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: 10412909
• 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/10412909
• 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; Modeling; 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; Resistance development; Role; Signal Transduction; Small Interfering RNA; South Texas; Specificity; Technology; Testing; Texas; Therapeutic; Toxic effect; 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 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; 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.

项目概要 乳腺癌（BCa）是女性癌症死亡的第二大原因。在女军人中，BCa 是 最常诊断出的癌症，占女性癌症的 30%，且在老年人中患病率更高 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）。很大一部分 ER 阳性 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无反应，发展为治疗抵抗性乳腺癌（TR-BC），并且 最终进展为无法治愈的转移。此外，TNBC 具有更具侵略性的临床过程，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 代表了乳腺癌治疗中未满足的最高需求。我们正在进行的关于 PELP1（一种致癌物质）的研究 核心调节蛋白最初在本实验室克隆，在多核受体 (NR) 中发挥着不可或缺的作用 与 BCa 进展相关的功能。 PELP1 表达在 BCa 中通常失调，引发 有利于表观遗传修饰的环境。同时，PELP1 是较差的预后指标 BCa 存活率以及治疗抵抗和转移的指标。我们开发了一流的小型 PELP1 (SMIP) 分子抑制剂对 TR-BC 和 TNBC 有效。 SMIP 阻止 PELP1 的能力 促进表观遗传修饰。该提案的目标是将领先的 SMIP 进一步发展为新颖的 临床治疗TR-BC和TNBC的药物。我们的首要假设是 PELP1 与 NR 结合 具有表观遗传修饰剂；因此，用 SMIP 靶向 PELP1 轴将在治疗中具有治疗效用 TR-BC 和 TNBC。在目标 1 中，我们将使用生化、 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 衍生物并进行研究，确定最大耐受剂量和体内剂量功效 TR-BC 和 TNBC 型号。在目标 3 中，我们将使用抗治疗测试优化 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）。该提案具有创新性，因为 SMIP 阻止了 来自多个致癌 PELP1 激活 NR 的信号传导能够独特地促进表观遗传修饰因子的抑制。 成功完成拟议工作将开发出一流的癌症疗法 该药物专门解决了目前缺乏TR-BC和TNBC靶向治疗的问题。该研究计划是 意义重大，因为它有望帮助确定对治疗和预防至关重要的治疗靶点 女军人群体中的晚期乳腺癌。