Development of TGF-beta antagonists for cancer therapy

基于有希望的临床前结果，多种tgf - β途径拮抗剂正处于治疗晚期癌症的早期临床试验中。然而，鉴于tgf - β的复杂生物学特性，用于癌症治疗的tgf - β拮抗剂的成功开发将取决于对这些药物如何起作用的清晰理解，以及如何选择将从这种治疗中受益的患者的相关问题。利用12只转移性乳腺癌小鼠同种异体移植模型，以转移负担为主要终点，我们之前发现了对tgf - β拮抗剂的异质性反应。tgf - β通路阻断在某些模型中抑制转移，而在其他模型中没有作用。重要的是，在这个扩大的模型面板中，我们发现tgf - 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性生物标志物将对tgf - β拮抗剂的安全有效临床应用至关重要。我们假设tgf - β拮抗剂的不良刺激作用是由于tgf - β对癌症干细胞亚群的抑制作用受到干扰，我们正在继续验证这一假设。我们正在与临床医生合作，分析接受tgf - β拮抗剂治疗的癌症患者的临床资料，将这些机制分析扩展到更相关的临床环境。目前，tgf - β领域的一个主要障碍是缺乏关于tgf - β在正常体内平衡和肿瘤发生中何时何地信号的信息。为了解决这个问题，我们已经生成并严格验证了转基因tgf - β通路报告小鼠，其中具有活性tgf - β信号的细胞通过荧光蛋白的表达而亮起绿色。这些细胞可以通过免疫荧光原位鉴定，并通过FACS分选回收用于分子分析。在与转移性乳腺癌小鼠模型的交叉实验中，我们观察到在发展中的肿瘤中tgf - β通路激活的异质性模式。我们现在正在应用空间转录组学和高维成像技术来识别不断发展的肿瘤生态系统中tgf - β应答细胞的性质和活动。我们预计，这一信息将导致更安全、更有效地部署tgf - β拮抗剂来治疗癌症。

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 previously 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, and we are continuing to test this hypothesis. We are collaborating with clinicians to analyze clinical material from cancer patients treated with TGF-beta antagonists, to extend these mechanistic analyses to the more relevant clinical setting. Currently, one 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 normal homeostasis and tumorigenesis. To address this issue, we have generated and rigorously validated a transgenic TGF-beta pathway reporter mouse, in which cells with active TGF-beta signaling light up green through expression of a fluorescent protein. These cells can be identified in situ by immunofluorescence and recovered by FACS sorting for molecular analyses. In intercrosses with mouse models of metastatic breast cancer, we observe heterogeneous patterns of TGF-beta pathway activation within the developing tumors. We are now applying spatial transcriptomic and high dimensional imaging technologies to identify the nature and activities of TGF-beta responder cells in the evolving tumor ecosystem. We anticipate that this information will lead to safer and more effective deployment of TGF-beta antagonists to treat cancer.