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

联合化学预防：预防 ER 阳性

• 批准号: 8182280
• 负责人: POWEL H BROWN
• 金额: $ 15.64万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 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/8182280
• 关键词: Combination; Chemoprevention; Prevention; Both; ER

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。临床试验有 证明了用抗雌激素药物治疗乳腺癌高风险的正常妇女 （选择性雌激素受体调节剂或SERM）可以大大降低其乳房的风险 癌症。但是，高风险女性经常不使用SERM，因为她们没有100％效果 而且由于抗雌激素的慢性疗法具有显着的副作用。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。我们有 先前表明RXR选择性类维生素类似（“ rexinoids”）阻止了ER阴性乳房的发展 小鼠的临床前模型中的癌症，尤其是Serm和Rexinoids的组合是 有效的。我们还使用Serm或Rexinoids（作为单一药物）进行了高风险的临床试验 妇女，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 通过将药物与不同的机制相结合，可以预防ER阳性和ER阴性乳腺癌 作用，通过结合这些药物，我们将在乳腺组织中诱导凋亡，并 短期使用联合预防剂将导致有效的预防，并减少副作用。 （1） 我们将调查Serm莫昔芬和雷克诺类似Bexarotene的慢性疗法是否会完全 预防p53-null小鼠模型中的乳腺癌（其中ER阳性和ER阴性乳腺 癌症发展）并确定这种联合疗法是否诱导癌前乳房凋亡 细胞。 （2）我们将调查对他莫昔芬和贝克索烯的短期治疗是否有效 防止乳腺癌的发展，我们将研究这种短期的机制 治疗可以提供持久的保护。 （3）我们将在绝经前进行II期临床试验 使用他莫昔芬和贝克索烯的组合，患有乳腺癌风险的妇女以增加乳腺癌的风险 高风险女性的短期治疗是否会诱导凋亡或抑制乳腺的增殖 上皮细胞。这些研究将奠定抗雌激素和A的组合的基础 未来III期乳腺癌预防试验中患有乳腺癌风险的女性雷毒素。