权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Grp94 targeted therapy for pancreatic ductal adenocarcinoma

Grp94靶向治疗胰腺导管腺癌

基本信息

批准号：
8445848
负责人：
SOLDANO FERRONE
金额：
$ 18.9万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-11 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8445848
关键词：
Address Adenocarcinoma Cell Aldehydes Animal Model Antibodies Apoptosis Apoptotic Biological Models Boston Cell Line Cell Migration Induction Cell Proliferation Cell surface Cells Characteristics Clinical Conduct Clinical Trials Data Disease Endoplasmic Reticulum Epitopes Family Felis catus Fluorouracil Freezing General Hospitals Growth Heat shock proteins Heat-Shock Proteins 90 Human Human Characteristics Immunodeficient Mouse Immunotherapeutic agent Immunotherapy In Vitro Individual Induction of Apoptosis Lesion Libraries Literature Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Massachusetts Molecular Chaperones Mus Neoplasm Metastasis Normal tissue morphology Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Patients Phage Display Phase I Clinical Trials Proteins Recurrence Research Role Severe Combined Immunodeficiency Signal Pathway Specificity Testing Therapeutic Tissue Microarray Translations Treatment Efficacy Tumor Antigens Tumor Cell Biology Wit base cancer cell cancer stem cell chemotherapeutic agent clinically relevant clinically significant combinatorial cyclopamine design effective therapy experience extracellular glucose-regulated protein 94 implementation trial improved in vivo inhibitor/antagonist innovation member migration neoplastic cell novel novel therapeutics outcome forecast public health relevance research study response selective expression skills smoothened signaling pathway theories tumor tumor immunology

项目摘要

DESCRIPTION (provided by applicant): At present, no effective therapy is available for the treatment of pancreatic ductal adenocarcinoma (PDAC), which continues to be one of the most lethal cancers. In response to the clinical need to develop innovative therapeutic strategies, this proposal will test the therapeutic efficacy of a novel combinatorial immunotherapeutic strategy, which targets not only differentiated PDAC cells, but also PDAC cancer initiating cells (CICs). These cells, identified as ALDHbright cells, have to be eradicated in order to "cure" a malignant disease, because, according to the cancer stem cell theory, these cells are responsible for disease recurrence and metastases. The tumor antigen selected as a target is the glucose-regulated protein of 94 kDa (Grp94), a member of the heat shock protein 90 (HSP90) family. Grp94 regulates the activation of several signaling pathways which are associated with cell proliferation, survival and migration. To target Grp94, we will take advantage of the unique specificity of the human mAb W9, which we have recently characterized. mAb W9 recognizes an extracellular Grp94 epitope that is selectively expressed on malignant cells, including human PDAC cells and PDAC CICs, but not in normal tissues. mAb W9 markedly inhibits the in vitro proliferation of human PDAC cells, including PDAC CICs, and induces their apoptosis. The anti-proliferative and pro-apoptotic activity of mAb W9 is enhanced by combining it with cyclopamine and 5-FU. Both cyclopamine and 5-FU inhibit the sonic hedgehog signaling pathway, which is aberrantly activated in PDAC, particularly in the stroma and PDAC CICs. To assess the in vivo relevance of these in vitro data, the specific aims of this proposal will test the following hypotheses: i) The expression of the mAb W9 defined Grp94 epitope in primary PDAC tumors is associated with their histopathological characteristics and with poor prognosis; ii) mAb W9, in combination with cyclopamine and 5-FU, is more effective than individual agents, or a combination of two agents, in eradicating PDAC tumors in immunodeficient mice orthotopically grafted with the PDAC cell line MIA PaCa-2; iii) The results obtained with the PDAC cell line MIA PaCa-2 will have potential clinical significance, as they are reproduced in immunodeficient mice orthotopically grafted with PDAC tumors surgically removed from patients. The information derived from the outlined studies in vitro and in animal model systems will provide a useful background to implement a Phase I clinical trial with the mAb W9 in patients with PDAC. The implementation of this trial will be facilitated by Dr. C. Ferrone's access to her patients wit PDAC at Massachusetts General Hospital, Boston, MA, her newly acquired skills in conducting clinical trials, and by the fully human nature of the mAb W9.

描述（申请人提供）：胰腺导管腺癌（pancreatic ductal adencarcinoma， PDAC）仍然是最致命的癌症之一，目前尚无有效的治疗方法。为响应临床需要，开发创新的治疗策略，这