Placenta Growth Factor Inhibition in Head and Neck Cancer

胎盘生长因子抑制头颈癌

• 批准号: 8142929
• 负责人: NATALIE A SUTKOWSKI
• 金额: $ 11.06万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-14 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8142929
• 关键词: Address; Angiogenesis Inhibition; Animal Model; Animals; Antibodies; Binding; Blood Vessels; Cell Line; Chemotaxis; Development; Endothelial Cells; Family; Gene Expression; Gene Expression Microarray Analysis; Goals; Growth; Growth Factor Inhibition; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Hematoxylin and Eosin Staining Method; Human; Hypoxia; Immunodeficient Mouse; Immunotherapeutic agent; In Vitro; Laboratories; Leukocytes; Malignant Epithelial Cell; Malignant Neoplasms; Mitogen-Activated Protein Kinases; Modeling; Mus; PTPRC gene; Patients; Pattern; Peripheral Blood Mononuclear Cell; Peritoneum; Pilot Projects; Placental Growth Factor; Production; Protocols documentation; Radiation; Recruitment Activity; Reporting; Resistance; Role; Signal Transduction; Small Interfering RNA; Specimen; Staining method; Stains; Study models; Technology; Testing; Therapeutic; Tissues; Transcript; Tumor Angiogenesis; Vascular Endothelial Growth Factors; Vascularization; Xenograft Model; Xenograft procedure; angiogenesis; antibody inhibitor; bevacizumab; cancer therapy; chemotherapy; human monoclonal antibodies; hypoxia inducible factor 1; in vitro testing; in vivo; inhibitor/antagonist; knock-down; macrophage; matrigel; member; monocyte; neoplastic cell; neovascularization; neutralizing antibody; new therapeutic target; novel; public health relevance; receptor; response; tumor; tumor growth; tumor xenograft

DESCRIPTION (provided by applicant): Placenta Growth Factor (PLGF) was recently identified as a novel therapeutic target for inhibiting tumor angiogenesis. PLGF is a member of the vascular endothelial growth factor (VEGF) family, which binds to and signals through the VEGF-R1 receptor. Tumor cells produce PLGF and VEGF in response to hypoxic conditions caused by chemotherapy, radiation or VEGF inhibition therapy. In tumors, hypoxia inducing factor HIF11 can upregulate PLGF and VEGF, which then enter the periphery, bind to and recruit endothelial cells, thus initiating neovascularization. While VEGF has an essential role in normal vascularization and development, PLGF does not. Normally, PLGF has a limited pattern of expression, but it is unexpectedly produced by different tumors. Therefore, inhibiting PLGF as a cancer treatment would be more selective, and is predicted to be less toxic than inhibiting VEGF. Furthermore, PLGF inhibition is predicted to enhance anti- angiogenic therapy with VEGF inhibitors, by blocking PLGF's ability to recruit macrophages. Macrophage recruitment to the tumor microenvironment has been associated with tumor resistance. In addition, mouse tumor model studies indicated that anti-PLGF neutralizing antibodies inhibited growth, angiogenesis and macrophage recruitment in a variety of tumors, suggesting that PLGF inhibition might be effective against human cancers. Recently, gene expression microarray studies have identified PLGF transcripts in a variety of head and neck squamous cell carcinomas (HNSCC), suggesting that PLGF inhibition might have therapeutic benefit in HNSCC. In this pilot study, we aim to investigate the role of PLGF in HNSCC, characterizing the activity of newly isolated human monoclonal antibodies (Hu MAbs) specific for PLGF. We hypothesize that PLGF inhibition will have anti-tumor activity in HNSCC, and will inhibit tumor angiogenesis and macrophage recruitment both in vitro and in vivo. PLGF specific Hu MAbs have recently been isolated in our laboratory using a novel in vitro technology. We propose in aim 1 to identify a role for PLGF in HNSCC in vitro, staining HNSCC specimens for PLGF prior to and after hypoxia induction through chemoradiation. In addition, we will compare antibody inhibition and siRNA knockdown of PLGF production in HNSCC cell lines and tumor specimens, looking at effects on VEGF-R1 binding, MAP kinase activity, angiogenesis induction and monocyte recruitment. We propose in aim 2 to identify a role for PLGF in HNSCC in vivo, using a xenograft animal model of tumor angiogenesis. Immunodeficient mice will be injected with human HNSCC cell lines expressing high, low, or knocked down levels of PLGF, in the presence or absence of PLGF Hu MAbs. Effects on tumor growth, neovascularization, and human leukocyte and macrophage recruitment will be evaluated. In summary, the goal of this pilot project proposal is to investigate the role of PLGF in HNSCC. It is expected that the proposed studies will provide the rationale for further exploration of this exciting new angiogenic target in head and neck cancer. PUBLIC HEALTH RELEVANCE: In this proposal, we aim to investigate the role of Placenta Growth Factor (PLGF), a member of the VEGF family, in head and neck squamous cell carcinoma (HNSCC). PLGF normally has limited expression, but is aberrantly expressed in tumors, causing angiogenesis and macrophage recruitment. Novel PLGF specific human monoclonal antibodies will be tested for in vitro and in vivo anti-tumor activity on HNSCC. The goal of this proposal is to investigate their activity for use as possible immunotherapeutic agents in HNSCC.

