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

• 批准号: 8692691
• 负责人: ANDREW P HINCK
• 金额: $ 30.09万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8692691
• 关键词: 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; 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; PC3 cell line; 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 carcinogenesis; public health relevance; receptor; receptor binding; research clinical testing; response; single molecule; small molecule; survivorship; tumor; tumor growth; tumor microenvironment; tumorigenesis

DESCRIPTION (provided by applicant): Transforming growth factor-beta isoforms (TGF?1, ?2, and ?3) 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 TGF? 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 TGF?s with affinities of 0.1-1 pM, ii) a requirement that two antibodies bind to homodimeric TGF? 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 TGF? inhibitors in which the ligand-binding domains of the TGF? 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 TGF? 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 TGF? - regulated immune suppression, angiogenesis, and EMT. The secondary objective of Aim 2 is to determine whether the fusions interfere with TGF?'s tumor suppressive and/or immune modulatory functions in immune competent mice - this will provide information as to how aggressively TGF? can be inhibited without interfering with its function in normal cells and tissues. The long-term goal is o produce fusions for neutralizing TGF?'s tumor promoting activity that are both safe and effective for use in clinical trials for advanced prostate cancer.

描述（由申请人提供）：转化生长因子 - β同工型（TGF？1，？2和？3）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抑制因子，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。对抗TGF的治疗益处？在动物的癌症模型中，使用中和抗体和小分子受体激酶抑制剂已得到充分证明，但是尚无抑制剂在人类的癌症治疗中得到批准。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虽然具有特异性和安全性，但功效有限。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，内源性受体复合物是一种粘结率为0.1-1 pm的异射线术，II）要求两种抗体与同型TGF结合？完全阻断受体结合，或iii）抗体的大尺寸（160 kDa）和/或与FC受体结合，从而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有希望的新类TGF？ TGF的配体结合域的抑制剂？受体被灵活的接头融合在一起。这些融合的优点包括i）潜在的较高亲和力，ii）封闭具有单个抑制剂的所有受体结合位点，iii）尺寸降低（24-91 kDa）。通过初步研究，已经产生了四个融合。这些有力抑制TGF？体外活性（EC50 2 nm -1 pm），并且在几种模型中抑制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，这些参数确定了治疗效率。 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.为了更好地了解抑制剂如何影响治疗功效，我们将研究它们的PD特性及其对TGF的影响？ - 受调节的免疫抑制，血管生成和EMT。 AIM 2的次要目标是确定融合会干扰免疫胜任小鼠中TGF肿瘤抑制和/或免疫调节功能的抑制作用 - 这将提供有关TGF如何积极的信息？可以抑制而不会干扰其在正常细胞和组织中的功能。长期目标是O产生融合，以中和TGF促进肿瘤促进活性，这些肿瘤既安全又有效，可用于晚期前列腺癌的临床试验。