Developing silastic-silicone for the local delivery of hormonal therapy to prevent and treat breast cancer

项目摘要/摘要： 乳腺癌仍然是一个相当大的健康问题。随着最近负担得起的多基因的增加 生殖系检测，估计有50万到100万妇女，其中许多非常年轻，将需要密集的乳房。 癌症筛查和预防选择。目前预防高危女性乳腺癌的选择 包括双侧乳房切除，或抗雌激素治疗和过早绝经。对于大多数女性来说，这些 都是严峻的选择。将抗雌激素局部注射到乳房组织可能是一种有吸引力的替代方案 预防癌症，并可能进一步提供系统治疗导管原位癌的替代方案 DCIS和早期乳腺癌，转移风险最小。 因此，我们建议使用放置在乳房组织下的硅橡胶硅胶装置作为局部分娩 抗雌激素治疗的策略。从硅橡胶硅胶中缓慢地将抗雌激素直接释放到 优先摄取乳房组织的乳腺实质将达到较高的局部浓度，而 将系统性风险降至最低。 在初步的体外和体内数据中，我们表明批准的抗雌激素可以通过一种 可植入硅橡胶-硅胶装置，提供持续高水平的抑制雌激素受体的药物 (Er)信号转导与乳腺癌细胞增殖。硅橡胶-硅胶选择性地给小鼠输送氟维司他 1年以上的乳腺组织，其抗肿瘤作用与系统性的 福尔维斯特暴露。 在本应用中，我们建议在可诱导的情况下测试和改进这种局部给药策略 预防模型和大动物模型。在三个具体目标中，我们将(目标1)确定 硅橡胶-硅橡胶释放氟维司琼预防诱导性大鼠乳腺癌模型的形成和 建立雌激素-PET成像作为肿瘤ER调节的联合诊断，并(目标2和3)优化 设计该装置，利用大型动物表征药物在组织中的扩散和渗透特性 山羊模型。这些实验将为快速临床转化为初步安全和 在乳腺癌DCIS环境中使用伴随的成像生物标记物进行疗效研究。 对乳腺癌高危个体的更好的认识和基因识别伴随着 对预防乳腺癌的新方法的需求增加。硅橡胶基硅橡胶的研制 具有经批准和有效的抗雌激素的持续局部给药装置应允许快速 过渡到临床测试。这一策略将提供另一种选择，以推迟或放弃乳房切除术 迅速增长的年轻女性被确认有超过40%的终生机会 罹患乳腺癌。如果成功，这种治疗方法应该可以转移到其他肿瘤和 更广泛的抗癌药物。

Project Summary/Abstract: Breast cancer remains a considerable health concern. With the recent increase in affordible multi-gene germ line testing, an estimated 0.5-1 million women, many very young, will be in need of intense breast cancer screening and prevention options. Options to prevent breast cancer in women with high risk currently include bilateral mastectomies, or anti-estrogen therapy and premature menopause. For most women, these are grim choices. Localized delivery of an anti-estrogen to breast tissue may be an attractive alternative for cancer prevention and may further provide an alternative to systemic therapy for ductal carinoma in situ (DCIS) and early stage breast cancer with minimal risk for metastasis. We, therefore, propose the use of a silastic-silicone device placed under breast tissue as a local delivery strategy for anti-estrogen therapy. The slow release of an anti-estrogen from silastic-silicone directly into the breast parenchyma with preferential breast tissue uptake will achieve a high local concentration while minimizing systemic exposure. In preliminary in vitro and in vivo data, we show that approved anti-estrogens can be delivered through an implantable silastic-silicone device that provide sustained high levels of drug that inhibit estrogen receptor (ER) signaling and breast cancer cell proliferation. Silastic-silicone delivers fulvestrant selectively to mouse mammary tissue for more than 1 year with anti-tumor effects similar to those acheived with systemic fulvestrant exposure. In this application, we propose to test and refine this localized drug delivery strategy in an inducible prevention model and large animal model. In three specific aims, we will (Aim 1) determine the efficacy of silastic-silicone released fulvestrant to prevent tumor formation in an inducible rat breast cancer model and establish estradiol-PET imaging as a co-diagnosic for tumor ER modulation, and (Aims 2 and 3) optimize the design of the device, characterize drug diffusion and penetration properties in tissue utilizing a large animal goat model. These experiments will lay the ground work for rapid clinical translation to initial safety and efficacy studies in a breast cancer DCIS setting with a companion imaging biomarker. The greater awareness and genetic identification of individuals at risk for breast cancer comes with an increased need for new approaches to breast cancer prevention. The development of a silastic-silicone based device for sustained local drug delivery with an approved and effective anti-estrogen should allow rapid transition into clinical testing. This strategy will provide an alternative option to delay or forgo mastectomies to the rapidly increasing number of young women identified to have a more than 40% lifetime chance of developing breast cancer. If successful this therapeutic approach should be transferable to other tumors and a broader range of anti-cancer agents.