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

• 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
• 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

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）：我们提出了一种新型的治疗策略，通过靶向细胞表面葡萄糖调节的蛋白GRP78（SGRP78），这是一种可应激诱导的主伴侣，在癌细胞中，在癌细胞上，在癌细胞上，在癌细胞上，在癌细胞上施加了积极促进到细胞表面，同时促进癌细胞的正常organs，同时促进正常的organs。胰腺导管腺癌（PDAC）是所有癌症中最致命的癌症之一，5年生存率<5％，因此迫切需要为PDAC开发有效的治疗。该提议是基于我们实验室的新兴证据，以及其他人的证据表明，在胰腺癌中，在人类和鼠类侵入性病变和PDAC病变中都显着表达了与PDAC细胞表面激活的AKT共定位的人类和PDAC病变。我们最近发现了一种高度特异性且有效的单克隆抗体MAB159，该抗体靶向SGRP78，导致内吞作用，抑制PI3K/AKT途径以及通过诱导凋亡诱导肿瘤细胞死亡。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，导致缺氧和营养剥夺。这与内在的高增殖和新陈代谢改变相结合，在癌细胞中产生了ER应力，导致GRP78上调并积极促进GRP78表面定位，作为主要的生存反应。用MAB159靶向SGRP78可在细胞表面诱导SGRP78复合物的内吞作用和降解，从而提供一种新型的方法来抑制AKT和其他潜在的致癌途径，以抑制肿瘤生长并与现有的胰腺癌治疗协同作用。另外，MAB159治疗诱导caspase-8激活，指示外外细胞死亡的激活。 AIM 1将确定MAB159在人PDAC中的作用的机制，以满足内吞作用，AKT激活的需求，SGRP78和诱导死亡的信号传导复合物之间的相互作用以及与吉西他滨的协同作用。基于我们令人兴奋的初步数据，MAB159不仅可以抑制人类PDAC的异种移植的生长，AIM 2将在PDX-1CRE中单独或联合治疗中MAB159的功效测试MAB159的功效。 krasg12d; p53f/+（PKC）内源性小鼠胰腺癌模型，该模型概括了人类胰腺癌的许多特征，并为剂功效提供了最剧烈的测试。同时，MAB159的功效将在具有复杂遗传改变的人PDAC的原位移植模型中进行测试。总而言之，该提案测试了两个新概念：1）SGRP78通过调节PI3K/AKT途径和PDAC中诱导死亡的信号复合物的一部分来促进肿瘤的增殖和生存，而2）新型治疗剂（MAB159靶向SGRP78）可能会在较大的细胞中降低正常和阻力。这项研究的结果可以很容易地应用于表达SGRP78并可以翻译成诊所的其他高度恶性和抗性肿瘤。