Combination Chemoprevention: Prevention of Both ER-Positive & ER-Negative BC

联合化学预防：预防 ER 阳性

基本信息

批准号：
8182291
负责人：
POWEL H BROWN
金额：
$ 23.97万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8182291
关键词：
Address Adverse effects Aftercare Agonist Antiestrogen Therapy Apoptosis BRCA1 gene Bexarotene Biological Markers Biopsy Blood Breast Breast Cancer Prevention Breast Cancer Prevention Trial Breast Cancer Risk Assessment Tool Cancer Prevention Trial Cell Death Induction Cells Chemoprevention Chemopreventive Agent Chronic Cleaved cell Clinical Trials Combined Modality Therapy Conduct Clinical Trials Cyclin D1 Development Epithelial Cells Estrogen Antagonists Estrogen receptor negative Estrogen receptor positive Foundations Future Generations Growth High Risk Woman Histology In complete remission Incidence Knockout Mice Lesion Malignant Neoplasms Mammary Neoplasms Mammary gland Measures Medical Methylation Mus Mutation Pharmaceutical Preparations Pharmacotherapy Phase Phase II Clinical Trials Physiologic pulse Placebos Pre-Clinical Model Premalignant Premalignant Cell Premenopause Prevention Preventive Primary Prevention RXR Recording of previous events Regulator Genes Retinoids Risk S-Phase Fraction Selective Estrogen Receptor Modulators Staining method Stains Stem cells TP53 gene Tamoxifen Testing Tissues Toxic effect Translational Research Woman caspase-3 high risk indexing lobular breast carcinoma in situ malignant breast neoplasm mouse model pre-clinical prevent promoter response tumor

项目摘要

Prevention of breast cancer using medical therapy (chemoprevention) is now possible. Clinical trials have demonstrated that treatment of normal women at high risk of breast cancer with anti-estrogen drugs (selective estrogen receptor modulators, or SERMs) can substantially reduce their risk of developing breast cancer. However, SERMs are frequently not used by high risk women because they are not 100% effective and because chronic therapy with anti-estrogens has significant side effects. In addition, while long-term anti-estrogens reduce the risk of ER-positive breast cancer, they do not reduce ER-negative breast cancer. Thus, more effective and less toxic strategies to prevent all types of breast cancer are needed. We have previously shown that RXR-selective retinoids ("rexinoids") prevent the development of ER-negative breast cancer in preclinical models in mice, and that the combination of SERMs and rexinoids is particularly effective. We have also conducted clinical trials using SERMs or rexinoids (as single agents) in high risk women and have demonstrated that these agents are tolerable. Here we will test the hypotheses that both ER-positive and ER-negative breast cancer can be prevented by combining drugs with different mechanisms of action, that by combining these drugs we will induce apoptosis in premalignant mammary tissue, and that short-term use of combined preventive agents will result in effective prevention with reduced side effects. (1) We will investigate whether chronic therapy with the SERM tamoxifen and the rexinoid bexarotene will totally prevent breast cancer in the p53-null mouse model (in which both ER-positive and ER-negative breast cancers develop) and determine whether this combination therapy induces apoptosis in precancerous breast cells. (2) We will investigate whether short-term treatment with tamoxifen and bexarotene will effectively prevent the development of breast cancer, and we will investigate the mechanism by which this short-term treatment can provide long-lasting protection. (3) We will conduct a Phase II clinical trial in premenopausal women at increased risk of breast cancer using the combination of tamoxifen plus bexarotene to determine whether short-term treatment in high risk women will induce apoptosis or suppress proliferation of mammary epithelial cells. These studies will lay the foundation for testing this combination of an anti-estrogen and a rexinoid in women at risk of breast cancer in future Phase III breast cancer prevention trials.

现在可以使用药物治疗（化学预防）预防乳腺癌。临床试验表明，使用抗雌激素药物（选择性雌激素受体调节剂或SERMS）治疗正常女性患乳腺癌的高风险可以大大降低其患乳腺癌的风险。但是，高风险女性经常不使用SERM，因为她们没有100％有效，并且由于抗雌激素的慢性治疗具有显着的副作用。另外，长期抗雌激素降低了ER阳性乳腺癌的风险，不会降低ER阴性乳腺癌。因此，需要更有效和毒性的策略，以防止所有类型的乳腺癌。我们先前已经表明，RXR选择性类维生素类动物（“ Rexinoids”）可以防止小鼠临床前模型中ER阴性乳腺癌的发展，并且Serms和Rexinoids的组合尤其有效。我们还使用Serm或Rexinoids（作为单一药物）进行了高风险女性的临床试验，并证明这些药物是可以忍受的。在这里，我们将测试两者的假设可以通过将药物与不同的作用机制相结合来预防ER阳性和ER阴性乳腺癌，即通过结合这些药物，我们将诱导乳腺癌前乳腺组织中的凋亡，而短期使用预防药物将导致有效预防和副作用减少。（1）我们将研究Serm他莫昔芬和Rexinoid Bexarotene的慢性治疗是否会完全预防p53-Null小鼠模型（其中ER阳性和ER阴性乳腺癌的发展）中的乳腺癌，并确定这种组合疗法是否诱导癌前乳腺细胞的凋亡。（2）我们将调查对他莫昔芬和贝克索烯的短期治疗是否会有效防止乳腺癌的发展，我们将研究这种短期治疗可以提供长期保护的机制。（3）我们将在绝经前进行II期临床试验使用他莫昔芬和蜜蜂的组合，患有乳腺癌风险的妇女可以确定高风险中的短期治疗是妇女是否会诱导凋亡或抑制乳腺上皮细胞的增殖。这些研究将为在未来III期乳腺癌预防试验中患有乳腺癌风险的女性中测试这种抗雌激素和逆性雷症的基础。