Developing Schweinfurthin Analogs as Glioma Therapies

描述(申请人提供)：据美国癌症协会估计，2008年美国将报告21,810例原发恶性脑瘤病例。美国癌症协会还估计，今年将有13,070人死于这些疾病。这项第二阶段的STTR计划倡导从SchweinFurtin系列天然产品中开发治疗原发中枢神经系统癌症的药物。施韦因富辛是美国国家癌症研究所分离的一系列天然产物，具有独特的抗癌细胞活性模式，表明了一种潜在的未开发和新的作用机制。该项目将通过实现三个具体目标来进一步开发这些药物：1)我们将合成288个新的施韦因呋喃类化合物的双二苯乙烯类似物，目的是提供更多的结构功能数据，改善这类化合物的活性和物理性质；2)我们将在第一阶段可行性研究中制定的测试方案之后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测试化合物；3)我们将对SchweinFursins的作用机制进行进一步的假设驱动的探索。目前胶质母细胞瘤和其他侵袭性中枢神经系统癌症患者的临床结果使开发这些适应症的新药物变得非常必要。这里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，并加深我们对这一新型化合物家族的作用机制的理解。公共卫生相关性：原发胶质瘤对肿瘤界来说是一个重大挑战。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微乎其微的好处。据美国癌症协会估计，2008年美国将报告21,810例原发恶性脑瘤病例。美国癌症协会还估计，今年将有13,070人死于这些疾病。显然，需要进行旨在改善这种疾病结果的研究，以解决目前治疗方法的不足。

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.