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

开发用于局部荷尔蒙治疗的硅橡胶，以预防和治疗乳腺癌

基本信息

批准号：
10180911
负责人：
Pamela N. Munster
金额：
$ 36.26万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10180911
关键词：
Ache Adverse effects Animal Model Animals Antiestrogen Therapy Antineoplastic Agents Awareness BRCA mutations Bilateral Biodistribution Breast Breast Cancer Cell Breast Cancer Detection Breast Cancer Model Breast Cancer Prevention Breast Cancer Risk Factor Breast Cancer Treatment Cell Proliferation Cessation of life Companions DNA Sequence Alteration Data Development Device Designs Devices Diagnosis Diffusion Dose Drug Delivery Systems Drug or chemical Tissue Distribution Duct (organ) structure Estradiol Estrogen Antagonists Estrogen Receptors Event Excision Exposure to Family history of Fulvestrant Genetic Germ Lines Germ-Line Mutation Goat Health High Risk Woman In Situ In Vitro Individual Interruption Life Mammary Gland Parenchyma Mastectomy Measures Methods Modeling Modification Mus Mutation Neoplasm Metastasis Organ PET/CT scan Patients Penetration Pharmaceutical Preparations Plasma Population Positron-Emission Tomography Pregnancy Premature Menopause Prevention Prevention Measures Prevention approach Prevention strategy Preventive Property Prostate Rattus Receptor Signaling Reducing Agents Reproducibility Risk Risk Reduction Safety Silastic Silicones Systemic Therapy Tamoxifen Testing Therapeutic Tissues United States Woman Work X-Ray Computed Tomography antitumor effect base cancer prevention clinical translation design efficacy study experimental study high risk hormone therapy imaging biomarker implantation improved in vivo lifetime risk local drug delivery malignant breast neoplasm mammary minimal risk mouse model mutation carrier novel novel strategies novel therapeutics prevent prophylactic mastectomy prototype research clinical testing safety study side effect systemic toxicity tool treatment strategy tumor tumorigenesis uptake young woman

项目摘要

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.

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治疗的增加种系测试，估计有 5-10 万名女性，其中许多是非常年轻的女性，将需要强烈的乳房护理癌症筛查和预防选择。当前高风险女性预防乳腺癌的选择包括双侧乳房切除术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。将抗雌激素局部递送至乳腺组织可能是一种有吸引力的替代方案癌症预防，并可能进一步为原位导管癌提供全身治疗的替代方案 (DCIS) 和转移风险极小的早期乳腺癌。因此，我们建议使用放置在乳房组织下方的硅橡胶装置作为局部分娩抗雌激素治疗策略。硅橡胶中的抗雌激素直接缓慢释放到体内乳腺组织优先吸收的乳腺实质将达到高局部浓度，同时最大限度地减少全身暴露。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植入式硅橡胶装置，可提供持续高水平的抑制雌激素受体的药物 (ER) 信号传导与乳腺癌细胞增殖。硅橡胶选择性地将氟维司群递送至小鼠乳腺组织1年以上，具有与全身治疗相似的抗肿瘤效果氟维司群暴露。在此应用中，我们建议在诱导型中测试和完善这种局部药物输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）确定硅橡胶释放氟维司群以预防诱导性大鼠乳腺癌模型中的肿瘤形成，以及建立雌二醇-PET 成像作为肿瘤 ER 调节的联合诊断，并且（目标 2 和 3）优化装置设计，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最初的安全性和安全性奠定基础。使用伴随成像生物标志物在乳腺癌 DCIS 环境中进行疗效研究。对乳腺癌风险个体的认识和基因识别的提高伴随着越来越需要新的乳腺癌预防方法。硅橡胶基材料的开发具有经批准且有效的抗雌激素的持续局部药物输送装置应能够快速过渡到临床测试。该策略将为延迟或放弃乳房切除术提供另一种选择越来越多的年轻女性被认为终生有超过 40% 的机会获得发展为乳腺癌。如果成功的话，这种治疗方法应该可以转移到其他肿瘤上抗癌药物的范围更广。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A long-term fulvestrant eluting implant is safe, non-toxic, and reduces the risk of breast cancer in in vivo models.

长期氟维司群洗脱植入物安全、无毒，可降低体内模型中患乳腺癌的风险。

DOI：
10.21203/rs.3.rs-3459372/v1
发表时间：
2023
期刊：
Research square
影响因子：
0
作者：
Thomas,Scott;Roche,Elysia;Desai,Pujan;Pawlowska,Nela;Bauer,Diana;Gingrich,David;Hsu,Emily;Deitchman,AmeliaN;Aweeka,Fran;Munster,PamelaN
通讯作者：
Munster,PamelaN