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

• 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
• 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

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.

项目总结/文摘:

项目成果

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
• 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