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已批准他莫昔芬是第一种乳腺癌化学预防剂。 Serm和芳香酶 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。预防ER+和ER-癌症需要新的不太有毒的化学预防剂 （为此，没有合适的预防剂）。 9-钙摩酸（9cra）和类似targretin的rexinoids 选择性与核性类维生素X受体（RXR）有效相互作用可有效预防ER+ 癌症单独或与抗雌激素结合使用。此外，targretin可防止乳腺癌 转基因小鼠模型中的癌症。在UAB，我们设计并合成了两类新类RXR- 选择性类维生素类似，称为UAB Rexinoids。我们确定了几种不同的低毒性UAB rexinoids 体内非常有效的乳腺癌化学预防。毒性最小的UAB Rexinoid，9cuab30确实 不显示困扰其他类类动物的临床使用的常见脂质毒性，例如9cra或 targretin，用于预防癌症。 9CUAB30已通过NCI快速计划完成临床前开发 作为一种新的化学预防剂。 NCI快速计划将资助9CUAB30的I期试验 确定人类的毒性和药代动力学。 [在特定目标1中，我们将设计第二代 基于我们有效铅的X射线晶体学3D结构的rexinoids来自两个新类别的rexinoids 绑定到rxr。候选雷克内氏素将用RXR结晶并在体外进行评估。有效和 然后，选择性RXR激动剂将使用我们的新七日屏幕前进到体内测试（特定目标2） 为了抑制肿瘤增殖和对甘油三酸酯水平的影响。主动雷克内尼素将在两个中进行研究 乳腺癌预防模型（MNU引发的ER+模型和DMBA MMTV-ERBB2 ER-转基因 模型）。在特定的目标3中，我们的第一个rexinoid候选者（9CUAB30）将作为我们的一部分进行IB期试验 孢子项目（这将遵循NCI赞助的正常志愿者LA期试验）。在IB阶段试验中， 我们将评估9CUAB30是否会改变乳腺中的增殖，凋亡或RXR下游基因 癌细胞。新型的第二代雷类动物将在该项目的第4年和第5年进行I期试验。一个 多元化的科学家团队已在类视感研究和临床方面拥有广泛的专业知识 化学预防的经验将有希望的第二代UAB Rexinoids转移到I期临床试验中。] 该孢子项目通过开发可能预防乳腺癌的药物来影响公共卫生。