UAB Rexinoids for Breast Cancer Prevention

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，但它们并非没有限制和风险。需要新的毒性较低的化学预防剂来预防ER+和ER-癌症（对于这些癌症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 rexinoids。我们鉴定了几种不同的低毒性UAB rexinoids，它们在体内乳腺癌化学预防中非常有效。毒性最小的UAB rexinoid，9 cUAB 30， 没有表现出困扰其他类维生素A临床使用的常见脂质毒性，如9 cRA或Targretin，用于癌症预防。9 cUAB 30作为一种新的化学预防剂已经完成了NCI RAPID计划的临床前开发。NCI RAPID计划将资助9 cUAB 30的I期试验，以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的基础上，从两个新的类rexinoids绑定到RXR的活性线索的X射线晶体学3D结构。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激动剂将进行体内测试（具体目标2），使用我们新的七天筛选来抑制肿瘤增殖和对甘油三酯水平的影响。将在两种乳腺癌预防模型（MNU启动的ER+模型和DMBA MMTV-erbB 2 ER-转基因模型）中研究活性rexinoids。在具体目标3中，我们的第一个rexinoid候选物（9 cUAB 30）将进入Ib期试验，作为我们SPORE项目的一部分（这将在NCI赞助的正常志愿者中的Ia期试验之后）。在Ib期试验中， 我们将评估9 cUAB 30是否改变乳腺癌细胞中的增殖、凋亡或RXR下游靶基因。新的第二代rexinoids将在项目的第4年和第5年进入I期试验。一个多元化的科学家团队已经组建，他们在类维生素A研究和临床化学预防经验方面拥有广泛的专业知识，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。

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.