Metronomic Small Molecule Inhibitor of Bcl2 in Head and Neck Cancer Therapy

Bcl2 节律小分子抑制剂在头颈癌治疗中的应用

基本信息

批准号：
8729053
负责人：
Jacques Eduardo Nor
金额：
$ 56.01万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-18 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8729053
关键词：
Ablation Affect Angiogenesis Inhibitors Antibodies Apoptosis Apoptotic Applications Grants Avastin BCL2 gene Bioluminescence Blood Vessels CXCL1 gene Cancer Biology Cancer cell line Cell Line Cell Survival Cessation of life Cisplatin Clinical Data Databases Dermal Development Dose Effectiveness Endothelial Cells Evaluation Fibroblasts Frequencies Goals Growth Head and Neck Cancer Head and Neck Neoplasms Head and Neck Squamous Cell Carcinoma Human IL8 gene IL8RB gene In Vitro Induction of Apoptosis Ionizing radiation Knowledge Maintenance Malignant Neoplasms Mediating Modeling Molecular Molecular Target Mus NF-kappa B Neoplasm Metastasis Neoplasms in Vascular Tissue Oral mucous membrane structure Outcome PTK787 Pathway interactions Patients Pharmaceutical Preparations Phase I Clinical Trials Physiological Prevention Process Proliferating Proteins Radiation Radiation therapy Recruitment Activity Regimen Research Research Personnel Resistance Resistance development SCID Mice Safety Schedule Scheme Signal Pathway Signal Transduction Signaling Molecule Solid Structure Survival Rate Therapeutic Therapeutic Effect Time Toxic effect Treatment Protocols Tumor Angiogenesis Tumor Biology Tumor-Derived Up-Regulation Vascular Endothelial Growth Factors Withdrawal Work angiogenesis autocrine base cancer cell cancer therapy chemokine chemotherapeutic agent chemotherapy density drug development effective therapy in vivo inhibitor/antagonist mouse model neoplastic cell neovascular novel outcome forecast receptor research study small molecule therapy resistant tumor tumor growth tumor progression tumor xenograft

项目摘要

Head & neck tumors are highly vascularized malignancies with poor survival rates with current-therapiesr It-is known that vascular endothelial growth factor (VEGF) is a strong inducer of tumor angiogenesis, and that VEGF enhances endothelial cell survival and resistance to treatment by upregulating the expression of Bcl-2. We have recently demonstrated that Bcl-2 functions as a pro-angiogenic signaling molecule, in addition to its well-known anti-apoptotic effect (Karl et a/., 2005). Inhibition of VEGF signaling with an antibody (e.g. Avastin), or with an inhibitor of one its receptors (e.g. PTK787) results in selective ablation of tumor blood vessels and inhibition of tumor growth. These results demonstrate that the VEGF/Bcl-2 pathway is critical for the maintenance of tumor vasculature. Structure based 30-database searching led to the development of novel small molecule inhibitors of Bcl-2 (TW-37 and TM-1252). We have demonstrated that TW-37 induces apoptosis of head & neck tumor cells and neovascular endothelial cells (but not dermal fibroblasts) in vitro, and that TW-37 is anti-angiogenic in vivo (Zeitlin et a/., 2006). This work demonstrated that a small molecule inhibitor of Bcl-2 represents a novel class of drugs that induces tumor cell apoptosis and is anti-angiogenic, two distinct and perhaps synergistic anti-tumor effects. However, we do not know the effect of a small molecule inhibitor of Bcl-2 on the resistance of head & neck tumors to radiation therapy and to conventional chemotherapy, and what is the better treatment sequence and timing. The broad long-term goals of this translational project are to understand the effect of therapeutic inhibition of Bcl-2 on the clinical outcome of patients with head & neck cancer. The objectives of this application are to evaluate the effect of a small molecule inhibitor used in a metronomic regimen (low dose, high frequency) in combination with radiation therapy and Cisplatin on angiogenesis in vitro and in vivo, and on the growth of head & neck tumors in vivo. We plan to accomplish these objectives by studying mechanisms involved in the process of small molecule inhibitor of Bcl-2-mediated endothelial cell and tumor cell apoptosis, when used in combination with ionizing radiation and chemotherapy. The SCID Mouse Model of Human Angiogenesis and in vivo bioluminescence will be used to evaluate the effect of timing and sequence of treatment on angiogenesis and tumor growth. And a Phase I clinical trial wilj be conducted in patients that were previously treated with radiation therapy and standard chemotherapy to begin evaluation of the safety and efficacy of a small molecule inhibitor of Bcl-2 for treatment of head & neck cancer. The knowledge generated here will enhance pur understanding about the function of Bcl-2 in head & neck tumor angiogenesis and growth, and will demonstrate if therapeutic blockade of Bcl-2 function affects resistance to ionizing radiation and chemotherapy.

头颈肿瘤是高度血管化的恶性肿瘤，目前的治疗方法生存率很低众所周知，血管内皮生长因子（VEGF）是肿瘤血管生成的强诱导剂，并且 VEGF 通过上调 Bcl-2 的表达来增强内皮细胞的存活和对治疗的抵抗力。我们最近证明，Bcl-2 除了具有促血管生成信号分子的功能外，还具有促血管生成信号分子的功能。众所周知的抗凋亡作用（Karl 等，2005）。用抗体抑制 VEGF 信号传导（例如阿瓦斯丁 (Avastin) 或其受体抑制剂（例如 PTK787）可选择性消融肿瘤血液血管和抑制肿瘤生长。这些结果表明 VEGF/Bcl-2 通路对于肿瘤血管系统的维持。基于结构的 30 个数据库搜索导致了新型 Bcl-2 小分子抑制剂（TW-37 和 TM-1252）。我们已经证明 TW-37 会诱导头颈肿瘤细胞和新生血管内皮细胞（但不是真皮成纤维细胞）的体外凋亡，并且TW-37在体内具有抗血管生成作用（Zeitlin等人，2006）。这项工作证明了小分子 Bcl-2 抑制剂代表了一类新型药物，可诱导肿瘤细胞凋亡并具有抗血管生成作用，两种不同且可能协同的抗肿瘤作用。然而，我们不知道小量的影响 Bcl-2分子抑制剂对头颈肿瘤放射治疗和常规治疗耐药性的影响化疗，以及更好的治疗顺序和时机。这一广泛的长期目标转化项目旨在了解 Bcl-2 治疗性抑制对临床结果的影响头颈癌患者。该应用程序的目的是评估小规模的影响节拍疗法（低剂量、高频率）中与放射结合使用的分子抑制剂疗法和顺铂对体外和体内血管生成以及体内头颈肿瘤生长的影响。我们计划通过研究小分子过程中涉及的机制来实现这些目标与电离结合使用时，可抑制 Bcl-2 介导的内皮细胞和肿瘤细胞凋亡放射和化疗。人类血管生成和体内生物发光的 SCID 小鼠模型将用于评估治疗时机和顺序对血管生成和肿瘤生长的影响。并且将在之前接受过放射治疗的患者中进行一期临床试验和标准化疗开始评估小分子抑制剂的安全性和有效性 Bcl-2 用于治疗头颈癌。这里产生的知识将增强您的理解关于 Bcl-2 在头颈肿瘤血管生成和生长中的功能，并将证明如果 Bcl-2 功能的治疗性阻断会影响对电离辐射和化疗的抵抗力。