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

开发用于治疗晚期乳腺癌的原癌基因 PELP1 强效抑制剂

• 批准号: 10516093
• 负责人: Ratna K Vadlamudi
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10516093
• 关键词: ADME Study; Accounting; Address; Aggressive Clinical Course; American; Antiestrogen Therapy; Aromatase Inhibitors; Biochemical; Biological Markers; Biological Models; Breast Cancer Model; Breast Cancer Prevention; Breast Cancer Treatment; Breast Cancer therapy; Cancer Etiology; Caring; Cessation of life; Clinical; Clinical Treatment; Couples; Development; Diagnosis; Dose; Drug Kinetics; Environment; Epigenetic Process; Estrogen Antagonists; Estrogen receptor positive; Exhibits; Female; General Population; Glutamic Acid; Goals; Healthcare Systems; In Vitro; Incidence; Knowledge; Lead; Leucine; Liposomes; Malignant Neoplasms; Mass Spectrum Analysis; Maximum Tolerated Dose; Mediating; Military Personnel; Modification; Molecular; Molecular Mechanisms of Action; Neoplasm Metastasis; Nuclear Receptors; Oncogenic; Outcome; Patients; Pharmaceutical Preparations; Play; Population; Pre-Clinical Model; Prevalence; Prevention; Proline; Proteins; Proto-Oncogenes; Repression; Research; Resistance; Role; Signal Transduction; Small Interfering RNA; South Texas; Specificity; Technology; Testing; Texas; Therapeutic; Toxic effect; Tumor Volume; Veterans; Woman; Work; Xenograft procedure; advanced breast cancer; breast cancer progression; breast cancer survival; cancer diagnosis; cancer therapy; clinically relevant; clinically significant; cost effective; effective therapy; efficacy testing; genome sequencing; histone modification; in vitro Model; in vivo; in vivo Model; in vivo evaluation; inhibitor; innovation; knock-down; malignant breast neoplasm; military veteran; molecular subtypes; mortality; new therapeutic target; novel therapeutics; patient derived xenograft model; peptidomimetics; prevent; prognostic indicator; programs; receptor function; response; small molecule; small molecule inhibitor; targeted cancer therapy; targeted treatment; therapeutic target; therapy development; therapy resistant; triple-negative invasive breast carcinoma; tumor progression; tumor xenograft; whole genome

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.

项目摘要 乳腺癌（BCA）是女性癌症死亡的第二大原因。在服务妇女中，BCA是 最常见的癌症，占雌性癌的30％，年龄较大的患病率增加 退伍军人。 BCA具有不同的分子亚型。雌激素受体（ER）阳性和三阴性乳房 癌症（TNBC）。 ER阳性的很大一部分最初对抗雌激素或芳香酶抑制剂做出反应 但最终对治疗无反应，发展治疗耐药性乳腺癌（TR-BC）和 最终发展为无法治愈的转移。此外，TNBC的临床课程更具侵略性 缺乏靶向疗法。开发具有TR-BC或TNBC的女性退伍军人的有效疗法 代表乳腺癌治疗中未满足的最高需求。我们正在进行的对PELP1的研究，一种致癌 最初在该实验室中克隆的核心测量蛋白在多个核接收器（NR）中表现出不可或缺的作用 与BCA进展相关的功能。 PELP1表达通常在BCA引起A中失调 同时，PELP1是较差的预后指标 BCA存活和耐药性和转移的指标。我们已经开发了一流的小 PELP1（SMIP）的分子抑制剂针对TR-BC和TNBC表现出效果。 SMIPS阻止PELP1的能力 促进表观遗传修饰。该提议的目的是进一步将铅SMIP发展成小说 用于TR-BC和TNBC临床治疗的药物。我们的总体假设是PELP1夫妇NRS 具有表观遗传修饰符；因此，用SMIP靶向PELP1轴将具有治疗方案 TR-BC和TNBC。在AIM 1中，我们将使用生化， 分子，无偏的质谱和整个基因组测序方法。在AIM 2中，我们将优化 SMIP衍生物并进行研究，以实现体内最大耐受剂量和剂量效率 TR-BC和TNBC模型。在AIM 3中，我们将使用耐药性测试优化SMIP的可翻译性 Xenographictics，转移模型和患者衍生的Xenographathics（PDX）。该建议是创新的，因为SMIPS块 来自多个致癌PELP1的信号传导激活了NRS，以唯一促进表观遗传修饰剂的表达。 成功完成拟议的工作将导致开发一流的癌症治疗 专门针对当前缺乏TR-BC和TNBC靶向疗法的药物。该研究计划是 重要的是，预计将有助于确定对治疗和预防至关重要的治疗靶标 服务妇女种群的晚期乳腺癌。