Development of TGF-beta antagonists for cancer therapy

尽管TGF-β具有肿瘤抑制剂和肿瘤促进剂的双重作用， 致癌作用，我们实验室和其他人的临床前数据先前表明， 拮抗TGF-β的策略可以选择性地减少不期望的肿瘤促进作用， 这种生长因子的作用，同时保留了对肿瘤抑制的期望作用， 正常的体内平衡基于这些有希望的临床前结果， 用于治疗晚期癌症的早期临床试验（NCI-06-C-0200）。然而，在这方面， 考虑到TGF-β的复杂生物学特性，成功开发用于治疗糖尿病的TGF-β拮抗剂， 癌症治疗将取决于对这些药物如何工作的清楚理解，以及相关的 问题是如何选择将从这种治疗中受益的患者。2009年，我们 从多个角度探讨了这个问题。作为我们主动识别 可能受益于治疗性抗TGF-β抗体治疗的患者，我们有 研究了TGF-β途径组分与临床/病理 使用代表800多个乳腺癌病例的组织微阵列， 马克谢尔曼博士，国家癌症研究所的这些数据为多种复杂的生物学提供了证据。 TGF-β通路对乳腺癌发展的影响。一个惊人的发现是， TGF-β通路的激活随着年龄的增长而显著降低，这一特征可能有助于 组织学上相似的肿瘤在老年和年轻患者中的不同表现。我们 继续应用全局和候选基因表达分析，分子组织学， 免疫表型和免疫耗竭方法来了解转移抑制 抗TGF-β抗体治疗对多种同基因小鼠移植影响 转移性乳腺癌的模型。我们建立了一个模型小组， 体内对TGF-β拮抗作用的反应，我们希望从中鉴定分子 抗TGF-β抗体的治疗性与不良反应/抗性的决定因素。等 这些信息应该有助于临床试验的患者选择。我们已经证明 紫杉醇和抗TGF-β治疗可以协同抑制转移，我们正在研究 优化药物调度和排序，以及解决潜在的机制， 特别关注抗肿瘤免疫反应

Despite the dual role for TGF-beta as both tumor suppressor and tumor promoter in carcinogenesis, preclinical data from our lab and others has previously suggested that strategies to antagonize TGF-beta may selectively reduce the undesirable tumor promoting effects of this growth factor, while sparing the desirable effects on tumor suppression and normal homeostasis. Based on these promising preclinical results, an anti-TGF-beta antibody is in early phase clinical trials for the treatment of advanced cancer (NCI-06-C-0200). However, given the complex biology of TGF-beta, the successful development of TGF-beta antagonists for cancer therapy will depend on a clear understanding of how these agents work, and the related question of how to select patients who will benefit from this type of treatment. In FY09, we have approached this question from a number of angles. As part of our initiative to identify patients who might benefit from treatment with therapeutic anti-TGF-beta antibodies, we have examined the relationship between TGF-beta pathway components and clinical/pathological features using tissue microarrays representing over 800 breast cancer cases, in collaboration with Dr. Mark Sherman, DCEG, NCI. The data provide evidence for multiple complex biologic effects of the TGF-beta pathway on breast cancer development. One striking finding is that TGF-beta pathway activation decreases dramatically with age, a feature that may contribute to the differing behavior of histologically similar tumors in old and young patients. We are continuing to apply global and candidate gene expression analysis, molecular histology, immunophenotyping and immunodepletion approaches to understanding the metastasis suppressing effect of anti-TGF-beta antibody treatment in a variety of syngeneic mouse transplantation models of metastatic breast cancer. We have established a panel of models showing differing responses to TGF-beta antagonism in vivo, from which we hope to identify molecular determinants of therapeutic vs adverse response/resistance to anti-TGF-beta antibodies. Such information should be helpful in patient selection for clinical trials. We have shown that treatment with paclitaxel and anti-TGF-beta can synergize to suppress metastasis, and we are optimizing drug scheduling and sequencing, as well as addressing underlying mechanisms with a particular focus on the anti-tumor immune response