UAB Rexinoids for Breast Cancer Prevention

UAB Rexinoids 用于预防乳腺癌

• 批准号: 7314562
• 负责人: DONALD D MUCCIO
• 金额: $ 38.18万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7314562
• 关键词: Agonist; Apoptosis; Apoptotic; Appendix; Aromatase Inhibitors; Bexarotene; Binding; Biological Availability; Biological Markers; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Prevention; Bromodeoxyuridine; Cell Proliferation; Chemoprevention; Chemopreventive Agent; Cholesterol; Class; Clinic; Clinical; Clinical Chemoprevention; Clinical Research; Clinical Trials; Combined Modality Therapy; Decision Making; Development; Disease; Dose; Dose-Limiting; Drug Design; Drug Kinetics; Drug or chemical Tissue Distribution; End Point; Ensure; Estrogen Antagonists; Estrogen receptor negative; Estrogen receptor positive; Evaluation; Funding; Future; Gene Expression; Gene Targeting; Generations; Goals; Homologous Gene; Human; Human Volunteers; Hypertriglyceridemia; In Situ Nick-End Labeling; In Vitro; Industry; Investments; LGD1069; Lipids; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Methylnitrosourea; Modeling; Morbidity - disease rate; Names; Nuclear; Nuclear Receptors; Numbers; Oral; Patients; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Plague; Prevention; Preventive; Principal Investigator; Protocols documentation; Public Health; Purpose; RXR; Randomized Controlled Clinical Trials; Rate; Rattus; Reproduction spores; Research; Retinoid Receptor; Retinoids; Risk; Schedule; Scientist; Selective Estrogen Receptor Modulators; Series; Serum; Structure; Structure-Activity Relationship; Surrogate Endpoint; Tamoxifen; Testing; Tissues; Toxic effect; Transgenic Model; Transgenic Organisms; Translating; Triglycerides; United States Food and Drug Administration; Vorozole; Woman; Work; alitretinoin; anastrozole; anticancer research; base; cancer prevention; day; design; dimethylbenzanthracene; drug development; drug efficacy; experience; in vivo; indexing; malignant breast neoplasm; mortality; mouse model; novel; pre-clinical; prevent; programs; receptor; receptor binding; research clinical testing; three dimensional structure; tumor; volunteer

The FDA has approved tamoxifen as the first breast cancer chemopreventive agent. SERM and aromatase inhibitor therapy is effective for estrogen receptor-positive (ER+) cancers, but they are not without limitations and risks. New less-toxic chemopreventive agents are needed for the prevention of ER+ and ER- cancers (for which no suitable preventive agent is available). 9-cis-Retinoic acid (9cRA) and rexinoids like Targretin that selectively interact with nuclear retinoid X receptors (RXRs) are effective in the prevention of ER+ cancer either alone or in combination with anti-estrogens. Additionally, Targretin prevents ER- mammary cancers in transgenic mouse models. At UAB, we designed and synthesized two new classes of RXR- selective retinoids, named UAB rexinoids. We identified several different low-toxicity UAB rexinoids that are very effective in vivo in mammary cancer chemoprevention. The least toxic UAB rexinoid, 9cUAB30, does not display common lipid toxicities that have plagued the clinical use of other retinoids, like 9cRA or Targretin, for cancer prevention. 9cUAB30 has finished preclinical development by the NCI RAPIDProgram as a new chemopreventive agent. The NCI RAPID Program will fund a phase I trial on 9cUAB30 to determine human toxicity and pharmacokinetics. [In Specific Aim 1, we will design second-generation rexinoids based on x-ray crystallographic 3D structures of our active leads from two new classes of rexinoids bound to RXR. Candidate rexinoids will be crystallized with RXR and evaluated in vitro. Potent and selective RXR agonists will then advance to in vivo testing (Specific Aim 2) using our new seven-day screen for inhibition of tumor proliferation, and effects on triglyceride levels. Active rexinoids will be studied in two mammary cancer prevention models (MNU-initiated ER+ model and DMBA MMTV-erbB2 ER- transgenic model). In Specific Aim 3, our first rexinoid candidate (9cUAB30) will enter a phase Ib trial as part of our SPORE project (this will follow the NCI sponsored phase la trial in normal volunteers). In the phase Ib trial, we will evaluate whether 9cUAB30 alters proliferation, apoptosis or RXR downstream target genes in breast cancer cells. Novel second-generation rexinoids will reach phase I trials in years 4 and 5 of the project. A diverse team of scientists has been assembled with extensive expertise in retinoid research and clinical chemoprevention experience to move promising second-generation UAB rexinoids to phase I clinical trials.] This SPORE project impacts public health by the development of drugs that may prevent breast cancer.

FDA已经批准他莫昔芬作为第一种乳腺癌化学预防剂。SERM和芳香化酶 抑制剂治疗对雌激素受体阳性（ER+）癌症有效，但并非没有局限性 和风险。需要新的毒性较小的化学预防剂来预防ER+和ER-癌症 (for没有合适的预防剂可用）。9-顺式维甲酸（9 cRA）和rexinoids，如Targretin 选择性地与核维甲酸X受体（RXR）相互作用，可有效预防ER+ 单独或与抗雌激素联合治疗癌症。此外，Targretin可预防ER-乳腺癌 转基因小鼠模型中的癌症。在UAB，我们设计并合成了两类新的RXR- 选择性类维生素A，命名为UAB rexinoids。我们确定了几种不同的低毒性UAB rexinoids， 在乳腺癌化学预防中非常有效。毒性最小的UAB rexinoid，9 cUAB 30， 不显示困扰其他类维生素A临床使用的常见脂质毒性，如9 cRA或 Targretin，用于预防癌症。9 cUAB 30已通过NCI RAPID计划完成临床前开发 作为一种新的化学预防剂。NCI RAPID计划将资助9 cUAB 30的I期试验， 确定人体毒性和药代动力学。[In具体目标1，我们将设计第二代 rexinoids基于我们来自两类新rexinoids的活性先导化合物的X射线晶体学3D结构 与RXR绑定。候选类Rexinoids将用RXR结晶并在体外进行评价。强效和 然后，选择性RXR激动剂将使用我们新的7天筛选进行体内测试（特定目标2） 用于抑制肿瘤增殖和对甘油三酯水平的影响。活性rexinoids将在两个研究 乳腺癌预防模型（MNU启动的ER+模型和DMBA MMTV-erbB 2 ER-转基因模型 模型）。在Specific Aim 3中，我们的第一个rexinoid候选药物（9 cUAB 30）将进入Ib期试验，作为我们的 SPORE项目（这将遵循NCI在正常志愿者中申办的Ia期试验）。在Ib期试验中， 我们将评估9 cUAB 30是否改变乳腺癌细胞的增殖、凋亡或RXR下游靶基因， 癌细胞新的第二代rexinoids将在项目的第4年和第5年进入I期试验。一 不同的科学家团队已经组装了广泛的专业知识，在类维生素A的研究和临床 化学预防经验，将有前途的第二代UAB rexinoids推向I期临床试验。 这个孢子项目通过开发可能预防乳腺癌的药物来影响公众健康。