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

描述（由申请人提供）：2010年，癌症成为全球死亡的主要原因，其全球负担预计到2020年将翻一番，到2030年将翻三倍（ACS数据），尽管在其预防和治疗方面投入了大量资金。这些努力使我们对癌症发病机制的理解取得了很大进展。针对癌症标志和使能特征的每一种或组合的治疗策略已经被设计出来，迄今为止治愈成功仅限于少数癌症。本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（PV 1）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（即黑色素瘤和胰腺癌和膀胱癌）中，用抗PV 1单克隆抗体进行PV 1缺失或PV 1功能阻断分别完全阻断肿瘤的建立或阻止肿瘤的生长。从机制上讲，抗PV 1治疗的抗肿瘤活性导致肿瘤内免疫抑制细胞（如髓源性抑制细胞和调节性T细胞）减少，活化的CD 4和CD 8 T细胞增加。总之，我们的数据支持这样的假设，即抗PV 1治疗选择性地抑制免疫抑制细胞的募集，这反过来将支持抗肿瘤免疫效应机制，也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性肿瘤微环境的建立、增加肿瘤内T细胞数量和抑制血管生成来抑制肿瘤生长。在内皮细胞表面上的位置和对抗体阻断的顺从性使PV 1成为实体瘤的有吸引力的治疗靶点，单独使用，特别是在联合治疗中。 每52人中就有一人会被诊断出患有黑色素瘤（终身风险），虽然大多数人被诊断为局部和高度可治疗，但85%的转移性黑色素瘤患者将无法存活五年。涉及抗CTLA 4抗体（ipilimumab）和新型小分子BrafV 600 E抑制剂（PLX 4032，vemurafenib）的新治疗最近彻底改变了转移性黑色素瘤治疗。然而，这些疗法是短暂的，仅在一部分患者中有效或与显著毒性相关，因此将受益于辅助疗法的协同效应以增加功效和/或管理毒性。使用自体黑色素瘤模型系统，我们提出：目的1-测试抗PV 1治疗的相关肿瘤微环境变化，目的2-抗PV 1治疗与黑色素瘤标准治疗联合的疗效。我们期望获得的数据与一般癌症的病理生理学相关，并将PV 1确立为癌症治疗的新靶点。

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.