Biological Effects of Calcitriol in Pancreatic Cancer

骨化三醇在胰腺癌中的生物学作用

• 批准号: 7529788
• 负责人: MACE L ROTHENBERG
• 金额: $ 30.63万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-24 至 2008-12-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7529788
• 关键词: 25-hydroxycholecalciferol-24-hydroxylase; Apoptosis; Applications Grants; Biologic Characteristic; Biological; Biological Availability; Biological Process; Blood; Calcitriol; Cancer cell line; Cell Proliferation; Cetuximab; Characteristics; Clinical; Clinical Trials; Control Groups; Correlative Study; Cytidine Deaminase; DN-101; Daily; Data; Development; Diagnostic; Disease; Dose; Dose-Limiting; Drug Formulations; E-Cadherin; End Point; Erlotinib/Gemcitabine; Evaluation; Exposure to; Failure; Gelatinase A; Goals; Grant; Growth; Human; Hypercalcemia; In Vitro; Incidence; Individual; Investigational Therapies; Lead; Malignant Neoplasms; Malignant neoplasm of pancreas; Matrix Metalloproteinases; Measurable; Measures; Neoplasm Metastasis; Oral; Outcome; Pathway interactions; Patients; Pharmacodynamics; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phase III Clinical Trials; Placebo Control; Placebos; Plasma; Preparation; Principal Investigator; Process; Protein Overexpression; Public Health; Randomized; Range; Rate; Research Personnel; Sampling; Schedule; Serum; Staging; Survival Rate; Systemic Therapy; Therapeutic; Time; Tissues; Toxic effect; Translational Research Working Group; Tumor Tissue; Upper arm; Vitamin D; Vitamin D3 Receptor; Xenograft procedure; analog; androgen independent prostate cancer; base; bevacizumab; carcinogenesis; chemotherapy; cytotoxicity; design; docetaxel; gemcitabine; improved; in vivo; insight; men; novel therapeutics; oxaliplatin; response; tumor

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.

描述（由申请方提供）：自吉西他滨获批以来的11年中，晚期胰腺癌患者的总生存期基本保持不变。最近奥沙利铂、贝伐单抗或西妥昔单抗在改善生存率方面的失败促使NCI的GI癌症指导委员会呼吁研究人员评估新的治疗方法，以找到这种疾病的新的可利用靶点。有挑衅性的证据表明，维生素D途径可能是一个这样的目标。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通过关键的致病机制（包括基质金属蛋白酶、E-钙粘蛋白和2-连环蛋白）降低体外细胞增殖率。维生素D水平最高的个体胰腺癌的发病率降低20 - 40%。以前的尝试，管理维生素D类似物在这种疾病的基础上，每天都受到限制的剂量限制性高钙血症的发展。DN-101是骨化三醇的专利制剂，每周而不是每天给药。其改善的生物利用度允许达到治疗血药浓度，而不伴有高钙血症。DN-101增强吉西他滨对胰腺癌细胞系和异种移植物的细胞毒性。自最初提交该资助以来，主要研究者和申办者已完成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IIB期研究，以评价吉西他滨+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。试验的主要临床终点为6个月生存率。该研究将有90%的把握度来检测任何一个研究治疗组中真实的6个月生存率> 50%。修订后的R21将支持肿瘤和血液中的生物学相关研究，以阐明DN-101可增强全身治疗疗效的方式。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预测DN-101在患有晚期胰腺癌的患者中的临床或生物学作用，和2）确定血浆和血清中可测量的生物靶标的变化是否预测或对应于这些患者中的临床结果。特异性目标1的研究将在从原始诊断组织中获得的组织上进行，以测量维生素D受体、E-钙粘蛋白、2-连环蛋白和p120的表达和定位。将对系列血浆或血清样本进行特定目标2研究，以测量治疗期间特定时间点MMP-2和MMP-9、维生素D代谢产物、胞苷脱氨酶活性、CYP 24活性和PTH的变化。应评审人员的要求，这些研究的功效分析已得到澄清。我们相信，在这个修订后的应用程序中概述的研究将提供重要的见解，维生素D可能会增加系统治疗的活性，并导致改善晚期胰腺癌患者的结果的生物学机制。公共卫生相关性：DN101是一种高剂量维生素D，目前正在评估与化疗联合用于晚期胰腺癌患者的临床试验。该项目将帮助我们了解DN101可能增强化疗活性的生物学机制。