Inhibition of the tumor-promoting effects of TGF-beta in advanced prostate cancer

抑制晚期前列腺癌中 TGF-β 的肿瘤促进作用

基本信息

批准号：
8847306
负责人：
ANDREW P HINCK
金额：
$ 31.02万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
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：
2013-07-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8847306
关键词：
4T1 Affinity American Animal Cancer Model Animal Model Antibodies Antibody Affinity Binding Binding Sites Cancer Etiology Cell Survival Cell surface Cessation of life Chimeric Proteins Clinical Trials Complex Cultured Cells Data Distant Metastasis Drug Kinetics Exhibits Extracellular Domain FDA approved Fc Receptor Genetic Goals Health Human Immune Immunologic Surveillance Immunosuppression In Vitro Injection of therapeutic agent Ligand Binding Domain Link Lung Malignant Neoplasms Malignant neoplasm of prostate Mammary Tumorigenesis Metastatic Neoplasm to the Bone Modeling Mus Neoplasm Metastasis Normal Cell Normal tissue morphology Organ PTEN gene Penetration Peptide Hydrolases Pharmacodynamics Primary Neoplasm Property Protein Isoforms Proteolysis Research Resistance Safety Series Signal Pathway Signal Transduction Signaling Protein Therapeutic Transforming Growth Factor beta Transforming Growth Factor beta Receptors Transgenic Mice Transgenic Model Treatment Efficacy Tumor Suppressor Proteins Xenograft Model advanced disease androgen independent prostate cancer angiogenesis cancer therapy cell motility comparative efficacy design epithelial to mesenchymal transition flexibility immune function improved in vitro activity in vivo inhibitor/antagonist kinase inhibitor men mouse model neoplastic cell neutralizing antibody novel novel strategies prostate cancer cell prostate cancer cell line prostate carcinogenesis receptor receptor binding research clinical testing response single molecule small molecule survivorship tumor tumor growth tumor microenvironment tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Transforming growth factor-beta isoforms (TGFβ1, β2, and β3) are secreted signaling proteins. They function as immunomodulatory factors and tumor suppressors in normal and early neoplastic cells, but in many established cancers, including androgen-independent prostate cancer, they promote tumor growth and metastasis. The therapeutic benefit of antagonizing TGFβ using neutralizing antibodies and small molecule receptor kinase inhibitors has been amply demonstrated in animal models of cancer, yet no inhibitors have been approved for cancer treatment in humans. The kinase inhibitor LY2157299 has significant off-target activity and has progressed slowly through clinical trials due to safety concerns. The pan-isoform neutralizing antibody GC1008, while specific and safe, has limited efficacy. The latter may be due to i) the limited affinity of the antibody (Kd 4-10 nM) that hinder its ability to compete against the endogenous receptor complex, a heterotetramer that binds the TGFβs with affinities of 0.1-1 pM, ii) a requirement that two antibodies bind to homodimeric TGFβ to completely block receptor binding, or iii) the large size of the antibody (160 kDa) and/or binding to Fc receptors that restricts its ability to penetrate the tumor and microenvironment. The objective of this study is to investigate a promising new class of TGFβ inhibitors in which the ligand-binding domains of the TGFβ receptors are fused together by flexible linkers. The advantages of these fusions include i) potentially higher affinities, ii) blockage of all receptor binding sites with a single inhibitor, and iii) reduced size (24-91 kDa). Through preliminary studies, four fusions have been generated. These potently inhibit TGFβ activity in vitro (EC50 2 nM -1 pM) and are highly effective in suppressing primary tumor growth and distant metastases in several models, including a xenograft model of human prostate cancer. The objective of Aim 1 is to generate a series of receptor fusions of varying affinity, blockage of receptor binding sites, and size - this will allow us to investigate our hypothesis tha these parameters determine therapeutic efficacy. The PK properties of the fusions will also be evaluated in Aim 1. The primary objective of Aim 2 is to evaluate the inhibitory effect of the fusions on primary tumor growth and number and size of metastatic colonies to the major organs in two genetic mouse models with spontaneous prostate carcinogenesis in an immune-competent background and a xenograft model of human prostate cancer in an immune compromised background. To better understand how the inhibitors influence therapeutic efficacy, we will investigate their PD properties and their effects on TGFβ - regulated immune suppression, angiogenesis, and EMT. The secondary objective of Aim 2 is to determine whether the fusions interfere with TGFβ's tumor suppressive and/or immune modulatory functions in immune competent mice - this will provide information as to how aggressively TGFβ can be inhibited without interfering with its function in normal cells and tissues. The long-term goal is o produce fusions for neutralizing TGFβ's tumor promoting activity that are both safe and effective for use in clinical trials for advanced prostate cancer.

描述（由适用提供）：转化生长因子β同工型（TGFβ1，β2和β3）是分泌的信号蛋白。它们充当正常和早期肿瘤细胞中的免疫调节因子和肿瘤补充剂，但是在许多已建立的癌症（包括雄激素独立的前列腺癌）中，它们会促进肿瘤的生长和转移。使用中和抗体和小分子受体激酶抑制剂拮抗TGFβ的治疗益处已在动物的癌症模型中得到充分证明，但是NO抑制剂已被批准用于人类的癌症治疗。激酶抑制剂LY2157299具有显着的脱靶活动，并且由于安全性而在临床试验中缓慢进展关注。泛氧化抗体中和抗体GC1008虽然具体且安全，但效率有限。后者可能是由于i）抗体（KD 4-10 nm）的有限亲和力，阻碍了其与内源性受体复合物竞争的能力，一种与内源性受体复合体竞争的能力，一种偶发的异光学术，其伴侣结合为0.1-1 pm的TGFβ，ii）两种抗体与同型TGFβ与完全结合的构造（或III II II）结合的，或II III II II II II II III（III II），或III II II II II II III（II II II）。和/或与FC受体结合，限制了其穿透肿瘤和微环境的能力。这项研究的目的是研究一种有希望的新型TGFβ抑制剂，其中TGFβ受体的配体结合结构域被柔性接头融合在一起。这些融合的优点包括i）潜在的较高亲和力，ii）所有受体结合位点具有单个抑制剂的阻塞，以及通过初步研究减少的iii），已经产生了四个融合。这些潜在的在体外抑制TGFβ活性（EC50 2 nm -1 pm），并且在抑制多种模型的原发性肿瘤生长和远处转移方面非常有效，包括人类前列腺癌的异种移植模型。目标1的目的是生成一系列不同亲和力，受体结合位点的阻塞和大小的受体融合 - 这将使我们能够研究我们的假设这些参数决定了理论有效性。融合的PK特性也将在目标1中进行评估。目标2的主要目的是评估融合物对两种遗传小鼠模型中主要器官模型的转移性菌落对原发性器官的抑制作用，并在免疫背景和人类的ProStrest癌症中，具有遗传性前列腺癌作用的两个遗传小鼠模型。为了更好地了解抑制剂如何影响理论的有效性，我们将研究其PD的性能及其对TGFβ调控的免疫抑制，血管生成和EMT的影响。目标2的次要目标是确定融合干扰免疫能力小鼠中TGFβ抑制肿瘤抑制和/或免疫调节功能 - 这将提供有关如何在不干扰其在正常细胞和组织中的功能的情况下如何抑制TGFβ的信息。长期目标是o产生融合，以中和TGFβ的肿瘤促进活性，这既安全又有效，可用于晚期前列腺癌的临床试验。