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

项目概要/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 生殖细胞检测，估计有50 - 100万妇女，许多非常年轻，将需要强烈的乳房 癌症筛查和预防选择。目前预防高危女性乳腺癌的选择 包括双侧乳房切除术、抗雌激素治疗和过早绝经。对于大多数女性来说， 都是残酷的选择将抗雌激素局部递送至乳腺组织可能是治疗乳腺癌的有吸引力的替代方案。 并可进一步为原位导管癌的全身治疗提供替代方案 （DCIS）和具有最小转移风险的早期乳腺癌。 因此，我们建议使用硅橡胶-硅胶装置放置在乳房组织下作为局部递送 抗雌激素治疗策略。抗雌激素从硅橡胶-硅酮直接缓慢释放到 具有优先乳腺组织摄取的乳腺实质将实现高局部浓度， 尽量减少全身接触。 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 提供持续高水平抑制雌激素受体药物的可植入硅橡胶-硅酮装置 (ER)信号传导和乳腺癌细胞增殖。硅橡胶-硅橡胶选择性地向小鼠递送氟维司群 乳腺组织超过1年的抗肿瘤作用与全身性 氟维司群暴露。 在本申请中，我们建议在诱导型细胞中测试和改进这种局部药物递送策略。 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-硅树脂释放氟维司群以预防诱导型大鼠乳腺癌模型中的肿瘤形成， 建立雌二醇-PET成像作为肿瘤ER调节的共同诊断，以及（目标2和3）优化 器械设计，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始安全性奠定基础， 在乳腺癌DCIS环境中使用伴随成像生物标志物的疗效研究。 随着人们对乳腺癌风险的认识和基因识别的提高， 对预防乳腺癌新方法的需求增加。硅橡胶-有机硅复合材料的研制 用于持续局部给药的装置，其具有批准的和有效的抗雌激素， 过渡到临床试验。这一策略将提供一个替代选择，以推迟或放弃乳房切除术， 越来越多的年轻女性被确定有超过40%的终身机会 患上了乳腺癌如果成功，这种治疗方法应该可以转移到其他肿瘤， 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.