Developing Schweinfurthin Analogs as Glioma Therapies

描述（由申请人提供）：根据美国癌症协会的估计，2008年美国将报告21，810例原发性恶性脑肿瘤病例。ACS还估计，今年将有13，070人死于这些疾病。该II期STTR计划倡导从schweinfurthin天然产物家族中开发用于原发性CNS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，对癌细胞系具有独特的活性模式，表明潜在的未开发和新的作用机制。本项目将对这类化合物进行进一步的开发，具体目标有三：1）合成288个新的Schweinfurthins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）我们将根据我们在第一阶段可行性研究中开发的分析方案，在这些化合物可用时对其进行测试，这将导致在胶质母细胞瘤的动物模型中测试化合物;和3）我们将进行进一步的假设驱动的schweinfurthins作用机制的探索。胶质母细胞瘤和其他侵袭性CNS癌症患者的当前临床结果使得开发用于这些适应症的新药物非常可取。本文提出的三个具体目标旨在使我们能够选择IND使能研究的候选者，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。虽然神经胶质瘤的发病率相对较低，为每10万人5-10例，但对这些疾病的治疗干预仅具有边际效益。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。ACS还估计，今年将有13，070人死于这些疾病。显然需要旨在改善这种疾病结局的研究，以解决当前治疗方法的不足。

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.