Plasmalemma vesicle-associated protein (PV-1) as a novel target in cancer immunot

质膜囊泡相关蛋白（PV-1）作为癌症免疫的新靶点

基本信息

批准号：
8491338
负责人：
RADU VIRGIL STAN
金额：
$ 21.11万
依托单位：
DARTMOUTH COLLEGE
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：
2013-04-04 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8491338
关键词：
Address Adjuvant Therapy Angiogenesis Inhibition Animal Model Antibodies Biological Models Biology Blood Vessels CD8B1 gene CTLA4 gene Cancer Patient Cancerous Caring Cause of Death Cell Count Cell Proliferation Cell membrane Cells Clinical Trials Combined Modality Therapy Data Development Diagnosis Endothelial Cells Environment Equilibrium Functional disorder Future Genotype Growth Growth Factor Human Hypoxia ITGAM gene Immune Immunocompetent Immunosuppressive Agents Immunotherapy In Vitro In complete remission Incidence Investments Leukocytes Life Location Malignant Neoplasms Malignant neoplasm of pancreas Malignant neoplasm of urinary bladder Mediating Metastatic Melanoma Monoclonal Antibodies Monophenol Monooxygenase Mus Mutation Myelogenous Myeloid Cells Neoplasm Metastasis Pathogenesis Patients Pharmaceutical Preparations Play Prevalence Prevention Progression-Free Survivals Proteins Recruitment Activity Regulatory T-Lymphocyte Relapse Research Role Site Skin Cancer Solid Neoplasm Solutions Suppressor-Effector T-Lymphocytes Surface T-Lymphocyte Testing Therapeutic Toxic effect Tumor Angiogenesis Up-Regulation Vascular Endothelial Growth Factors Vascular Endothelium Vesicle angiogenesis base cancer therapy cancer type effective therapy falls human disease inhibiting antibody inhibitor/antagonist killings lifetime risk macrophage mast cell meetings melanoma migration monocyte mouse model neoplastic cell neutrophil novel partial response plasmalemmal vesicle pre-clinical prevent public health relevance research study response small molecule standard of care success therapeutic target tumor tumor growth tumor microenvironment young adult

项目摘要

DESCRIPTION (provided by applicant): Cancer became the leading cause of death worldwide in 2010 and its global burden is projected to double by 2020 and to triple by 2030 (ACS data), despite enormous investments in its prevention and treatment. These efforts have led to great progress in our understanding of cancer pathogenesis. Therapeutic strategies addressing each or combinations of the cancer hallmarks and enabling features have been devised, with curative success so far limited to only a few cancers. This application proposes experiments aimed at validating a novel target for cancer therapy. Plasmalemmal vesicle associated protein-1 (PV1) is an endothelial specific protein expressed on the surface of endothelial cells of all solid tumors. Excitingly, PV1 deletion or PV1 function blockade with anti-PV1 monoclonal antibodies completely blocks the establishment or arrests the growth of tumors, respectively, in several immunocompetent mouse models of cancer (i.e. melanoma and pancreatic and bladder cancer). Mechanistically, the anti-tumor activity of anti-PV1 therapy results in a decrease of the intratumoral immune suppressive cells such as myeloid derived suppressor cells and regulatory T cells and an increase in the activated CD4 and CD8 T cells. Taken together, our data support the hypothesis that anti-PV1 therapy selectively inhibits the recruitment of immune suppressive cells, which in turn will both bolster the anti-tumor immune effector mechanisms and may also inhibit tumor angiogenesis. If correct, this will yield a completely novel multivalent strategy to inhibit tumor growth by selective inhibition of the establishment of an immunosuppressive tumor microenvironment, increase in the intratumoral T cells numbers and inhibition of angiogenesis. The location on the surface of endothelial cells and amenability to antibody blockade make PV1 an attractive therapeutic target for solid tumors, alone and especially in combination therapy. One in 52 people will be diagnosed with melanoma (lifetime risk), and while the majority is diagnosed while localized and highly treatable, eighty-five percent of those diagnosed with metastatic melanoma will not survive for five years. New treatments involving the anti-CTLA4 antibody (ipilimumab) and a novel small molecule BrafV600E inhibitor (PLX4032, vemurafenib) have recently revolutionized metastatic melanoma therapy. However, these therapies are short lived, effective in only a subset of patients or associated with significant toxicities and thus would benefit of the synergistic effects of adjuvant therapies to increase efficacy and/or manage toxicity. Using an autochthonous melanoma model system, we propose: Aim 1- to test the relevant tumor microenvironment changes underlying anti-PV1 therapy and, Aim 2- the efficacy of anti-PV1 therapy in combination with melanoma standard of care. The data we expect to obtain are relevant to the pathophysiology of cancer in general and will establish PV1 as a novel target for cancer treatment.

描述（由申请人提供）：2010 年，癌症成为全球头号死亡原因，尽管在预防和治疗方面投入巨资，但其全球负担预计到 2020 年将增加一倍，到 2030 年将增加两倍（ACS 数据）。这些努力使我们对癌症发病机制的理解取得了巨大进展。针对癌症特征和有利特征的每一个或组合的治疗策略已经被设计出来，迄今为止治疗成功仅限于少数癌症。该申请提出了旨在验证癌症治疗新靶点的实验。质膜囊泡相关蛋白-1 (PV1) 是一种内皮特异性蛋白，在所有实体瘤的内皮细胞表面表达。令人兴奋的是，在几种免疫活性小鼠癌症模型（即黑色素瘤、胰腺癌和膀胱癌）中，PV1 缺失或用抗 PV1 单克隆抗体阻断 PV1 功能分别完全阻止了肿瘤的形成或阻止了肿瘤的生长。从机制上讲，抗PV1疗法的抗肿瘤活性导致肿瘤内免疫抑制细胞（例如骨髓源性抑制细胞和调节性T细胞）减少，以及活化的CD4和CD8 T细胞增加。综上所述，我们的数据支持这样的假设：抗 PV1 疗法选择性抑制免疫抑制细胞的招募，进而增强抗肿瘤免疫效应机制，还可能抑制肿瘤血管生成。如果正确的话，这将产生一种全新的多价策略，通过选择性抑制免疫抑制肿瘤微环境的建立、增加肿瘤内 T 细胞数量和抑制血管生成来抑制肿瘤生长。在内皮细胞表面的位置和对抗体阻断的适应性使 PV1 成为实体瘤有吸引力的治疗靶点，尤其是在联合治疗中。每 52 人中就有 1 人会被诊断出患有黑色素瘤（终生风险），虽然大多数人是在局部且高度可治疗的情况下被诊断出来的，但 85% 被诊断为转移性黑色素瘤的人将无法存活五年。涉及抗 CTLA4 抗体（伊匹单抗）和新型小分子 BrafV600E 抑制剂（PLX4032、维莫非尼）的新疗法最近彻底改变了转移性黑色素瘤治疗。然而，这些疗法的寿命较短，仅对一小部分患者有效或与显着的毒性相关，因此将受益于辅助疗法的协同作用以提高疗效和/或控制毒性。使用本土黑色素瘤模型系统，我们建议：目标 1 - 测试抗 PV1 治疗相关的肿瘤微环境变化，目标 2 - 抗 PV1 治疗与黑色素瘤标准护理相结合的疗效。我们期望获得的数据总体上与癌症的病理生理学相关，并将将 PV1 确立为癌症治疗的新靶点。