Combined Modality Targeted Therapy of Pancreatic Cancer with Death Receptor

死亡受体联合靶向治疗胰腺癌

基本信息

批准号：
8375482
负责人：
DONALD J. BUCHSBAUM
金额：
$ 19.02万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8375482
关键词：
Accounting Adaptor Signaling Protein Address Advanced Malignant Neoplasm Adverse effects Agonist American Society of Clinical Oncology Animal Model Antibodies Apoptosis Apoptosis Inhibitor Attention BIRC2 gene Biological Markers Biology Cancer Center Cancer Model Cancer Patient Cancer cell line Caspase Cell Death Cell Line Cell surface Cessation of life Clinical Clinical Trials Combined Modality Therapy Complex Data Death Domain Development Disease Disseminated Malignant Neoplasm Doctor of Medicine Dose Enrollment Epidermal Growth Factor Receptor Evaluation Exhibits External Beam Radiation Therapy Family Funding Future Goals Grant Hepatocyte Human Human Genome In Vitro Induction of Apoptosis Instruction Lead Licensing Ligands Literature Malignant Neoplasms Malignant neoplasm of pancreas Manuscripts Mediating Membrane Minnesota Modality Modeling Molecular Molecular Profiling Monoclonal Antibodies Monoclonal Antibody C225 Monoclonal Antibody Therapy Mus Newly Diagnosed Normal Cell Pancreas Pathway interactions Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II Clinical Trials Play Predisposition Primates Production Progress Reports Property Proteomics Protocols documentation Public Health Quality Control RNA Helicase Radiation Radiation therapy Radiation-Sensitizing Agents Reagent Recruitment Activity Regimen Regulation Reporting Research Resistance Role Science Signal Transduction Site Staging TNF gene TNFRSF10A gene TNFRSF10B gene TNFSF10 gene Tail Technology Testing Therapeutic Therapeutic Agents Tissue Sample Tissues Toxic effect Toxicology Translating Translational Research Translations Treatment Efficacy Treatment Protocols Tumor Cell Line Universities University of Alabama at Birmingham Cancer Center University of Minnesota Cancer Center Xenograft Model Xenograft procedure abstracting assay development base cancer cell cancer therapy chemotherapeutic agent chemotherapy clinical efficacy cytotoxicity docetaxel drug development gemcitabine in vivo industry partner inhibitor/antagonist irinotecan malignant breast neoplasm neoplastic cell novel novel therapeutics oxaliplatin pancreas xenograft pancreatic cancer cells pancreatic neoplasm patient population pre-clinical preclinical study programs protein complex receptor response small molecule synergism therapeutic target treatment strategy trend tumor tumor immunology

项目摘要

PROJECT SUMMARY (See instructions); This proposal is a continuation of Project 2 in the original SPORE grant. Pertinent to this proposal, we have developed an anti-DRS monoclonal antibody therapy for pancreatic cancer through in vitro studies, animal model efficacy and with an industry partner (Daiichi Sankyo), Phase I and recently completed Phase II trials in pancreatic cancer. We have also discovered a novel molecule (DDX3) which appears to play a major role in regulation of anti-DRS mediated apoptosis. In this proposal, we will explore two strategies to enhance the efficacy of anti-DRS monoclonal therapy especially in pancreatic tumor cell lines which are intermediate or resistant to anti-DRS. The two strategies are to evaluate the addition of a monoclonal anti-DR4 reagent or the addition of small molecule modulators ofthe apoptosis cascade. The two apoptosis modulators to be evaluated are AT-101, a Bcl-2 family inhibitor, and AT-406, an lAP family inhibitor. These two strategies will be studied using in vitro analysis and orthotopic and metastatic xenogeneic pancreatic cancer models leading to a Phase I trial of the best strategy. In addition, we will continue studies of DDX3 and the DRS/DDX3 complex as a putative biomarker for tumor cell sensitivity/resistance to death receptor mediated anti-tumor efficacy and as the target of enhancement strategies for anti-DR mediated anti-tumor effects.

项目摘要（请参阅说明）；该提案是原始孢子赠款中项目2的延续。与该提议有关，我们有通过体外研究开发了用于胰腺癌的抗DRS单克隆抗体疗法模型功效和行业合作伙伴（Daiichi Sankyo），第一阶段并最近完成了II期试验在胰腺癌中。我们还发现了一个新颖的分子（DDX3），它似乎起着主要作用在调节抗DRS介导的凋亡中。在此提案中，我们将探讨两种策略来增强抗DRS单克隆疗法的功效，尤其是在中间或中间的胰腺肿瘤细胞系中对抗DR的抗性。这两种策略是评估单克隆抗DR4试剂的添加或凋亡级联反应的小分子调节剂的添加。两个凋亡调节剂是评估是Bcl-2家族抑制剂AT-101，而AT-406是圈型家族抑制剂。这两种策略将使用体外分析以及矫形和转移性异构胰腺癌模型进行研究导致对最佳策略的第一阶段试验。此外，我们将继续研究DDX3和 DRS/DDX3复合物作为肿瘤细胞敏感性/抗死亡受体介导的推定生物标志物抗肿瘤功效，并作为抗DR介导的抗肿瘤作用增强策略的目标。