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，几种不同的转化生长因子-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，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。我们在2012财年的主要重点是与一组可移植的转移性乳腺癌同基因小鼠模型合作，开发对抗转化生长因子-β抗体治疗反应的预测生物标志物，并探索与传统化疗药物的联合治疗。转移性负担是我们的主要终点。利用这个小组，我们发现，尽管转化生长因子-β拮抗剂在某些模型中抑制转移，但在其他模型中，它对转移没有影响，甚至可以刺激转移。我们已经排除了一些对转化生长因子-β拮抗反应有可能的候选预测生物标记物，基于发现的方法的工作正在进行中，包括测试我们在相关项目Zia BC 005785中确定的转化生长因子-β介导的肿瘤抑制的基因签名。我们正在研究在一些模型中看到的转化生长因子-β拮抗的不良影响的机制。我们还试图通过与免疫调节化疗药物的联合治疗来提高转化生长因子-β抗体的疗效。

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.