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（由申请人提供）：目前，尚无有效的治疗胰腺导管腺癌（PDAC），这仍然是最致命的癌症之一。为了应对制定创新治疗策略的临床需求，这建议将测试一种新型组合免疫治疗策略的治疗功效，该策略不仅针对分化PDAC细胞，还针对PDAC癌引发细胞（CICS）。为了“治愈”恶性疾病，必须消除这些被鉴定为Aldhbright细胞的细胞，因为根据癌症干细胞理论，这些细胞负责疾病复发和转移。被选为靶靶的肿瘤抗原是葡萄糖调节的蛋白94 kDa（GRP94），这是热休克蛋白90（HSP90）家族的成员。 GRP94调节与细胞增殖，存活和迁移有关的几种信号通路的激活。为了靶向GRP94，我们将利用我们最近表征的人类MAB W9的独特特异性。 MAB W9识别出在恶性细胞（包括人PDAC细胞和PDAC CIC）上选择性表达的细胞外GRP94表位，但在正常组织中却没有。 MAB W9显着抑制了包括PDAC CIC的人类PDAC细胞的体外增殖，并诱导其凋亡。通过将其与环原胺和5-FU结合，可以增强MAB W9的抗增殖和促凋亡活性。环马嘌呤和5-FU都抑制了声波刺猬信号通路，该通路在PDAC中被异常激活，尤其是在基质和PDAC CIC中。为了评估这些体外数据的体内相关性，该提案的具体目的将检验以下假设：i）MAB W9在原发性PDAC肿瘤中定义的GRP94表位的表达与其组织病理学特征和预后不良有关； ii）MAB W9与环主要和5-FU结合使用，比单个药物更有效，或者两种药物的组合在消除与PDAC细胞系MIA PACA-2的原始小鼠免疫缺陷小鼠中的PDAC肿瘤中； iii）使用PDAC细胞系MIA PACA-2获得的结果将具有潜在的临床意义，因为它们在原始小鼠的原始小鼠原始疗法中被从患者手术中切除的PDAC肿瘤进行了繁殖。从体外和动物模型系统中概述的研究得出的信息将提供有用的背景，可在PDAC患者中使用MAB W9实施I期临床试验。 C. Ferrone博士在马萨诸塞州波士顿的马萨诸塞州综合医院与她的患者访问PDAC的机会将促进该试验的实施，这是她在进行临床试验方面的新获得的技能，以及MAB W9的完全人性。