Development of TGF-beta antagonists for cancer therapy

基于有希望的临床前结果，各种转化生长因子-β途径拮抗剂正处于治疗晚期癌症的早期临床试验阶段。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。使用12个转移性乳腺癌小鼠同基因同种异体移植模型，以转移负荷为主要终点，我们揭示了对转化生长因子-β拮抗的异质性反应。在某些模型中，阻断转化生长因子-β途径可抑制肿瘤转移，而对其他模型则无影响。重要的是，在这个扩展的模型小组中，我们发现转化生长因子-β拮抗剂实际上在25%的模型中刺激了转移，这表明改进的机制理解和良好的预测生物标志物将是安全和有效地在临床上应用转化生长因子-β拮抗剂的关键。我们假设转化生长因子-β拮抗剂的不良刺激作用是由于干扰了转化生长因子-β对肿瘤干细胞亚群的抑制作用。我们正在使用我们的伙伴项目Zia BC 005785中开发的癌症干细胞报告以及其他正交技术来验证这一假设。目前，转化生长因子-β领域的一个主要障碍是相对缺乏关于转化生长因子-β信号在成年生物体中何时何地处于内稳态，以及肿瘤生态系统中反应细胞的光谱在肿瘤进展过程中如何变化的信息。为了解决这个问题，我们已经产生并严格验证了一个转基因的转化生长因子-β途径报告鼠，在其中，具有活跃的转化生长因子-β信号的组织通过表达荧光蛋白而发出绿色光。值得注意的是，当小鼠接受转化生长因子-β信号的小分子抑制剂治疗时，转化生长因子-β途径在显示肿瘤外毒性的组织中高度活跃。通过荧光成像(荧光和共聚焦显微镜)结合GFP的免疫组织化学，这一有价值的新工具使有机体能够在细胞水平上评估转化生长因子-β信号。这只小鼠对成年动物体内转化生长因子-β途径的激活模式以及在肿瘤进展过程中这些模式是如何改变的提供了重要的见解。

Based on promising preclinical results, a variety of 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. Using a panel of 12 mouse syngeneic allograft models of metastatic breast cancer, with metastatic burden as the primary endpoint, we uncovered heterogeneous responses to TGF-beta antagonism. TGF-beta pathway blockade inhibited metastasis in some models, while having no effect on others. Importantly, in this expanded model panel, we found that TGF-beta antagonism actually stimulated metastasis in 25% of the models, suggesting that improved mechanistic understanding and good predictive biomarkers will be crucial for safe and effective deployment of TGF-beta antagonists clinically. We hypothesized that the undesirable stimulatory effect of TGF-beta antagonism is due to interference with inhibitory effects of TGF-beta on the cancer stem cell subpopulation. We are testing this hypothesis, using the cancer stem cell reporter developed in our companion project ZIA BC 005785, as well as other orthogonal techniques. Currently, a major barrier in the TGF-beta field is the relative lack of information about when and where TGF-beta signals in the adult organism in homeostasis, and how the spectrum of responding cells in the tumor ecosystem changes during tumor progression. To address this issue, we have generated and rigorously validated a transgenic TGF-beta pathway reporter mouse, in which tissues with active TGF-beta signaling light up green through expression of a fluorescent protein. Strikingly the TGF-beta pathway is highly active in tissues that show off-tumor toxicities when mice are treated with small molecule inhibitors of TGF-beta signaling. Through fluorescence imaging (epifluorescent and confocal microscopy) coupled with immunohistochemistry for GFP, this valuable new tool allows an organism to cellular level assessment of TGF-beta signaling. This mouse is giving important insights into patterns of TGF-beta pathway activation in the adult animal and how these are altered during tumor progression.