Development of TGF-beta antagonists for cancer therapy

尽管TGF-β在肿瘤发生中具有肿瘤抑制和肿瘤促进的双重作用，但我们实验室和其他实验室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这种生长因子的不良肿瘤促进作用，同时保留对肿瘤抑制和正常体内平衡的理想作用。基于这些有希望的临床前结果，几种不同的TGF-β途径拮抗剂正在进行治疗晚期癌症的早期临床试验。 然而，鉴于TGF-β的复杂生物学特性，成功开发用于癌症治疗的TGF-β拮抗剂将取决于对这些药物如何工作的清楚理解，以及如何选择将从这种治疗中受益的患者的相关问题。 我们在2012财年的主要重点是与一组转移性乳腺癌的可移植同基因小鼠模型合作，开发对抗TGF-β抗体治疗反应的预测性生物标志物，并探索与传统化疗药物的联合治疗。 转移负担是我们的主要终点。 使用这个面板，我们发现虽然TGF-β拮抗作用在一些模型中抑制转移，但在其他模型中对转移没有影响，甚至可以刺激转移。 我们已经排除了一些对TGF-β拮抗作用有反应的合理候选预测生物标志物，并且正在进行基于发现的方法的工作，包括测试我们在相关项目ZIA BC 005785中鉴定的TGF-β介导的肿瘤抑制的基因特征。 我们正在研究在某些模型中观察到的TGF-β拮抗作用的不良作用的机制。 我们还试图通过与免疫调节化学治疗剂的组合疗法来增强TGF-β抗体的治疗功效。

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, several different TGF-beta pathway antagonists are in early phase clinical trials for the treatment of advanced cancer. 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. Our major focus in FY12 has been to work with a panel of transplantable syngeneic mouse models of metastatic breast cancer to develop predictive biomarkers of response to anti-TGF-beta antibody therapy, and to explore combination therapy with conventional chemotherapeutics. Metastatic burden is our primary endpoint. Using this panel, we have found that while TGF-beta antagonism inhibits metastasis in some models, it has no effect on or can even stimulate metastasis in other models. We have excluded a number of plausible candidate predictive biomarkers of response to TGF-beta antagonism and work with discovery-based approaches is ongoing, including testing gene signatures of TGF-beta-mediated tumor suppression that we identified in the related project ZIA BC 005785. We are investigating the mechanisms that underlie the undesirable effects of TGF-beta antagonism that are seen in some models. We are also attempting to enhance therapeutic efficacy of TGF-beta antibodies by combination therapy with immunomodulatory chemotherapeutics.