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

项目摘要 乳腺癌（BCa）是女性癌症死亡的第二大原因。在女军人中，BCa是 最常诊断的癌症，占女性癌症的30%，老年人的患病率增加 老兵BCa有不同的分子亚型;雌激素受体（ER）阳性和三阴性乳腺癌 癌症（TNBC）。很大一部分ER阳性BCa最初对抗雌激素或芳香化酶抑制剂有反应 但最终表现出对治疗的无反应性，发展为治疗抵抗性乳腺癌（TR-BC）， 最终发展为无法治愈的转移。此外，TNBC具有更具侵略性的临床过程，并且总体而言， 缺乏针对性治疗。为患有TR-BC或TNBC的女性退伍军人开发有效疗法 这是乳腺癌治疗中最大的未满足需求。我们正在进行的关于PELP 1的研究， 辅助调节蛋白最初在本实验室克隆，在多核受体（NR）中发挥不可或缺的作用， 与BCa进展相关的功能。PELP 1表达通常在BCa中失调， 表观遗传修饰的有利环境。同时，PELP 1是一个预后指标， BCa存活率和治疗抗性和转移的指标。我们开发了一流的小型 PELP 1的分子抑制剂（SMIP）显示出对TR-BC和TNBC有效。SMIP阻止PELP 1的能力 来促进表观遗传修饰该提案的目的是进一步将领先的SMIP开发成一种新颖的 用于临床治疗TR-BC和TNBC的药物。我们的总体假设是PELP 1与NRs结合， 因此，用SMIP靶向PELP 1轴将具有治疗效用， TR-BC和TNBC。在目标1中，我们将使用生物化学， 分子、无偏质谱和全基因组测序方法。在目标2中，我们将优化 SMIP衍生物和进行研究，建立体内最大耐受剂量和剂量功效， TR-BC和TNBC模型。在目标3中，我们将使用治疗抗性测试优化的SMIP的可翻译性。 异种移植物、转移模型和患者来源的异种移植物（PDX）。这一建议是创新的SMIP块 来自多个致癌PELP 1激活的NR的信号传导以独特地促进表观遗传修饰物的抑制。 成功完成拟议的工作将导致开发一流的癌症治疗方法 药物专门解决目前缺乏TR-BC和TNBC靶向治疗。这项研究计划是 因为预期其有助于鉴定对治疗和预防以下疾病至关重要的治疗靶点， 晚期乳腺癌的发病率

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.