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Developing LG007 as a novel therapeutic agent to treat triple negative breast cancer

开发 LG007 作为治疗三阴性乳腺癌的新型治疗剂

基本信息

批准号：
10477444
负责人：
Yaguang Xi
金额：
$ 37.39万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10477444
关键词：
4T1 Adjuvant African American Age-Years Animal Model Biological Assay Biological Markers Breast Cancer Cell Breast Cancer Model Breast Cancer cell line Breast cancer metastasis Cancer Patient Caucasians Cause of Death Cells Chemotherapy-Oncologic Procedure Clinical Clinical Trials Communities Data Development Diagnosis Disease Drug Kinetics ERBB2 gene Early treatment Epidermal Growth Factor Receptor Estrogen Receptors Ethnic Origin Evaluation Experimental Designs FDA approved Future Guidelines High Prevalence Hispanic Human In complete remission Incidence Investigation Lead Malignant Neoplasms Mediating Medical MicroRNAs Modeling Molecular Mechanisms of Action Mus Names Neoadjuvant Therapy Neoplasm Metastasis Oncogenic Paclitaxel Patient-derived xenograft models of breast cancer Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Pharmacology and Toxicology Preparation Progesterone Receptors Prognosis Property Recurrence Research Role Safety Sampling Specificity Sulindac Testing Therapeutic Agents Tissue Microarray Toxic effect Translating Translations Treatment Efficacy United States Woman Work anticancer activity base cancer subtypes clinical application comparative efficacy drug candidate drug development economic disparity effective therapy efficacious treatment efficacy evaluation epidemiology study ethnic minority population experience experimental study health disparity in vitro activity in vivo interest loss of function malignant breast neoplasm mortality mouse model novel novel therapeutics patient derived xenograft model research clinical testing screening social disparities socioeconomics targeted treatment therapeutically effective tool transcriptome sequencing triple-negative invasive breast carcinoma tumor tumor growth tumor xenograft young woman

项目摘要

PROJECT SUMMARY: For women in the United States, breast cancer is the most common malignancy and the second leading cause of death. In this application, we focus upon a specific subtype of breast cancer known as triple-negative breast cancer (TNBC). Compared to other breast cancer subtypes, TNBC is considered more aggressive and extremely difficult to treat with standard therapies. As a result, it has a high recurrence rate and a high overall mortality rate. TNBC accounts for up to 20% of all breast cancers, with a higher incidence in ethnic minority populations and young women (usually <40 years of age). Approximately 70% of patients with advanced TNBC die of disease recurrence and/or metastasis within 5 years of initial diagnosis. Therefore, there is an urgent need for the medical community to develop more effective therapeutic options for this deadly disease. In this project, we will investigate a novel experimental compound, named LG007, for its anti-cancer activity in TNBC. Of significance, we will utilize robust TNBC Patient-Derived Xenograft (PDX) mouse models to study the in vivo efficacy of LG007. Our preliminary results demonstrated that LG007 effectively inhibits TNBC tumor growth and metastasis. Notably, we found that LG007 treatment could robustly shrink large human-derived TNBC PDX tumors, with a near-complete response. These preliminary results strongly support the premise that LG007 is a novel and potent drug candidate capable of treating progressive TNBC and associated metastasis. Furthermore, we demonstrated that LG007 is able to target and regulate miR-10b, a well-known oncogenic miRNA that promotes tumor development and metastasis. Therefore, we hypothesize that miR-10b is a primary target of LG007 that is critically involved in the molecular mechanisms of action by which LG007 inhibits tumor growth and metastasis. Three specific aims are proposed in pursuit of the project’s objective to develop a new therapy for the treatment of TNBC. In Aim 1, we will determine the mechanistic roles of miR-10b and one of its targets, NR4A3, in the anti-TNBC activity of LG007. In Aim 2, we will investigate the in vivo efficacy of LG007 utilizing a variety of advanced mouse models that mimic the clinical setting of TNBC and its associated recurrence and metastasis. In Aim 3, we will characterize the pharmacological and toxicological properties of LG007 in preparation for future translation to clinical testing. We expect that the results obtained from this study will lead to the development of a novel, safe, and effective treatment for patients with advanced TNBC.

项目概要：对于美国女性来说，乳腺癌是最常见的恶性肿瘤，也是第二大病因死亡之在这个应用程序中，我们集中在一个特定的亚型乳腺癌称为三阴性乳腺癌，癌症（TNBC）。与其他乳腺癌亚型相比，TNBC被认为更具侵袭性，很难用标准疗法治疗因此，它具有高复发率和高总体死亡率。 TNBC占所有乳腺癌的20%，少数民族人群的发病率较高，年轻女性（通常<40岁）。大约70%的晚期TNBC患者死于疾病首次诊断后5年内复发和/或转移。因此，迫切需要医疗社区为这种致命疾病开发更有效的治疗方案。在这个项目中，我们将研究一个新的实验化合物，命名为LG 007，其抗癌活性， TNBC。重要的是，我们将利用稳健的TNBC患者来源的异种移植物（PDX）小鼠模型来研究TNBC患者来源的异种移植物（PDX）。 LG 007的体内功效。我们的初步结果表明，LG 007有效地抑制TNBC肿瘤，生长和转移。值得注意的是，我们发现LG 007治疗可以显著缩小大的人源性 TNBC PDX肿瘤，几乎完全缓解。这些初步结果有力地支持了这样一个前提， LG 007是一种新型的有效候选药物，能够治疗进行性TNBC和相关转移。此外，我们证明了LG 007能够靶向和调节miR-10 b，一种众所周知的致癌基因。促进肿瘤发展和转移的miRNA。因此，我们假设miR-10 b是一种主要的 LG 007的一个靶点，它与LG 007抑制肿瘤的分子作用机制密切相关生长和转移。为了实现该项目的目标，提出了三个具体目标，用于治疗TNBC的疗法。在目标1中，我们将确定miR-10 b及其一种作用机制。在LG 007的抗TNBC活性中靶向NR 4A 3。在目标2中，我们将研究LG 007的体内功效利用模拟TNBC的临床环境及其相关的小鼠模型，复发和转移。在目标3中，我们将表征以下物质的药理学和毒理学性质： LG 007，为将来转化为临床试验做准备。我们希望从这项研究中获得的结果这将为晚期TNBC患者开发一种新型，安全，有效的治疗方法。