Development of TGF-beta antagonists for cancer therapy

开发用于癌症治疗的 TGF-β 拮抗剂

基本信息

批准号：
10014476
负责人：
Lalage Wakefield
金额：
$ 58.78万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
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/10014476
关键词：
Adult Advanced Malignant Neoplasm Affect Allografting Antibodies Biology Cessation of life Clinical Clinical Treatment Clinical Trials Companions Complex Data Set Development Disease Ecosystem Embryonic Development Epithelial Estrogen receptor negative Generations Goals Homeostasis Human Immunologic Surveillance In Vitro Knowledge Literature Maintenance Malignant Neoplasms Metastatic breast cancer Modeling Mus Neoplasm Metastasis Pathway interactions Patients Pattern Pharmacology Phase Play Primary Neoplasm Proteins Reporter Response Elements Role TP53 gene Techniques Testing Therapeutic Uses Transforming Growth Factor beta Transforming Growth Factor-Beta Overexpression Transgenic Organisms Transplantation Tumor Suppression Tumor Suppressor Proteins Work Yang angiogenesis anti-tumor immune response base cancer stem cell cancer therapy candidate marker cell motility cellular targeting clinical development genetic regulatory protein genetic signature in vivo insight malignant breast neoplasm mature animal mouse model mutational status neoplastic cell novel novel strategies outcome forecast pre-clinical predictive marker primary endpoint response side effect therapeutic target therapy outcome transcriptome transcriptomics treatment optimization treatment response treatment strategy tumor tumor microenvironment tumor progression tumorigenesis

项目摘要

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.

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发挥作用的清晰了解，以及如何选择将从此类药物中受益的患者的相关问题。治疗。使用一组 12 个转移性乳腺癌小鼠同基因同种异体移植模型，以转移负担为主要终点，我们发现了对 TGF-β 拮抗作用的异质反应。 TGF-β途径阻断可抑制某些模型中的转移，而对另一些模型则没有影响。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临床上安全有效地部署 TGF-β 拮抗剂至关重要。我们已经证明，在这个更大的组中，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）不能可靠地预测治疗结果。对未经治疗的原发性肿瘤的转录组进行分析，可以识别对 TGF-β 拮抗作用的抑制反应和刺激反应特异的基因特征。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，特别是基础亚型和密蛋白低亚型的患者，可能最有可能对 TGF-β 拮抗剂产生所需的治疗反应。通过对小鼠模型组对 TGF-β 的体外反应进行分析，我们推测 TGF-β 拮抗剂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。我们正在努力使用我们的配套项目 ZIA BC 005785 中开发的癌症干细胞报告基因以及其他正交技术来测试这在体内是否属实。最后，为了更好地识别和描绘正常小鼠和荷瘤小鼠体内 TGF-β 作用的细胞靶标，我们培育了一种转基因 TGF-β 报告小鼠，其中新型 Smad 反应元件的激活驱动荧光蛋白的表达。该小鼠为成年动物 TGF-β 通路激活模式以及该通路的药理抑制如何影响这些模式提供了重要的见解。