P-4: Inhibitors of telomerase in treatment of Pancreatic Adenocarcinoma

P-4：端粒酶抑制剂治疗胰腺癌

基本信息

批准号：
8328171
负责人：
MICHEL M OUELLETTE
金额：
$ 20.25万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8328171
关键词：
Advanced Malignant Neoplasm Affinity Age Animal Experiments Animals Autopsy Binding Bioluminescence Cancer Patient Cancer cell line Carboplatin Cells Cessation of life Chronic Lymphocytic Leukemia Clinical Treatment Clinical Trials Collaborations Combination Drug Therapy Data Development Diagnosis Disease Disorder by Site Dose Drug Design Effectiveness Erlotinib Exposure to Firefly Luciferases Functional disorder Goals Growth Human Image Imaging Device Knowledge Lead Life Link Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Malignant neoplasm of liver Malignant neoplasm of lung Malignant neoplasm of pancreas Measurement Measures Monitor Mus Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Normal tissue morphology Paclitaxel Pain Pancreas Pancreatic Adenocarcinoma Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phase Phase I Clinical Trials Progression-Free Survivals Property Quality of life Radiation Radiation therapy Reaction Reducing Agents Regimen Residual Neoplasm Safety Site Stem cells Telomerase Telomerase Inhibitor Telomerase inhibition Telomere Maintenance Testing Therapeutic Time Toxic effect Tumor Burden Tumor Cell Line Tumor Volume Unresectable Validation Xenograft Model Xenograft procedure base cancer cell cancer stem cell chemotherapy cohort conventional therapy gemcitabine human tissue in vivo light emission malignant breast neoplasm neoplastic cell novel optical imaging pancreatic cancer cells pancreatic juice pancreatic neoplasm pre-clinical pre-clinical research preclinical study programs research study standard care symptom management telomere tomography tumor tumor growth

Advanced Malignant Neoplasm Affinity Age Animal Experiments Animals Autopsy Binding Bioluminescence Cancer Patient Cancer cell line Carboplatin Cells Cessation of life Chronic Lymphocytic Leukemia Clinical Treatment Clinical Trials Collaborations Combination Drug Therapy Data Development Diagnosis Disease Disorder by Site Dose Drug Design Effectiveness Erlotinib Exposure to Firefly Luciferases Functional disorder Goals Growth Human Image Imaging Device Knowledge Lead Life Link Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Malignant neoplasm of liver Malignant neoplasm of lung Malignant neoplasm of pancreas Measurement Measures Monitor Mus Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Normal tissue morphology Paclitaxel Pain Pancreas Pancreatic Adenocarcinoma Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phase Phase I Clinical Trials Progression-Free Survivals Property Quality of life Radiation Radiation therapy Reaction Reducing Agents Regimen Residual Neoplasm Safety Site Stem cells Telomerase Telomerase Inhibitor Telomerase inhibition Telomere Maintenance Testing Therapeutic Time Toxic effect Tumor Burden Tumor Cell Line Tumor Volume Unresectable Validation Xenograft Model Xenograft procedure base cancer cell cancer stem cell chemotherapy cohort conventional therapy gemcitabine human tissue in vivo light emission malignant breast neoplasm neoplastic cell novel optical imaging pancreatic cancer cells pancreatic juice pancreatic neoplasm pre-clinical pre-clinical research preclinical study programs research study standard care symptom management telomere tomography tumor tumor growth

