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

头颈部肿瘤是高度血管化的恶性肿瘤，目前的治疗方法存活率很低。 已知血管内皮生长因子(VEGF)是肿瘤血管生成的强大诱导剂， 血管内皮细胞生长因子通过上调Bcl-2的表达来增强内皮细胞的存活率和耐受性。 我们最近已经证明，除了其自身的功能外，Bcl2还发挥着促血管生成信号分子的作用。 众所周知的抗细胞凋亡作用(Karl et a/.，2005)。用抗体(例如， 阿瓦斯丁)或其受体之一的抑制剂(例如PTK787)导致选择性消融肿瘤血液 血管和抑制肿瘤生长。这些结果表明，血管内皮生长因子/Bcl-2信号转导通路在细胞周期调控中起关键作用 肿瘤血管的维持。基于结构的30个数据库的搜索导致了 新型Bcl-2小分子抑制剂(TW-37和TM-1252)我们已经证明了TW-37诱导 头颈部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 而TW-37在体内是抗血管生成的(Zeitlin等人，2006年)。这项工作证明了一个小分子 Bcl2抑制剂代表了一类诱导肿瘤细胞凋亡和抗血管生成的新型药物， 两种截然不同的、或许是协同作用的抗肿瘤作用。但是，我们不知道一个小的 Bcl2分子抑制物对头颈部肿瘤放射治疗和常规化疗耐药的影响 化疗，以及什么是更好的治疗顺序和时机。它的广泛的长期目标是 翻译计划是了解治疗抑制Bcl-2对急性髓细胞白血病临床结局的影响。 头颈癌患者。这个应用程序的目的是评估一个小的 分子抑制剂在节律疗法(低剂量、高频)中与放射的结合使用 治疗和顺铂对体内外血管生成和头颈部肿瘤生长的影响。 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 Bcl2介导的内皮细胞和肿瘤细胞凋亡的抑制剂与电离联合使用 放疗和化疗。人血管生成的SCID小鼠模型及体内生物发光 将用于评估治疗的时机和顺序对血管生成和肿瘤生长的影响。 一期临床试验将在以前接受过放射治疗的患者身上进行。 和标准化疗开始评估一种小分子抑制物的安全性和有效性 BCL-2用于治疗头颈癌。在这里产生的知识将加强您的理解 关于Bcl-2在头颈部肿瘤血管生成和生长中的作用，并将证明是否 治疗性阻断Bc l-2功能会影响对电离辐射和化疗的抵抗。

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.