描述（由申请人提供）：胎盘生长因子（PLGF）最近被确定为抑制肿瘤血管生成的新型治疗靶标。 PLGF是血管内皮生长因子（VEGF）家族的成员，该家族与VEGF-R1受体结合并通过信号。肿瘤细胞会响应化学疗法，放射线或VEGF抑制疗法引起的低氧疾病而产生PLGF和VEGF。在肿瘤中，缺氧诱导因子HIF11可以上调PLGF和VEGF，然后进入外围，结合并募集内皮细胞，从而启动新血管形成。尽管VEGF在正常的血管形成和发育中起着至关重要的作用，但PLGF却没有。通常，PLGF的表达方式有限，但它是由不同肿瘤产生的。因此，抑制PLGF作为癌症治疗将更具选择性，并且预计毒性比抑制VEGF更小。此外，预测PLGF抑制作用可以通过阻断PLGF募集巨噬细胞的能力来增强使用VEGF抑制剂的抗血管生成疗法。巨噬细胞募集到肿瘤微环境已与肿瘤耐药性有关。此外，小鼠肿瘤模型的研究表明，抗PLGF中和抗体抑制了多种肿瘤的生长，血管生成和巨噬细胞募集，这表明PLGF抑制作用可能有效地针对人类癌症。最近，基因表达微阵列研究已经确定了各种头颈部鳞状细胞癌（HNSCC）中的PLGF转录本，这表明PLGF抑制作用可能在HNSCC中具有治疗益处。在这项试点研究中，我们旨在研究PLGF在HNSCC中的作用，以新分离的人类单克隆抗体（HU MAB）的活性为特定的PLGF的活性。我们假设PLGF抑制作用将在HNSCC中具有抗肿瘤活性，并且会在体外和体内抑制肿瘤血管生成和巨噬细胞募集。最近，使用一种新型的体外技术在我们的实验室中分离了PLGF特定的HU mAB。我们建议在AIM 1中确定PLGF在体外HNSCC中的作用，在通过化学放疗诱导缺氧之前和之后染色PLGF的HNSCC标本。此外，我们将比较HNSCC细胞系和肿瘤标本中PLGF产生的抗体抑制和siRNA敲低，研究对VEGF-R1结合，MAP激酶活性，血管生成诱导和单核细胞募集的影响。我们建议使用肿瘤血管生成的异种移植动物模型来确定PLGF在体内HNSCC中的作用。在存在或不存在PLGF HU mAb的情况下，免疫缺陷的小鼠将注入人类HNSCC细胞系，表达高，低或敲低的PLGF水平。将评估对肿瘤生长，新血管形成以及人类白细胞和巨噬细胞募集的影响。总之，该试点项目提案的目标是调查PLGF在HNSCC中的作用。预计拟议的研究将提供基本原理，以进一步探索头颈癌中这种令人兴奋的新血管生成靶标。 公共卫生相关性：在此提案中，我们旨在调查VEGF家族成员胎盘生长因子（PLGF）在头颈部鳞状细胞癌（HNSCC）中的作用。 PLGF通常的表达有限，但在肿瘤中异常表达，导致血管生成和巨噬细胞募集。新型PLGF特异性人类单克隆抗体将在HNSCC上测试体外和体内抗肿瘤活性。该提案的目的是调查其在HNSCC中使用的免疫治疗剂的活动。