Schweinfurthins: novel treatment for breast cancer

描述(申请人提供)：根据美国癌症协会的数据，2008年美国估计发生了182,000例浸润性乳腺癌，其中40,000人死于乳腺癌。在患有转移性乳腺癌的女性中，5年生存率为27%。在这项SBIR第一阶段应用中提出的研究旨在评估开发用于乳腺癌治疗的合成雪威因呋喃西林的可行性。美国国家癌症研究所的工作人员从一系列天然产品中分离出了第一批施韦因富辛，并在NCI 60细胞系生物测定中显示出显著的抗乳腺癌、白血病/淋巴瘤、肾脏、黑色素瘤和中枢神经系统亚组的活性。施韦因富辛似乎有一种新的作用机制，并可能具有广泛的适用性，以满足乳腺癌患者重大的未得到满足的医疗需求。虽然最初是在天然产物筛选过程中发现的，但这些化合物的天然来源仅提供少量物质，并已证明重新分离是不可靠的。爱荷华大学的萜类治疗公司及其合作者已经设计和合成了50多个SchweinFurtin类似物，其中包括几个在体外对人乳腺癌细胞株具有低纳摩尔效力的化合物。这一I期可行性应用的目标是建立人工合成的雪威因呋喃西林在人乳腺癌异种移植模型中的体内疗效。该项目将通过两个具体目标进一步开发用于治疗乳腺癌的合成施韦因呋喃西林：1)单独分析合成施韦因呋喃西林及其与目前用于乳腺癌治疗的药物联合使用对人乳腺癌细胞株的体外抑制作用，并选择用于体内疗效模型的化合物进行测试；2)在乳腺癌异种移植模型中单独测试合成施韦因呋喃西林并与标准疗法联合使用，以建立体内疗效。这些研究的数据将支持SBIR第二阶段的提议，将合成的SchweinFurtin推进到IND使能研究。 公共卫生相关性：尽管转移性乳腺癌的治疗取得了重要进展，但仍然需要创新的新疗法。根据美国癌症协会的数据，2008年美国估计发生了18.2万例浸润性乳腺癌，其中4万人死于乳腺癌。在患有转移性乳腺癌的女性中，5年生存率为27%。需要研究寻找转移性乳腺癌的新治疗方法，如合成的雪威因呋喃西林，以改善患者的预后。

DESCRIPTION (provided by applicant): According to the American Cancer Society an estimated 182,000 cases of invasive breast cancer occurred in the US in 2008, with 40,000 deaths due to breast cancer. Among women with metastatic breast cancer, the 5-year survival rate is 27%. The studies proposed in this SBIR phase I application are designed to assess the feasibility of developing synthetic schweinfurthins for the treatment of breast cancer. The first schweinfurthins from a family of natural products were isolated by workers at the National Cancer Institute and showed remarkable activity against the breast, leukemia/lymphoma, renal, melanoma and CNS sub-panels of the NCI 60-cell line bioassay. The schweinfurthins appear to have a novel mechanism of action and could have broad applicability to address the significant unmet medical need of patients with breast cancer. While initially discovered during a natural products screen, the natural sources of these compounds supply only small amounts and have proven unreliable for re-isolation. Terpenoid Therapeutics and its collaborators at the University of Iowa have designed and synthesized over fifty schweinfurthin analogues, including several compounds which have low nanomolar potency against human breast cancer cell lines in vitro. The goal of this phase I feasibility application is to establish in vivo efficacy of synthetic schweinfurthins in human breast cancer xenograft models. This project will undertake the further development of synthetic schweinfurthins for the treatment of breast cancer through two specific aims: 1) Analyze synthetic schweinfurthins alone and in combination with drugs currently used in the treatment of breast cancer for in vitro growth inhibition of human breast cancer cell lines and select compounds for testing in in vivo efficacy models; and 2) Test a synthetic schweinfurthin alone and in combination with standard therapies in breast cancer xenograft models to establish in vivo efficacy. The data from these studies will support a Phase II SBIR proposal to advance a synthetic schweinfurthin into IND-enabling studies. PUBLIC HEALTH RELEVANCE: In spite of important advances in the treatment of metastatic breast cancer, there remains a need for innovative new therapies. According to the American Cancer Society an estimated 182,000 cases of invasive breast cancer occurred in the US in 2008, with 40,000 deaths due to breast cancer. Among women with metastatic breast cancer, the 5-year survival rate is 27%. Research to identify novel treatments for metastatic breast cancer, such as the synthetic schweinfurthins, is needed to improve the outcomes for patients.