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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：
10889411
负责人：
Yaguang Xi
金额：
$ 38.4万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10889411
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 Invaded 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 Predisposition Preparation Progesterone Receptors Prognosis Property Recurrence Recurrent disease Research Role Safety Sampling Specificity Sulindac Testing Therapeutic Agents Tissue Microarray Toxic effect Toxicology Translating Translations Treatment Efficacy Tumor Promotion United States Woman Work anticancer activity 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 gain of function health disparity in vitro activity in vivo interest loss of function malignant breast neoplasm mortality mouse model novel novel therapeutics patient derived xenograft model pharmacologic 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，也是第二大原因死亡。在此应用中，我们重点关注一种称为三阴性乳腺癌的特定乳腺癌亚型癌症（TNBC）。与其他乳腺癌亚型相比，TNBC 被认为更具侵袭性且极端用标准疗法很难治疗。因此，其复发率高，总体死亡率高。 TNBC 占所有乳腺癌的 20%，在少数族裔人群中发病率较高，年轻女性（通常<40岁）。大约 70% 的晚期 TNBC 患者死于疾病初次诊断后 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，我们将研究一种名为 LG007 的新型实验化合物，因为它具有抗癌活性。 TNBC。重要的是，我们将利用稳健的 TNBC 患者衍生异种移植 (PDX) 小鼠模型来研究 LG007的体内功效。我们的初步结果表明LG007有效抑制TNBC肿瘤生长和转移。值得注意的是，我们发现 LG007 治疗可以显着缩小大型人类来源的细胞。 TNBC PDX 肿瘤，几乎完全缓解。这些初步结果有力地支持了以下前提： LG007 是一种新型有效的候选药物，能够治疗进行性 TNBC 和相关转移。此外，我们证明 LG007 能够靶向和调节 miR-10b（一种众所周知的致癌基因）促进肿瘤发生和转移的miRNA。因此，我们假设 miR-10b 是主要的 LG007 的靶标，关键参与 LG007 抑制肿瘤的分子作用机制生长和转移。为了实现该项目开发新的目标，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-10b 的机制作用及其之一 LG007 的抗 TNBC 活性中的靶标 NR4A3。在目标2中，我们将研究LG007的体内功效利用各种先进的小鼠模型来模拟 TNBC 及其相关的临床环境复发和转移。在目标 3 中，我们将表征其药理学和毒理学特性 LG007 正在为未来转化为临床测试做准备。我们期望从这项研究中获得的结果将为晚期 TNBC 患者开发一种新颖、安全、有效的治疗方法。