Development of TGF-beta antagonists for cancer therapy

开发用于癌症治疗的 TGF-β 拮抗剂

• 批准号: 10702429
• 负责人: Lalage Wakefield
• 金额: $ 70.62万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702429
• 关键词: Address; Adult; Advanced Malignant Neoplasm; Allografting; Biology; Cells; Clinical; Clinical Treatment; Companions; Complex; Confocal Microscopy; Coupled; Development; Ecosystem; Embryonic Development; Epithelial; Genetic; Goals; Homeostasis; Human; Immunohistochemistry; Immunologic Surveillance; Knowledge; Light; Maintenance; Malignant Neoplasms; Metastatic breast cancer; Modeling; Mus; Neoplasm Metastasis; Organism; Pathway interactions; Patients; Pattern; Pharmacology; Play; Prognosis; Proteins; Reporter; Role; Signal Transduction; Techniques; Testing; Therapeutic; Tissues; Toxic effect; Transforming Growth Factor beta; Transforming Growth Factor-Beta Overexpression; Transgenic Organisms; Tumor Suppressor Proteins; Work; angiogenesis; antagonist; base; cancer stem cell; cancer therapy; cell motility; clinical development; early phase clinical trial; fluorescence imaging; genetic regulatory protein; improved; in vivo; insight; mature animal; mouse model; neoplastic cell; novel strategies; pre-clinical; predictive marker; primary endpoint; response; small molecule inhibitor; therapeutic target; tool; treatment optimization; treatment response; treatment strategy; tumor; tumor microenvironment; tumor progression; tumorigenesis

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.

基于有希望的临床前结果，各种TGF-β途径拮抗剂正在早期临床试验中治疗晚期癌症。但是，鉴于TGF-β的复杂生物学，TGF-beta拮抗剂用于癌症治疗的成功发展将取决于对这些药物的工作原理的清晰了解，以及如何选择将从这种类型治疗中受益的患者的相关问题。我们使用一对转移性乳腺癌的12小鼠同种异体移植模型，并具有转移性负担为主要终点，我们发现了对TGF-β拮抗作用的异质反应。在某些模型中，TGF-beta途径阻断抑制了转移，同时对其他模型没有影响。 重要的是，在这个扩展的模型小组中，我们发现TGF-β拮抗作用实际上刺激了25％的模型中的转移，这表明改善的机械理解和良好的预测生物标志物对于在临床上安全有效地部署TGF-beta拮抗剂至关重要。我们假设TGF-β拮抗作用的不良刺激作用是由于干扰了TGF-β对癌症干细胞亚群的抑制作用。我们正在使用我们的伴侣项目Zia BC 005785以及其他正交技术中开发的癌症干细胞报告基因进行检验。当前，TGF-β领域的主要障碍是相对缺乏有关成人生物体中TGF-β信号在稳态中的何时何地的信息，以及肿瘤生态系统中肿瘤生态系统中反应细胞在肿瘤进展过程中的变化如何变化。为了解决这个问题，我们已经生成并严格验证了转基因TGF-beta途径记者小鼠，其中具有活性TGF-beta信号的组织通过表达荧光蛋白的表达来呈绿色。令人惊讶的是，当小鼠用TGF-β信号传导的小分子抑制剂治疗时，TGF-β途径在表现出肿瘤毒性的组织中高度活跃。通过荧光成像（Epifluorescent和共聚焦显微镜）与GFP的免疫组织化学相结合，这种有价值的新工具使生物体可以对TGF-beta信号的细胞水平评估。这只小鼠对成年动物中TGF-β途径激活的模式以及在肿瘤进展过程中如何改变了TGF-β途径的模式。