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 抑制剂治疗对雌激素受体阳性(ER)癌症是有效的，但也并非没有局限性 和风险。预防ER和ER癌需要新的毒性较低的化学预防药物 (没有合适的预防性试剂可供使用)。9-顺式维甲酸(9cRA)和类维甲酸 选择性地与核维甲酸X受体(RXRs)相互作用在预防ER方面是有效的 单独致癌或与抗雌激素联合致癌。此外，塔格列汀还可预防ER-乳房 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- 选择性维甲酸，命名为UAB rexinoids。我们确定了几种不同的低毒UAB Rexinoid 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已完成NCI RAPID计划的临床前开发 作为一种新的化学预防药物。NCI快速计划将于9月30日资助一项第一阶段试验，以 测定人体毒性和药代动力学。[在具体目标1中，我们将设计第二代 基于我们的两类新的Rexinoid活性引线的x射线晶体三维结构 绑定到RXR。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激动剂将使用我们新的七天筛查进行体内试验(特定目标2) 用于抑制肿瘤的增殖，以及对甘油三酯水平的影响。活性Rexinoid将分两个阶段进行研究 乳腺癌预防模型(MNU启动ER模型和DMBA MMTV-erbB2 ER转基因模型 模型)。在具体目标3中，我们的第一个rexin候选药物(9cUAB30)将进入Ib阶段试验，作为我们 孢子项目(这将遵循NCI赞助的在正常志愿者中进行的LA阶段试验)。在Ib期试验中， 我们将评估9cUAB30是否改变了乳腺的增殖、凋亡或RXR下游靶基因 癌细胞。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。一个 不同的科学家团队在维甲酸研究和临床方面拥有广泛的专业知识。 化学预防经验将有希望的第二代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.