Developing Schweinfurthin Analogs as Glioma Therapies

描述（由申请人提供）：根据美国癌症协会估计，2008年美国将报告21,810例原发性恶性脑肿瘤。美国癌症学会还预计，今年将有13070人死于这些疾病。该II期STTR项目倡导从天然产物家族中开发用于原发性中枢神经系统癌症的药物。schweinfurthins是由美国国家癌症研究所分离的天然产物家族，具有独特的抗癌活性模式，表明一种潜在的未开发的新型作用机制。本项目将开展这类药物的进一步开发，具体目标有三个：1)我们将合成288种新的双二苯乙烯类似物，旨在为这类化合物提供更多的结构功能数据，提高活性和物理性质；2)我们将根据I期可行性研究开发的分析方案对这些化合物进行测试，这将导致在胶质母细胞瘤动物模型中对化合物进行测试；3)我们将对schweinfurthins的作用机制进行进一步的假设驱动探索。胶质母细胞瘤和其他侵袭性中枢神经系统癌症患者目前的临床结果使得开发针对这些适应症的新药非常必要。本文提出的三个具体目标旨在使我们能够选择一个候选药物进行IND研究，并进一步了解这一新型化合物家族的作用机制。公共卫生相关性：原发性胶质瘤是肿瘤学界面临的重大挑战。虽然胶质瘤的发病率相对较低，每10万人中有5-10人，但对这些疾病的治疗干预只有边际效益。据美国癌症协会估计，2008年美国将报告21,810例原发性恶性脑肿瘤。美国癌症学会还预计，今年将有13070人死于这些疾病。为了解决当前治疗方法的不足，显然需要进行旨在改善这种疾病治疗结果的研究。

DESCRIPTION (provided by applicant): According to the American Cancer Society an estimated 21,810 cases of primary malignant brain tumor will be reported in the US in 2008. The ACS also estimates that 13,070 deaths will occur due to these diseases in this year. This Phase II STTR program advocates the development of drugs for primary CNS cancers from the schweinfurthin family of natural products. The schweinfurthins are a family of natural products isolated by the National Cancer Institute and have a unique pattern of activity against cancer cell lines indicating a potentially untapped and novel mechanism of action. This project will undertake the further development of these agents by carrying out three specific aims: 1) we will synthesize 288 new bis-stilbene analogs of the schweinfurthins aimed at providing more structure function data, improving activity and physical properties for this class of compounds; 2) we will test these compounds as they become available following an assay scheme developed in our Phase I feasibility studies, this will lead to testing of compounds in animal models of glioblastoma; and 3) we will undertake further hypothesis driven explorations of the mechanism of action of the schweinfurthins. The current clinical outcome of patients with glioblastoma and other aggressive CNS cancers makes development of new agents for these indications highly desirable. The three specific aims proposed here are designed to allow us to choose a candidate for IND enabling studies and to further our understanding of the mechanism of action of this novel family of compounds. PUBLIC HEALTH RELEVANCE: Primary glioma represents a significant challenge to the oncology community. While the incidence of glioma is relatively low at 5-10 per 100,000 individuals, therapeutic interventions for these diseases are of only marginal benefit. According to the American Cancer Society an estimated 21,810 cases of primary malignant brain tumor will be reported in the US in 2008. The ACS also estimates that 13,070 deaths will occur due to these diseases in this year. Research aimed at improving outcomes for this disease is clearly needed to address shortcomings in current therapies.