Development of Potent Inhibitors of proto-oncogene PELP1 for Treating Advanced Breast Cancer

项目总结 乳腺癌(BCA)是女性癌症死亡的第二大原因。在女军人中，BCA是 最常见的确诊癌症，占女性癌症的30%，老年人患病率上升 退伍军人。BCA有不同的分子亚型；雌激素受体(ER)阳性和三重阴性的乳房 癌症(TNBC)。很大一部分ER阳性的BCA最初对抗雌激素或芳香酶抑制剂有反应 但最终表现出对治疗的无反应，发展为耐药乳腺癌(tr-bc)，以及 最终发展为无法治愈的转移。此外，TNBC的临床病程和总体上更具侵略性 缺乏针对性的治疗。女性退伍军人合并TRBC或TNBC的有效治疗方法的发展 代表了乳腺癌治疗中未得到满足的最高需求。我们正在进行的关于PELP1的研究，一种致癌的 本实验室首次克隆的辅调节蛋白在多核受体(NR)中起着不可或缺的作用 与BCA进展相关的功能。PELP1在BCA中的表达通常是失调的，导致 有利于表观遗传修饰的环境。同时，PELP1是较差的预后指标 BCA存活率和治疗耐药及转移的指标。我们开发了一款一流的小型 PELP1分子抑制物(SMIP)对tr-bc和tnbc均有抑制作用。SMIP阻断PELP1的S能力 以促进表观遗传修饰。这项提议目标是将一个主要的SMIP进一步发展成一部小说 临床治疗tr-bc和tnbc的药物。我们的主要假设是PELP1将NR 因此，用SMIPs靶向PELP1轴将在治疗中具有治疗作用 包括tr-bc和tnbc。在目标1中，我们将利用生化方法确定铅SMIPs的作用机制， 分子、无偏质谱学和全基因组测序方法。在目标2中，我们将优化 SMIP衍生物，并进行研究，确定体内最大耐受剂量和剂量功效 TR-BC和TNBC模型。在目标3中，我们将使用治疗抵抗来测试优化的SMIP的可译性 异种移植物，转移模型和患者来源的异种移植物(PDX)。这项建议是创新的，因为SMIP阻止 来自多个致癌基因PELP1的信号激活NRs，以独特地促进表观遗传修饰物的抑制。 拟议工作的成功完成将导致开发一流的癌症治疗方法 专门针对目前缺乏tr-bc和tnbc靶向治疗的药物。这项研究计划是 具有重要意义，因为预计它将有助于确定对治疗和预防 服役女性人群中的晚期乳腺癌。

Project summary Breast cancer (BCa) is the second leading cause of cancer death in women. Among Servicewomen, BCa is the most commonly diagnosed cancer, accounting for 30% of female cancers with increased prevalence in older Veterans. BCa has distinct molecular subtypes; estrogen receptor (ER) positive and triple negative breast cancer (TNBC). A significant portion of ER-positive BCa initially respond to anti-estrogens or aromatase inhibitors but eventually exhibit unresponsiveness to therapy, develop therapy-resistant breast cancer (TR-BC), and ultimately progress to incurable metastasis. Moreover, TNBC has a more aggressive clinical course and overall lack of targeted therapies. Development of effective therapies for female Veterans with TR-BC or TNBC represents the highest unmet need in breast cancer treatment. Our ongoing research on PELP1, an oncogenic coregulator protein originally cloned in this lab, displays an integral role in multiple nuclear receptor (NR) functions associated with BCa progression. PELP1 expression is commonly dysregulated in BCa eliciting a conducive environment for epigenetic modifications. Concomitantly, PELP1 is a prognostic indicator for poorer BCa survival and indicator of therapy resistance and metastases. We have developed a first-in-class small molecule inhibitor of PELP1 (SMIP) displaying effectivity against TR-BC and TNBC. SMIPs block PELP1’s ability to promote epigenetic modifications. The objective of this proposal is to further develop a lead SMIP into a novel drug for the clinical treatment of TR-BC and TNBC. Our overarching hypothesis is that PELP1 couples NRs with epigenetic modifiers; therefore, targeting the PELP1 axis with SMIPs will have a therapeutic utility in treating both TR-BC and TNBC. In Aim 1, we will determine lead SMIPs mechanism of action using biochemical, molecular, unbiased mass spectroscopy, and whole genome sequencing approaches. In Aim 2, we will optimize SMIP derivatives and conduct studies establishing the maximum tolerated dose and dose efficacy in vivo using TR-BC and TNBC models. In Aim 3, we will test the translatability of optimized SMIPs using therapy resistant xenografts, metastatic models, and patient derived xenografts (PDX). This proposal is innovative as SMIPs block signaling from multiple oncogenic PELP1 activated NRs to uniquely promote repression of epigenetic modifiers. Successful completion of the proposed work will result in the development of a first-in-class cancer therapy drug specifically addressing the current lack of TR-BC and TNBC targeted therapies. This research program is significant as it is expected to aid in identifying therapeutic targets critical to the treatment and prevention of advanced breast cancer in the population of Servicewomen.