Targeting Cell Surface GRP78 as a Novel Therapy for Pancreatic Cancer

靶向细胞表面 GRP78 作为胰腺癌的新疗法

基本信息

批准号：
8700022
负责人：
AMY S LEE
金额：
$ 21.46万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8700022
关键词：
Address Affect Animals Apoptosis Biological Models Biology Blood Vessels Cancer Model Cancer cell line Cell Death Cell surface Cells Cessation of life Clinic Combined Modality Therapy Complex Coupled Data Desmoplastic Diagnostic Endocytosis Endocytosis Inhibition GRP78 gene Genes Growth Human Hypoxia Image Immunoglobulin G Intercellular Fluid Laboratories Lead Lesion Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Measures Metabolism Modeling Molecular Chaperones Monoclonal Antibodies Mus Mutation Normal Cell Nutrient Oncogenic Organ PI3K/AKT Pancreatic Ductal Adenocarcinoma Pathway interactions Phosphotransferases Proteins Proto-Oncogene Proteins c-akt Regulation Resistance Signal Transduction Stress Surface Survival Rate TNFRSF10A gene TP53 gene Testing Therapeutic Therapeutic Agents Translating Transplantation Treatment Efficacy Tumor Suppression Up-Regulation Xenograft procedure arm base biological adaptation to stress cancer cell cancer therapy caspase-8 combat deprivation efficacy testing endoplasmic reticulum stress gemcitabine glucose-regulated proteins neoplastic cell novel novel strategies novel therapeutics pancreatic cancer cells pancreatic neoplasm pressure public health relevance response sensor tumor tumor growth tumor progression tumor xenograft uptake

项目摘要

DESCRIPTION (provided by applicant): We propose a novel therapeutic strategy to combat pancreatic cancer by targeting the cell surface glucose regulated protein GRP78 (sGRP78), a stress-inducible master chaperone which is actively promoted to the cell surface upon endoplasmic reticulum (ER) stress in cancer cells, while sparing normal organs. Pancreatic ductal adenocarcinoma (PDAC) is one of deadliest of all cancers with a 5 yr survival rate of <5%, thus there is an urgent need for developing an efficacious therapy for PDAC. This proposal is based on emerging evidence from our laboratory and others that in pancreatic cancer GRP78 is prominently expressed in both human and murine pre-invasive and PDAC lesions and sGRP78 co-localizes with activated AKT at the cell surface of PDAC. We have recently discovered a highly specific and potent monoclonal antibody, MAb159, that targets sGRP78 leading to endocytosis, inhibition of the PI3K/AKT pathway, and tumor cell death by inducing apoptosis. Our hypothesis is that pancreatic cancer characterized by a dense stroma is subjected to an adverse microenvironment resulting in hypoxia and nutrient deprivation. This coupled with intrinsic high proliferation and altered metabolism, creates ER stress in the cancer cells leading to GRP78 upregulation and active promotion of GRP78 surface localization as a major pro-survival response. Targeting sGRP78 with MAb159 induces endocytosis and degradation of sGRP78 complex at the cell surface, thereby offering a novel approach to blunt AKT and potentially other oncogenic pathways to suppress tumor growth and synergize with existing therapy in pancreatic cancer. Additionally, MAb159 treatment induces caspase-8 activation, indicative of activation of extrinsic cell death. Aim 1 will determine the mechanisms o action of MAb159 in human PDAC, addressing the requirement of endocytosis, AKT activation, the interactions between sGRP78 and the death-inducing signaling complex and synergy with gemcitabine. Based on our exciting preliminary data that MAb159 not only inhibits but can regress xenograft growth of human PDAC, Aim 2 will test the efficacy of MAb159, alone or in combination therapy, in the Pdx-1Cre; KrasG12D; p53f/+ (PKC) endogenous mouse pancreatic cancer model which recapitulates many of the features of human pancreatic cancer and offers a most vigorous test for agent efficacy. In parallel, the efficacy of MAb159 will be tested in orthotopic transplantation models of human PDAC with complex genetic alterations. In summary, this proposal tests two new concepts: 1) sGRP78 promotes tumor proliferation and survival in part through regulation of the PI3K/AKT pathway and the death-inducing signaling complex in PDAC, and 2) a novel therapeutic agent (MAb159 targeting sGRP78) may reverse tumor growth and resistance while sparing normal cells. The results of this study can be readily applied to other highly malignant and resistant tumors expressing sGRP78 and translatable to the clinic.

描述（由申请人提供）：我们提出了一种通过靶向细胞表面葡萄糖调节蛋白 GRP78 (sGRP78) 来对抗胰腺癌的新治疗策略，GRP78 是一种应激诱导的主伴侣，在内质网 (ER) 上主动促进到细胞表面癌细胞受到压力，同时不影响正常器官。胰腺导管腺癌（PDAC）是所有癌症中最致命的一种，其5年生存率<5%，因此迫切需要开发针对PDAC的有效疗法。该提议基于我们实验室和其他实验室的新证据，即在胰腺癌中，GRP78 在人类和小鼠侵袭前病变和 PDAC 病变中显着表达，并且 sGRP78 与 PDAC 细胞表面的激活 AKT 共定位。我们最近发现了一种高度特异性和有效的单克隆抗体 MAb159，它以 sGRP78 为靶点，导致内吞作用、抑制 PI3K/AKT 通路，并通过诱导细胞凋亡来导致肿瘤细胞死亡。我们的假设是，以致密基质为特征的胰腺癌受到不利的微环境的影响，导致缺氧和营养缺乏。这与内在的高增殖和代谢改变相结合，在癌细胞中产生内质网应激，导致 GRP78 上调并积极促进 GRP78 表面定位作为主要的促生存反应。用 MAb159 靶向 sGRP78 可诱导细胞表面 sGRP78 复合物的内吞作用和降解，从而提供了一种钝化 AKT 和潜在其他致癌途径的新方法，以抑制肿瘤生长并与胰腺癌的现有疗法产生协同作用。此外，MAb159 治疗可诱导 caspase-8 激活，表明外源性细胞死亡的激活。目标 1 将确定 MAb159 在人 PDAC 中的作用机制，解决内吞作用、AKT 激活、sGRP78 与死亡诱导信号复合物之间的相互作用以及与吉西他滨的协同作用的要求。基于我们令人兴奋的初步数据，即 MAb159 不仅可以抑制人 PDAC 的异种移植物生长，还可以使人 PDAC 的异种移植物生长消退，Aim 2 将测试 MAb159 单独或联合治疗在 Pdx-1Cre 中的功效；克拉斯G12D； p53f/+ (PKC) 内源性小鼠胰腺癌模型概括了人类胰腺癌的许多特征，并提供了最有力的药物功效测试。与此同时，MAb159 的功效将在具有复杂遗传改变的人类 PDAC 原位移植模型中进行测试。总之，该提案测试了两个新概念：1) sGRP78 部分通过调节 PI3K/AKT 通路和 PDAC 中的死亡诱导信号复合物来促进肿瘤增殖和存活，2) 一种新型治疗剂（靶向 sGRP78 的 MAb159）可以逆转肿瘤的生长和抵抗力，同时保护正常细胞。这项研究的结果可以很容易地应用于其他表达sGRP78的高度恶性和耐药的肿瘤，并可转化为临床。