血清中的基线特征是否可以预测晚期胰腺癌患者的临床或生物效应；2)确定血浆和血清中可测量的生物指标的变化是否预测或对应于这些患者的临床结果。针对特定目标1的研究将在从原始诊断组织获得的组织上进行，以测量维生素D受体、E-钙粘素、2-连环蛋白和p120的表达和定位。针对特定目标2的研究将在连续的血浆或血清样本上进行，以测量治疗期间特定时间点的基质金属蛋白酶-2和-9、维生素D代谢物、胞苷脱氨酶活性、细胞色素P24活性和甲状旁腺素的变化。应审查员的要求，已澄清了这些研究的权力分析。我们相信，这一修订申请中概述的研究将为维生素D增强系统治疗活性并改善晚期胰腺癌患者预后的生物学机制提供重要的见解。与公共卫生相关：DN101是一种大剂量维生素D，正在进行一项针对晚期胰腺癌患者的临床试验，与化疗相结合进行评估。这个项目将帮助我们了解DN101可能增强化疗活性的生物学机制。

DESCRIPTION (provided by applicant): Overall survival for patients with advanced stage pancreatic cancer has remained largely unchanged in the 11 years since the approval of gemcitabine. The recent failures of oxaliplatin, bevacizumab, or cetuximab to improve survival have prompted NCI's GI Cancer Steering Committee to call on investigators to evaluate novel therapeutic approaches to find new exploitable targets in this disease. There is provocative evidence that the vitamin D pathway may be one such target. The vitamin D receptor (VDR) is overexpressed in the vast majority of human pancreatic cancers and exposure to vit D reduces in vitro cell proliferation rates through key pathogenetic mechanisms including matrix metalloproteinases, E-cadherin and 2-catenin. Individuals with the highest vit D levels have a 20-40% lower incidence of pancreatic cancer. Prior attempts to administer vit D analogs on a daily basis in this disease have been limited by the development of dose-limiting hypercalcemia. DN-101 is a proprietary formulation of calcitriol that is administered on a weekly rather than a daily basis. Its improved bioavailability allows therapeutic plasma concentrations to be achieved without associated hypercalcemia. DN-101 potentiates the cytotoxicity of gemcitabine against pancreatic cancer cell lines and xenografts. Since the original submission of this grant, the principal investigator and sponsor have finalized the design and begun initiation of a 4-arm, randomized, placebo-controlled Phase IIB study in patients with advanced stage disease to evaluate gemcitabine + placebo; gemcitabine + DN-101; gemcitabine, erlotinib, and placebo; and gemcitabine, erlotinib, and DN-101. The primary clinical endpoint of the trial will be 6-month survival rate. The study will have 90% power to detect a true 6-month survival rate >50% in either of the investigational treatment arms. This revised R21 will support biological correlative studies in tumor and blood to elucidate the way(s) in which DN-101 may enhance the efficacy of systemic therapy. Our two specific aims are: 1) to determine whether baseline characteristics in the tumor and/or serum predict the clinical or biological effects of DN-101 in patients with advanced pancreatic cancer and 2) to determine whether changes in biological targets measurable in plasma and serum predict for or correspond to clinical outcomes in these patients. The studies for Specific Aim 1 will be performed on tissue obtained from the original diagnostic tissue to measure expression and localization of the vitamin D receptor, E-cadherin, 2-catenin, and p120. Studies for Specific Aim 2 will be performed on serial plasma or serum samples to measure changes in MMP-2 and -9, vit D metabolites, cytidine deaminase activity, CYP24 activity and PTH at specific time points during treatment. As requested by the reviewers, the power analysis for these studies have been clarified. We believe that the studies outlined in this revised application will provide important insights into biological mechanisms by which vitamin D may augment the activity of systemic therapy and lead to improved outcomes for patients with advanced pancreatic cancer. PUBLIC HEALTH RELEVANCE: DN101, a form of high-dose Vitamin D, is being evaluated in combination with chemotherapy in a clinical trial for people with advanced pancreatic cancer. This project will help us understand the biological mechanisms by which DN101 might enhance the activity of that chemotherapy.