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

描述(由申请人提供)：2010年，癌症成为全球主要的死亡原因，预计到2020年，其全球负担将翻一番，到2030年将翻两番(美国癌症协会数据)，尽管在其预防和治疗方面投入了巨大的资金。这些努力使我们对癌症发病机制的理解有了很大的进步。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设计出来，到目前为止，治疗成功仅限于少数几种癌症。这项申请提出了旨在验证癌症治疗的新靶点的实验。 质膜囊泡相关蛋白-1(PV1)是一种表达于所有实体瘤内皮细胞表面的内皮特异性蛋白。令人兴奋的是，在几种免疫活性的肿瘤模型(如黑色素瘤和胰腺癌和膀胱癌)中，用抗PV1的单抗完全阻断了肿瘤的建立或阻止了肿瘤的生长。从机制上讲，抗PV1治疗的抗肿瘤活性导致瘤内免疫抑制细胞如髓系抑制细胞和调节性T细胞减少，而活化的CD4和CD8T细胞增加。综上所述，我们的数据支持这样的假设，即抗PV1治疗选择性地抑制免疫抑制细胞的募集，这反过来将增强抗肿瘤免疫效应机制，并可能抑制肿瘤血管生成。如果正确，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。PV1在血管内皮细胞表面的位置和对抗体阻断的易感性使其成为实体瘤的治疗靶点，特别是在联合治疗中。 每52个人中就有一个将被诊断为黑色素瘤(终生风险)，虽然大多数人是在局部和高度可治疗的情况下被诊断出来的，但被诊断为转移性黑色素瘤的人中有85%将无法存活五年。最近，包括抗CTLA4抗体(Ipilimumab)和新型小分子BRAFV600E抑制剂(PLX4032，vemurafenib)在内的新疗法使转移性黑色素瘤的治疗发生了革命性的变化。然而，这些疗法是短暂的，只对一小部分患者有效，或者与显著的毒性相关，因此将受益于辅助疗法的协同效应，以提高疗效和/或管理毒性。利用自体黑色素瘤模型系统，我们提出：目的1-检测抗PV1治疗下相关肿瘤微环境的变化，目的2-联合抗PV1治疗和黑色素瘤标准治疗的疗效。我们希望获得的数据与一般癌症的病理生理学相关，并将确立PV1作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.