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，目前的治疗方法生存率很低。 已知血管内皮生长因子（VEGF）是肿瘤血管生成的强诱导剂， VEGF通过上调Bcl-2的表达增强内皮细胞的存活和对治疗的抗性。 我们最近证实，Bcl-2作为促血管生成的信号分子，除了它的功能外， 众所周知的抗凋亡作用（Karl等人，2005年）。用抗体（例如， Avastin）或其一种受体的抑制剂（例如PTK 787）导致肿瘤血液的选择性消融 血管和抑制肿瘤生长。这些结果表明，VEGF/Bcl-2通路对于 维持肿瘤血管系统。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诱导 体外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）的凋亡， 并且TW-37在体内是抗血管生成的（Zeitlin等人，2006年）。这项工作表明，一个小分子 Bcl-2抑制剂代表一类新的药物，其诱导肿瘤细胞凋亡并且是抗血管生成的， 两种不同的，也许是协同的抗肿瘤作用。但是，我们不知道一个小的影响 Bcl-2分子抑制剂对头颈部肿瘤放疗和常规化疗耐药性的影响 化疗，什么是更好的治疗顺序和时机。这一广泛的长期目标 转化项目是为了了解治疗性抑制Bcl-2对临床结果的影响 头颈癌患者。本申请的目的是评估一个小的影响， 分子抑制剂，用于节拍疗法（低剂量，高频率）与放射联合治疗 在体外和体内，顺铂治疗对血管生成的影响，以及在体内对头颈部肿瘤生长的影响。 我们计划通过研究参与小分子过程的机制来实现这些目标。 Bcl-2介导内皮细胞和肿瘤细胞凋亡的抑制剂，当与电离 放疗和化疗人血管生成的SCID小鼠模型及体内生物发光 将用于评价治疗时机和顺序对血管生成和肿瘤生长的影响。 第一阶段的临床试验将在以前接受过放射治疗的患者中进行 和标准化疗，以开始评估小分子抑制剂的安全性和有效性， Bcl-2在头颈癌治疗中的应用这里产生的知识将增强pur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， Bcl-2功能的治疗性阻断影响对电离辐射和化学疗法的抗性。

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.