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：
8645617
负责人：
RADU VIRGIL STAN
金额：
$ 17.09万
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/8645617
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）：尽管在预防和治疗方面进行了巨大的投资，但癌症已于2010年在2010年全球死亡的主要原因，到2030年的全球负担预计将翻一番，到2030年将达到三倍（ACS数据）。这些努力在我们对癌症发病机理的理解方面取得了巨大进步。已经设计了解决癌症标志和促成特征的每种或组合的治疗策略，到目前为止的成功仅限于几种癌症。该应用提出了旨在验证癌症治疗的新目标的实验。血浆囊泡相关蛋白1（PV1）是一种在所有实体瘤的内皮细胞表面表达的内皮特异性蛋白。令人兴奋的是，抗PV1单克隆抗体的PV1缺失或PV1功能阻断完全阻断了建立或在几种免疫能力的癌症小鼠模型中分别阻止肿瘤的生长（即黑色素瘤，胰腺和胰腺和膀胱癌）。从机械上讲，抗PV1治疗的抗肿瘤活性导致肿瘤内免疫抑制细胞的降低，例如髓样衍生的抑制细胞和调节性T细胞，并增加了活化的CD4和CD8 T细胞。综上所述，我们的数据支持以下假设：抗PV1治疗有选择地抑制免疫抑制细胞的募集，这反过来又将增强抗肿瘤免疫效应器机制，也可能抑制肿瘤的血管生成。如果正确，这将产生一种完全新颖的多价策略，可以通过选择性抑制免疫抑制性肿瘤微环境，增加肿瘤内T细胞数量并抑制血管生成，从而抑制肿瘤生长。内皮细胞表面的位置以及抗体阻断的舒适性使PV1成为实体瘤的吸引力治疗靶标，尤其是在联合治疗中。 52分之一的人将被诊断出患有黑色素瘤（终生风险），尽管大多数人被诊断出何时局部和高度治疗，但被诊断为转移性黑色素瘤的患者中有85％将无法生存五年。涉及抗CTLA4抗体（ipilimumab）和一种新型的小分子BRAFV600E抑制剂（PLX4032，Vemurafenib）的新疗法最近彻底改变了转移性黑色素瘤疗法。但是，这些疗法的生命短，仅在一部分患者中有效或与重大毒性有关，因此将受益于辅助疗法的协同作用，以提高疗效和/或管理毒性。我们提出：目标1-用于测试相关肿瘤微环境的抗抗PV1治疗的变化，并瞄准2-抗PV1治疗与黑色素瘤护理标准的功效。我们期望获得的数据通常与癌症的病理生理学有关，并将将PV1作为癌症治疗的新靶标。