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: 7965792
• 负责人: Lalage Wakefield
• 金额: $ 82.3万
• 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/7965792
• 关键词: Address; Advanced Malignant Neoplasm; Adverse effects; Age; Antibodies; Behavior; Biological Markers; Biology; Candidate Disease Gene; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Combined Modality Therapy; Complex; Cooperative Research and Development Agreement; Data; Development; Disease; Division of Cancer Epidemiology and Genetics; Employee Strikes; Epithelial; Gene Expression; Goals; Growth Factor; Histologic; Histology; Homeostasis; Human; Immune response; Immunologic Surveillance; Immunophenotyping; Malignant Neoplasms; Modeling; Molecular; Molecular Analysis; Mus; National Cancer Institute; Neoplasm Metastasis; Paclitaxel; Pathway interactions; Patient Selection; Patients; Pharmaceutical Preparations; Phase; Play; Pre-Clinical Model; Proteins; Resistance; Role; Schedule; Staging; Therapeutic; Tissue Microarray; Transforming Growth Factor beta; Transforming Growth Factor-Beta Overexpression; Transgenic Organisms; Transplantation; Tumor Promoters; Tumor Suppression; Tumor Suppressor Proteins; Work; Yang; angiogenesis; base; cancer therapy; carcinogenesis; cell motility; in vivo; insight; malignant breast neoplasm; neoplastic cell; novel strategies; outcome forecast; pre-clinical; programs; response; treatment strategy; tumor; tumor progression; tumorigenesis; Address; Advanced Malignant Neoplasm; Adverse effects; Age; Antibodies; Behavior; Biological Markers; Biology; Candidate Disease Gene; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Combined Modality Therapy; Complex; Cooperative Research and Development Agreement; Data; Development; Disease; Division of Cancer Epidemiology and Genetics; Employee Strikes; Epithelial; Gene Expression; Goals; Growth Factor; Histologic; Histology; Homeostasis; Human; Immune response; Immunologic Surveillance; Immunophenotyping; Malignant Neoplasms; Modeling; Molecular; Molecular Analysis; Mus; National Cancer Institute; Neoplasm Metastasis; Paclitaxel; Pathway interactions; Patient Selection; Patients; Pharmaceutical Preparations; Phase; Play; Pre-Clinical Model; Proteins; Resistance; Role; Schedule; Staging; Therapeutic; Tissue Microarray; Transforming Growth Factor beta; Transforming Growth Factor-Beta Overexpression; Transgenic Organisms; Transplantation; Tumor Promoters; Tumor Suppression; Tumor Suppressor Proteins; Work; Yang; angiogenesis; base; cancer therapy; carcinogenesis; cell motility; in vivo; insight; malignant breast neoplasm; neoplastic cell; novel strategies; outcome forecast; pre-clinical; programs; response; treatment strategy; tumor; tumor progression; tumorigenesis

Despite the dual role for TGF-beta as both tumor suppressor and tumor promoter in carcinogenesis, preclinical data from our lab and others has previously suggested that strategies to antagonize TGF-beta may selectively reduce the undesirable tumor promoting effects of this growth factor, while sparing the desirable effects on tumor suppression and normal homeostasis. Based on these promising preclinical results, an anti-TGF-beta antibody is in early phase clinical trials for the treatment of advanced cancer (NCI-06-C-0200). 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. In FY09, we have approached this question from a number of angles. As part of our initiative to identify patients who might benefit from treatment with therapeutic anti-TGF-beta antibodies, we have examined the relationship between TGF-beta pathway components and clinical/pathological features using tissue microarrays representing over 800 breast cancer cases, in collaboration with Dr. Mark Sherman, DCEG, NCI. The data provide evidence for multiple complex biologic effects of the TGF-beta pathway on breast cancer development. One striking finding is that TGF-beta pathway activation decreases dramatically with age, a feature that may contribute to the differing behavior of histologically similar tumors in old and young patients. We are continuing to apply global and candidate gene expression analysis, molecular histology, immunophenotyping and immunodepletion approaches to understanding the metastasis suppressing effect of anti-TGF-beta antibody treatment in a variety of syngeneic mouse transplantation models of metastatic breast cancer. We have established a panel of models showing differing responses to TGF-beta antagonism in vivo, from which we hope to identify molecular determinants of therapeutic vs adverse response/resistance to anti-TGF-beta antibodies. Such information should be helpful in patient selection for clinical trials. We have shown that treatment with paclitaxel and anti-TGF-beta can synergize to suppress metastasis, and we are optimizing drug scheduling and sequencing, as well as addressing underlying mechanisms with a particular focus on the anti-tumor immune response

尽管TGF-β在致癌作用中既是肿瘤抑制剂和肿瘤启动子均具有双重作用，但我们实验室和其他人的临床前数据以前表明，拮抗TGF-β的策略可以选择性地降低这种生长的不良肿瘤促进肿瘤的影响，同时促进对肿瘤抑制和正常官员的影响影响。基于这些有希望的临床前结果，抗TGF-β抗体是在治疗晚期癌症的早期临床试验中（NCI-06-C-0200）。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。在09财年，我们从多个角度解决了这个问题。作为我们旨在确定可能受益于治疗性抗TGF-beta抗体治疗的患者的一部分，我们研究了TGF-BETA途径成分与临床/病理特征之间使用代表800多个乳腺癌病例的组织微阵列的临床/病理特征之间的关系，与DCEG Mark Sherman，DCEG，NCI合作。数据为TGF-β途径对乳腺癌发育的多种复杂生物学作用提供了证据。一个惊人的发现是，随着年龄的增长，TGF-beta途径激活急剧降低，这一特征可能有助于老年和年轻患者的组织学相似肿瘤的不同行为。我们将继续应用全球和候选基因表达分析，分子组织学，免疫表型和免疫移动方法来理解抗TGF-beta抗体治疗的转移抑制作用在各种转移性乳腺癌移植模型中。我们已经建立了一组模型，显示了体内对TGF-β拮抗作用的不同反应，我们希望从中确定治疗性与对抗TGF-β抗体的不良反应/抗性的分子决定因素。此类信息应有助于患者选择临床试验。我们已经表明，用紫杉醇和抗TGF-β的治疗可以协同抑制转移，我们正在优化药物调度和测序，并解决具有抗肿瘤免疫反应的基本机制