UAB Rexinoids for Breast Cancer Prevention

UAB Rexinoids 用于预防乳腺癌

基本信息

批准号：
8182309
负责人：
DONALD D MUCCIO
金额：
$ 40.26万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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/8182309
关键词：
Acids Agonist Apoptosis Apoptotic 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 Clinic Clinical Clinical Chemoprevention Clinical Research Clinical Trials Clinical Trials Design Combined Modality Therapy Decision Making Development Disease Dose Dose-Limiting Drug Design Drug Kinetics Drug or chemical Tissue Distribution Ensure Estrogen Antagonists Estrogen receptor negative Estrogen receptor positive Funding Future Gene Expression Gene Targeting Generations Goals Homologous Gene Human Human Volunteers Hypertriglyceridemia In Situ Nick-End Labeling In Vitro Industry Investments Lipids Malignant Neoplasms Mammary Neoplasms Mammary gland Methylnitrosourea Modeling Morbidity - disease rate Names Nuclear Nuclear Receptors Oral Patients Phase Phase I Clinical Trials Phase II Clinical Trials Plague Prevention Preventive Protocols documentation Public Health RXR 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 Mice Transgenic Model Translating Triglycerides Vorozole Woman Work alitretinoin anastrozole anticancer research base cancer chemoprevention cancer prevention design dimethylbenzanthracene drug development drug efficacy experience high risk in vivo indexing malignant breast neoplasm mortality mouse model novel phase 1 study pre-clinical preclinical evaluation prevent programs randomized trial receptor receptor binding research clinical testing three dimensional structure tumor volunteer

项目摘要

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。为了预防ER+和ER癌症，需要新的不太毒性化学预防剂（对于没有合适的预防剂）。选择性与核Vetinoid X受体（RXR）选择性相互作用的9-钙摩酸（9cra）和像targretin（如targretin）有效预防ER+ 癌症单独或与抗雌激素结合使用。此外，targretin可防止转基因小鼠模型中的乳腺癌。在UAB，我们设计并合成了两种新的RXR选择性类维生素类别，称为UAB Rexinoids。我们确定了几种不同的低毒性UAB rexinoids，它们在乳腺癌化学预防中非常有效。毒性最小的UAB Rexinoid，9cuab30确实没有显示出常见的脂质毒性，而这些毒性困扰着其他类维生素类动物的临床使用，例如9cra或targretin进行预防癌症。 9CUAB30已作为新的化学预防剂完成了NCI RapidProgram的临床前开发。 NCI快速计划将资助9CUAB30的I期试验，以确定人类的毒性和药代动力学。 [在特定的目标1中，我们将基于从两种与RXR结合的新类别的rexinoids的活性导线的X射线晶体学3D结构设计第二代rexinoids。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的七天筛选来抑制肿瘤增殖，并对甘油三酸酯水平的影响，然后使用我们的新的7天筛选进行体内测试（特定目标2）。将在两个乳腺癌预防模型（MNU引起的ER+模型和DMBA MMTV-ERBB2 ER-转基因模型）中研究活性雷克内素。在特定的目标3中，我们的第一个雷素候选者（9CUAB30）将作为我们的孢子项目的一部分进入IB期试验（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是否会在乳腺癌细胞中改变增殖，凋亡或RXR下游靶基因。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在视力素研究和临床化学预防经验方面拥有广泛的专业知识，以将有希望的第二代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。