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

项目总结： 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 对死亡的恐惧。在这项应用中，我们关注一种特殊的乳腺癌亚型，称为三阴性乳癌。 癌症(TNBC)。与其他乳腺癌亚型相比，TNBC被认为更具侵袭性和极端 很难用标准疗法来治疗。因此，它具有很高的复发率和较高的总体死亡率。 TNBC占所有乳腺癌的20%，在少数民族人群中发病率较高， 年轻女性(通常为40岁)。大约70%的晚期TNBC患者死于疾病 初诊后5年内复发和/或转移。因此，迫切需要医疗保健服务 社区为这一致命疾病开发更有效的治疗方案。 在这个项目中，我们将研究一种新的实验化合物，命名为LG007，用于研究其在 TNBC。有意义的是，我们将利用强大的TNBC患者衍生的异种移植(PDX)小鼠模型来研究 LG007的体内疗效。我们的初步结果表明，LG007有效地抑制了TNBC肿瘤 生长和转移。值得注意的是，我们发现LG007治疗可以强劲地缩小巨大的人类来源 TNBC PDX肿瘤，反应接近完全。这些初步结果有力地支持了这样一个前提： LG007是一种新的、有效的候选药物，能够治疗进展性TNBC及其相关转移。 此外，我们还证明了LG007能够靶向和调控众所周知的致癌基因miR-10b 促进肿瘤发展和转移的miRNA。因此，我们假设miR-10b是主要的 LG007的靶点，与LG007抑制肿瘤的分子作用机制密切相关 生长和转移。为实现该项目的目标，提出了三个具体目标，即开发新的 治疗TNBC的方法。在目标1中，我们将确定miR-10b及其一个 靶点NR4A3，在LG007的抗肿瘤活性中。在目标2中，我们将研究LG007的体内疗效 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，我们将表征其药理和毒理学特性。 LG007，为将来的临床测试做准备。我们预计从这项研究中获得的结果 将为晚期TNBC患者开发一种新的、安全和有效的治疗方法。

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.