Development of TGF-beta antagonists for cancer therapy

基于有希望的临床前结果，多种TGF-β通路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，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。使用一组12只小鼠转移性乳腺癌同基因同种异体移植模型，以转移负荷为主要终点，我们发现了对TGF-β拮抗作用的异质性反应。TGF-β通路阻断在一些模型中抑制转移，而对其他模型没有影响。重要的是，在这个扩展的模型组中，我们发现TGF-β拮抗作用实际上在25%的模型中刺激了转移，这表明良好的预测生物标志物对于TGF-β拮抗剂在临床上的安全有效部署至关重要。我们已经证明，许多逻辑或文献建议的候选生物标志物（例如，TGF-β表达水平，p53突变状态）不能可靠地预测该较大组中的治疗结果。对未经治疗的原发性肿瘤的转录组的分析允许鉴定对TGF-β拮抗作用的抑制性与刺激性应答特异性的基因特征。将这些特征应用于人类乳腺癌转录组数据集表明，患有雌激素受体阴性疾病的患者，特别是基础亚型和低密蛋白亚型的患者，可能最有可能对TGF-β拮抗剂产生所需的治疗反应。在小鼠模型组中对TGF-β的体外反应的分析使我们假设TGF-β拮抗作用的不良刺激作用是由于干扰TGF-β对癌症干细胞亚群的抑制作用。我们正在努力测试这是否是真的在体内，使用我们的同伴项目ZIA BC 005785中开发的癌症干细胞报告，以及其他正交技术。最后，在一个新的倡议，以更好地识别和描绘TGF-β的行动在正常和荷瘤小鼠体内的细胞靶点，我们已经产生了一个转基因TGF-β报告小鼠，其中一个新的Smad反应元件的激活驱动荧光蛋白的表达。这只小鼠对成年动物中TGF-β途径激活的模式以及这些如何受到该途径的药理学抑制的影响提供了重要的见解。

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 good predictive biomarkers will be crucial for safe and effective deployment of TGF-beta antagonists clinically. We have demonstrated that many of the logical or literature-suggested candidate biomarkers (eg. TGF-beta expression levels, p53 mutation status) do not reliably predict therapeutic outcome in this larger panel. Analysis of the transcriptomes of treatment-naive primary tumors allowed identification of gene signatures that were specific to the inhibitory vs the stimulatory response to TGF-beta antagonism. Applying these signatures to human breast cancer transcriptomic datasets suggested that patients with estrogen receptor-negative disease, particularly of the basal and claudin-low subtypes, might be most likely to have the desired therapeutic response to TGF-beta antagonists. Analysis of in vitro responses to TGF-beta across the mouse model panel led us to hypothesize 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 working to test whether this is true in vivo, using the cancer stem cell reporter developed in our companion project ZIA BC 005785, as well as other orthogonal techniques. Finally, in a new initiative to better identify and delineate the cellular targets of TGF-beta action in vivo in normal and tumor-bearing mice, we have generated a transgenic TGF-beta reporter mouse, in which activation of a novel Smad response element drives expression of a fluorescent protein. This mouse is giving important insights into patterns of TGF-beta pathway activation in the adult animal and how these are affected by pharmacologic inhibition of the pathway.