UAB Rexinoids for Breast Cancer Prevention

FDA已批准他莫昔芬作为第一种乳腺癌化学预防药物。血清和芳香酶抑制剂治疗雌激素受体阳性(ER)癌症是有效的，但它们也不是没有局限性和风险。需要新的毒性较低的化学预防药物来预防ER和ER癌症(没有合适的预防药物可用)。9-顺式维甲酸(9cRA)和雷公藤甲素等选择性地与核维甲酸X受体(RXRs)相互作用的维甲酸类化合物在预防ER方面是有效的 单独致癌或与抗雌激素联合致癌。此外，塔格列汀在转基因小鼠模型中预防ER乳腺癌。在UAB，我们设计并合成了两类新的RXR选择性维甲酸，命名为UAB rexinoid。我们确定了几种不同的低毒UAB rexinoid，它们在体内对乳腺癌的化学预防非常有效。毒性最小的UAB rexinid，9cUAB30，可以 没有表现出困扰其他维甲酸类药物临床使用的常见脂质毒性，如9cRA或塔格列汀，用于癌症预防。9cUAB30作为一种新的化学预防药物，已经完成了NCI RAPID计划的临床前开发。NCI快速计划将资助9cUAB30的I期试验，以确定人体毒性和药代动力学。[在具体目标1中，我们将根据我们的活性引线的X射线晶体3D结构设计第二代rexinoid，这些结构来自与RXR结合的两类新的rexinoid。候选的rexinoid将与RXR结晶并在体外进行评估。强大而有力 然后，选择性RXR激动剂将进入体内测试(特定目标2)，使用我们新的七天筛查来抑制肿瘤增殖，以及对甘油三酯水平的影响。我们将在两种乳腺癌预防模型(MNU启动的ER模型和DMBA MTV-erbB2 ER转基因模型)中研究活性Rexinoid。在具体目标3中，我们的第一个rexinid候选药物(9cUAB30)将作为我们孢子项目的一部分进入Ib阶段试验(这将是在NCI赞助的正常志愿者LA阶段试验之后)。在Ib期试验中， 我们将评估9cUAB30是否改变乳腺癌细胞的增殖、凋亡或RXR下游靶基因。新的第二代Rexinoid将在该项目的第4年和第5年达到第一阶段试验。已经组建了一个拥有维甲酸研究和临床化学预防经验的多样化的科学家团队，将有希望的第二代UAB rexinoid转移到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。

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.