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项目摘要

Telomeres progressively shorten in almost all normal human tissues with increased age. In preneoplasia, telomeres are exceptionally short. Almost all human malignant tumors express telomerase to maintain these short telomeres. This activity is absent or is at lower levels in normal tissues. This has led to approaches for inhibiting telomerase as a target for cancer therapeutics. Cancer stem cells have been shown to be both telomerase expressing and containing short telomeres. This suggests that telomerase inhibitors are likely to target both the bulk of the more differentiated tumor cells as well as the stem cells that provide the unlimited growth of most advanced cancers. This project will conduct pre-clinical orthotopic xenograft animal experiments followed by clinical trials in patients with pancreatic cancer. The preclinical experiments will evaluate the in vivo effectiveness of a novel telomerase inhibitor just entering clinical trials, GRN163L, on human pancreatic cancer cells in mice bearing orthotopic tumors in the pancreas. GRN163L has enhanced stability and displays extremely specific and high-affinity binding to telomerase. These properties increase the chances of effectively inhibiting telomerase in cancer cells throughout the body with relatively low doses of the drug. We have already demonstrated that our lead compound, GRN163L, is an effective inhibitor of telomerase in several types of cancer cell lines. The proposed experiments will use bioluminescence imaging to follow human pancreatic tumor cell lines treated in vivo with GRN163L alone and in combination with chemotherapy. The goal is to monitor the spatio-temporal distribution of pancreatic tumor cells during the disease course from minimal residual disease to metastasis with and without GRN163L and combinations of chemotherapy. The experiments should unambiguously prove or disprove the link between the inhibition of telomerase and decreased proliferation of tumor cells in vivo. In this proposal, we will exploit this knowledge to conduct early stage clinical trials on pancreatic cancer patients with locally advanced, unresectable, or metastatic disease. For these patients, a standard treatment option is the combination of gemcitabine with erlotinib (www.nccn.org). In a phase l/ll trial, prolonged exposure to GRN163L will be administered in combination with gemcitabine/erlotinib chemotherapy, and the safety and efficacy of GRN163L will be determined. The primary endpoints will be telomerase inhibition, survival and progression-free survival. From a subset of patients, pancreatic juice will be obtained to measure the impact of GRN163L on telomerase activity at the tumor site. From patients that agree to participate in an ongoing rapid autopsy program, measurements of telomere size in tumors will also be obtained at time of death. This trial is likely to the first clinical trials testing a telomerase inhibitor in patients with pancreatic cancer.

端粒几乎在所有正常的人体组织中逐渐缩短。在肿瘤中，端粒非常短。几乎所有人类恶性肿瘤表达端粒酶维护这些简短的端粒。这种活性在正常组织中不存在或处于较低水平。这已经引起了抑制端粒酶作为癌症治疗剂的目标。癌症干细胞已经被证明是表达端粒酶和含有短端粒的端粒酶。这表明端粒酶抑制剂可能靶向大部分更分化的肿瘤细胞以及干细胞这提供了大多数高级癌症的无限生长。该项目将进行前临床前原位异种移植动物实验进行了胰腺癌患者的临床试验。这临床前实验将评估刚进入的新型端粒酶抑制剂的体内有效性临床试验，GRN163L，对携带原位肿瘤的小鼠人胰腺癌细胞的临床试验胰腺。 GRN163L具有增强的稳定性，并且显示出极为特异性和高亲和力结合到端粒酶。这些特性增加了有效抑制癌细胞中端粒酶的机会在整个身体中，药物剂量相对较低。我们已经证明了我们的领导 GRN163L化合物是几种类型的癌细胞系中端粒酶的有效抑制剂。这建议的实验将使用生物发光成像跟随人胰腺肿瘤细胞系单独用GRN163L并与化学疗法结合使用体内治疗。目标是监视疾病过程中胰腺肿瘤细胞的时空分布来自最小残留有或没有GRN163L的转移疾病以及化学疗法的组合。实验应明确证明或反驳端粒酶抑制和减少之间的联系体内肿瘤细胞的增殖。在此提案中，我们将利用这一知识来进行早期阶段对局部晚期，无法切除或转移性疾病的胰腺癌患者进行的临床试验。对于这些患者，标准治疗选择是吉西他滨与厄洛替尼的组合（www.nccn.org）。在一项L/LL试验中，将长时间接触GRN163L 使用吉西他滨/厄洛替尼化学疗法，将确定GRN163L的安全性和功效。主要终点将是端粒酶抑制，存活和无进展生存。从子集在患者中，将获得胰汁，以测量GRN163L对端粒酶活性的影响肿瘤部位。来自同意参加正在进行的快速尸检计划的患者，在死亡时也将获得肿瘤中端粒大小的测量。该审判可能是在胰腺癌患者中测试端粒酶抑制剂的首次临床试验。