TGFBeta receptor antagonists as anticancer agents

TGFβ受体拮抗剂作为抗癌剂

基本信息

批准号：
6443680
负责人：
Michael Reiss
金额：
$ 24.95万
依托单位：
UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-01 至 2005-06-30
项目状态：
已结题

项目摘要

Transforming Growth Factor-betas are polypeptides that are constitutively secreted and activated by many carcinomas. They contribute to the tumor's ability to invade and metastasize, to induce angiogenesis and to escape from immune destruction. By the same token, cancer cells themselves are generally refractory to TGFbeta-mediated growth arrest. This particular set of circumstances raises the question whether blocking the effects of tumor-derived TGFbeta on normal tissue (stromal cells, microvascular endothelial cells and immune cells) might constitute a novel approach to cancer treatment. In the past, several different strategies have been employed to counteract the biological effects of TGFbeta in cancer and other diseases. These have included the use of TGFbeta neutralizing antibodies, of TGFbeta- binding proteins, such as decorin, and of TGFbeta1 antisense RNA oligonucleotides. Animal experiments and small-scale clinical studies using each of these approaches have provided proof of concept that inactivation of TGFbeta has the predicted anti-tumor effect. However, larger scale testing and further clinical development of any of these compounds has been marred by technical difficulties and limited availability. We now propose an alternative strategy to blocking TGFbeta action by targeting the key molecule in TGFbeta signaling, i.e. the type I TGFbeta receptor (TbetaR-I) serine-threonine kinase. Small molecular selective TbetaR-I antagonists are likely to be more effective than the approaches mentioned above, and should not be subject to the same limitations in terms of production and bioavailability. Our collaborators at SCIOS, Inc. have identified several promising lead compounds that inhibit TbetaR-I kinase activity in cell-free as well as in cellular systems in vitro. In addition, we have developed the capability to measure effects of TbetaR-I kinase inhibitors in vivo, using a proprietary highly sensitive antibody that selectively detects phosphorylated Smad2. We intend to examine the effects of lead compounds against normal cells in vitro using a number of different assays for TGFbeta's biological effects. The best TbetaR-I antagonists will then be tested for their antitumor activity against transplantable tumors in mice, with particular attention to their effects on metastasis, angiogenesis and anti-tumor immunity. Finally, optimization of the compounds in terms of potency, selectivity and bioavailability will be carried out to derive analogs with a favorable toxicity profile that can be developed further for clinical use.

转化生长因子-β是由许多癌持续分泌和激活的多肽。它们有助于肿瘤侵袭和转移、诱导血管生成和逃避免疫破坏的能力。出于同样的原因，癌细胞本身通常难以抵抗 TGFbeta 介导的生长停滞。这种特殊的情况提出了一个问题：阻断肿瘤来源的 TGFbeta 对正常组织（基质细胞、微血管内皮细胞和免疫细胞）的影响是否可能构成一种新的癌症治疗方法。过去，已经采用了几种不同的策略来抵消 TGFbeta 在癌症和其他疾病中的生物效应。这些包括使用TGFbeta中和抗体、TGFbeta结合蛋白（例如核心蛋白聚糖）和TGFbeta1反义RNA寡核苷酸。使用这些方法中的每一种的动物实验和小规模临床研究都提供了概念证明，即 TGFbeta 失活具有预期的抗肿瘤作用。然而，任何这些化合物的更大规模测试和进一步临床开发都因技术困难和有限的可用性而受到损害。我们现在提出了一种通过靶向 TGFbeta 信号转导中的关键分子（即 I 型 TGFbeta 受体 (TbetaR-I) 丝氨酸-苏氨酸激酶）来阻断 TGFbeta 作用的替代策略。小分子选择性 TbetaR-I 拮抗剂可能比上述方法更有效，并且在生产和生物利用度方面不应受到相同的限制。我们 SCIOS, Inc. 的合作者已经鉴定出几种有前景的先导化合物，它们可以在体外以及细胞系统中抑制 TbetaR-I 激酶活性。此外，我们还开发了使用选择性检测磷酸化 Smad2 的专有高灵敏度抗体来测量 TbetaR-I 激酶抑制剂的体内作用的能力。我们打算使用多种不同的 TGFbeta 生物效应测定方法，在体外检查先导化合物对正常细胞的影响。然后将测试最好的 TbetaR-I 拮抗剂对小鼠移植性肿瘤的抗肿瘤活性，特别关注它们对转移、血管生成和抗肿瘤免疫的影响。最后，将在效力、选择性和生物利用度方面对化合物进行优化，以获得具有良好毒性特征的类似物，并可进一步开发用于临床应用。