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：
9343735
负责人：
Lalage Wakefield
金额：
$ 85.82万
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/9343735
关键词：
Address Adult Advanced Malignant Neoplasm Adverse effects Allografting Antibodies Biological Biology Cells Cessation of life Clinical Clinical Data Clinical Treatment Clinical Trials Complex Data Development Ecosystem Embryonic Development Epithelial Gene Expression Profile Generations Genomic approach Goals Heterogeneity Homeostasis Human Immune response Immunologic Surveillance Knowledge Ligands Literature Maintenance Malignant Neoplasms Mammary gland Metabolic Metastatic breast cancer Methods Modeling Molecular Mus Neoplasm Metastasis Organ Outcome Output Pathway interactions Patients Pharmaceutical Preparations Phase Play Pre-Clinical Model Primary Neoplasm Protein Isoforms Role Signal Transduction Staging TGFB1 gene Testing Therapeutic Uses Transforming Growth Factor beta Transforming Growth Factor-Beta Overexpression Transgenic Organisms Treatment Efficacy Tumor Suppression Tumor Suppressor Proteins Work angiogenesis base cancer therapy cell motility genetic regulatory protein improved in vivo knock-down mouse model neoplastic cell novel strategies outcome forecast overexpression pre-clinical predicting response predictive marker response therapeutic target transcriptomics transforming growth factor beta3 treatment response treatment strategy tumor tumor microenvironment tumor progression tumorigenesis

项目摘要

Based on promising preclinical results, several different 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 or stimulating metastasis in other models. We are continuing to apply targeted and discovery-based approaches to address molecular and biological mechanisms underlying the heterogeneity of therapeutic response and to generate useful predictive biomarkers. Unexpectedly, neither TGF-beta expression levels nor extent of TGF-beta pathway activation in the primary tumor predict response to anti-TGF-beta therapy. However, tumors from models showing a desirable response to TGF-beta antagonism are characterized by transcriptomic evidence of TGF-beta pathway activation in the untreated state. Thus in vivo, the output of TGF-beta signaling may be a more sensitive indicator of the activation status of the TGF-beta pathway than any of the input parameters such as ligand levels and status of signal transduction components. We are generating gene expression signatures that might predict response to anti-TGF-beta therapy and will test these in additional preclinical models. We have also identified candidate molecular determinants of the therapeutic response to TGF-beta and are testing these by knockdown and overexpression approaches in the tumor models. We are also continuing to address ways of improving the therapeutic efficacy of TGF-beta antagonism. Correlative clinical data and literature evidence suggest that whereas TGF-beta1 is primarily associated with poor outcome in many cancers, TGF-beta3 may actually oppose TGF-beta1 and be associated with good outcome. We have optimized a method for accurate quantitation of TGF-beta protein isoform expression and have shown that the mammary gland is one of the few adult organs to express significant levels of TGF-beta3. We find TGF-beta1 to be consistently upregulated and TGF-beta3 to be downregulated when compared with the normal mammary gland. Our preliminary data with TGF-beta isoform-selective antibodies suggests that there is no advantage to sparing TGF-beta3 in terms of therapeutic efficacy, but that there may be positive metabolic consequences of this approach. Our integrated genomic approaches are also suggesting drugs that could be combined with TGF-beta antagonists to improve therapeutic efficacy, and we are actively pursuing the top leads in our preclinical models.

基于有希望的临床前结果，在早期临床试验中，用于治疗晚期癌症。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或刺激转移。我们正在继续采用靶向和基于发现的方法来解决治疗反应异质性和产生有用的预测生物标志物的异质性的分子和生物学机制。出乎意料的是，在原发性肿瘤中，TGF-β表达水平和TGF-β途径激活的程度都没有预测对抗TGF-β疗法的反应。然而，来自表现出对TGF-β拮抗作用的理想反应的模型的肿瘤的特征在于未处理状态下TGF-β途径激活的转录组。因此，在体内，TGF-beta信号传导的输出可能比任何输入参数（例如配体级别和信号转导组件的状态）更敏感地指标。我们正在生成基因表达特征，可以预测对抗TGF-β疗法的反应，并将在其他临床前模型中测试这些疗法。我们还确定了对TGF-β的治疗反应的候选分子决定因素，并通过肿瘤模型中的敲低和过表达方法来测试这些反应。我们还在继续解决提高TGF-beta拮抗作用的治疗功效的方法。相关临床数据和文献证据表明，尽管TGF-BETA1在许多癌症中主要与不良结果有关，但TGF-BETA3实际上可能反对TGF-BETA1，并且与良好的结果有关。我们优化了一种准确定量TGF-β蛋白同工型表达的方法，并表明乳腺是表达大量TGF-BETA3的少数成年器官之一。我们发现与正常乳腺相比，TGF-BETA1始终上调，TGF-BETA3被下调。我们使用TGF-β同工型选择性抗体的初步数据表明，在治疗效率方面，保留TGF-BETA3没有优势，但是这种方法可能会产生积极的代谢后果。我们的综合基因组方法还提出了可以与TGF-β拮抗剂相结合的药物，以提高治疗功效，我们正在积极地追求临床前模型中的最高领导者。