Development of TGF-beta antagonists for cancer therapy

尽管转化生长因子-β作为肿瘤抑制因子和肿瘤促进剂在肿瘤发生中的双重作用，我们实验室和其他人的临床前数据已经表明，拮抗转化生长因子-β的策略可能选择性地减少这种生长因子的不良促癌作用，同时避免对肿瘤抑制和正常体内平衡的预期作用。基于这些有希望的临床前结果，一种抗转化生长因子-β抗体正在进行治疗晚期癌症的早期临床试验(NCI-06-C-0200)。然而，考虑到转化生长因子-β的复杂生物学，成功开发用于癌症治疗的转化生长因子-β拮抗剂将取决于对这些药物如何发挥作用的清楚了解，以及如何选择将从这种治疗中受益的患者的相关问题。在2009财年，我们从多个角度探讨了这个问题。作为我们确定可能从治疗性抗转化生长因子-β抗体治疗中受益的患者的举措的一部分，我们与NCI DCEG的Mark Sherman博士合作，利用代表800多例乳腺癌病例的组织微阵列，研究了转化生长因子-β途径成分与临床/病理特征之间的关系。这些数据为转化生长因子-β途径在乳腺癌发生中的多种复杂生物学效应提供了证据。一个引人注目的发现是，转化生长因子-β途径的激活随着年龄的增长而急剧减少，这一特征可能有助于老年和年轻患者组织学上相似的肿瘤的不同行为。我们正在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，以了解抗转化生长因子-β抗体治疗在各种转移性乳腺癌同基因小鼠移植模型中的转移抑制效果。我们已经建立了一组在体内对转化生长因子-β拮抗剂有不同反应的模型，我们希望从这些模型中识别抗转化生长因子-β抗体的治疗或不良反应/耐药性的分子决定因素。这些信息应该有助于临床试验的患者选择。我们已经证明，紫杉醇和抗转化生长因子-β治疗可以协同抑制转移，我们正在优化药物安排和排序，并特别关注抗肿瘤免疫反应来解决潜在的机制。

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