Oral Cancer, Chemoprevention, and Anti-Angiogenesis

描述（由申请方提供）：头颈部鳞状细胞癌（HNSCC）是一种侵袭性肿瘤，是世界上第六大常见恶性肿瘤。尽管在治疗方面取得了许多进展，但在过去的50年里，五年生存率保持不变。这种不良结果是由于许多变量，包括延迟诊断以及多原发肿瘤的发展。因此，至关重要的是，除了早期发现之外，还必须采取有效的战略来预防这一毁灭性疾病。血管生成表型的表达是HNSCC发展的非常早期和绝对必要的步骤，使其成为癌症预防的有吸引力的靶点。然而，一些关键的生物学问题仍然存在关于进展过程中血管生成表型的时间，机制和动力学。此外，尚未对针对预防HNSCC的抗血管生成疗法的效用进行详细和系统的评价。该提案的长期目标是开发基于抑制血管生成的HNSCC的新型无毒化学预防策略。这项工作的假设是，血管生成抑制剂可以有效地预防HNSCC。 具体目标是：（1）。表征HNSCC中“血管生成开关”的发展，2）研究HNSCC发展过程中血管生成表型的机制和动力学，和3）确定抗血管生成剂ZD 6474或ABT-510作为HNSCC临床前动物模型中的化学预防疗法是否有效。 使用临床前动物模型以及人类组织/细胞，拟议的工作将确定HNSCC中血管生成表型转换的时间。它还将研究这种转换的机制和动力学。最后，它将确定血管生成抑制剂是否是预防HNSCC的有效治疗方式，这将对大量患者具有显着的临床益处，这些患者具有在整个上呼吸消化道发展多个病变的巨大风险。

DESCRIPTION (provided by applicant): Head and neck squamous cell carcinoma (HNSCC) is an aggressive neoplasm that is the sixth most common malignancy in the world. Despite numerous advances in treatment, the five-year survival has remained unchanged for the last 50 years. This poor outcome is due to a number of variables including delayed diagnosis as well as the development of multiple primary tumors. Therefore, it is essential to supplement early detection with effective strategies for the prevention of this devastating disease. The expression of the angiogenic phenotype is both a very early and an absolutely essential step in the development of HNSCC, making it an attractive target for cancer prevention. However, a number of critical biologic questions remain regarding the timing, mechanisms and dynamics of the angiogenic phenotype during progression. In addition, a detailed and systematic evaluation of the utility of anti-angiogenic therapies targeting the prevention of HNSCC has not been performed. The long-term goal of this proposal is to develop novel, nontoxic chemopreventive strategies for HNSCC that are based upon the inhibition of angiogenesis. The hypothesis of this work is that inhibitors of angiogenesis can effectively prevent HNSCC. The specific aims are: 1.) to characterize the development of the "angiogenic switch" in HNSCC, 2) to investigate the mechanisms and dynamics of the angiogenic phenotype during the development of HNSCC, and 3) to determine if anti-angiogenic agents ZD6474 or ABT-510 are effective as chemopreventive therapies in a pre-clinical animal model of HNSCC. Using preclinical animal models as well as human tissue/cells, the proposed work will determine the timing of the switch of the angiogenic phenotype in HNSCC. It will also investigate the mechanisms and dynamics of this switch. Finally, it will determine if inhibitors of angiogenesis are an effective treatment modality for the prevention of HNSCC, which would be of dramatic clinical benefit to large numbers of patients who are at tremendous risk for developing multiple lesions throughout their upper aerodigestive tract.