Targeting Glucose Metabolism with HJC0152 for Treating Metastatic Breast Cancer

HJC0152 靶向葡萄糖代谢治疗转移性乳腺癌

基本信息

批准号：
10239029
负责人：
Qiang Shen
金额：
$ 42.42万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10239029
关键词：
Address Affinity Animal Model Animals Apoptosis Aromatase Inhibitors Automobile Driving Binding Biotin Brain Breast Cancer Cell Breast Cancer Patient Breast cancer metastasis Cells Cessation of life Clinical Complex Crystallography Development Disease Distant Metastasis Drug Targeting Energy Metabolism Enzymes Estrogen Antagonists Estrogen Receptors Estrogen receptor negative Estrogen receptor positive FDA approved Fluorescein Foundations Glycolysis Glycolysis Inhibition Goals Growth Head and Neck Squamous Cell Carcinoma Human In Vitro Investigational Drugs Life Link Liver Longevity Lung Malignant Epithelial Cell Malignant Neoplasms Mammary Neoplasms Mammary gland Mediating Metabolism Metastatic Neoplasm to the Lung Metastatic breast cancer Metastatic to Modeling Molecular Molecular Probes Molecular Target Mus Neoplasm Metastasis Normal Cell Oncogenic Oral Organ Oxygen Pathway interactions Patients Pharmaceutical Preparations Prognosis Proliferating Proteins Resistance Role Selective Estrogen Receptor Modulators Specificity Survival Rate Time Toxic effect Treatment Efficacy Work aggressive breast cancer analog base bone cancer cell cancer therapy carcinogenesis cell motility clinical development clinically relevant drug development effective therapy glucose metabolism glucose uptake improved in vivo innovation malignant breast neoplasm mortality mouse model novel preclinical development response targeted agent targeted treatment tool triple-negative invasive breast carcinoma tumor tumor progression tumor xenograft

项目摘要

The majority of breast cancer (BC)-associated deaths are a direct result of invasive progression and metastasis developed in other organs such as the brain, bones, lungs, or other organs. An estimated 50 -80% of invasive BC patients will develop metastasis, resulting in a sharp decrease of 5 -year survival rate from 99% in patients with localized BCs to 27% in patients with distant metastasis. The only available targeted therapies for metastatic BCs (MBCs) are Selective Estrogen Receptor (ER) Modulators (SERMs) and Aromatase Inhibitors (AIs), which are only effective in about half of ER-positive BC patients. There are currently no other available targeted therapies for nonresponsive/resistant ER-positive BCs and all ER-negative BCs. These facts manifest the urgent need for identifying non–ER-based molecular targets and developing targeted therapies to block the progression of various subtypes of BCs to metastatic diseases. BC cells have abnormal glycolysis and the proliferating BC cells rely on dysregulated glycolysis, therefore sensitive to inhibition of glycolysis. Triple- negative BC (TNBC), the most aggressive and highly metastatic subtype of BC, was found to have increased glucose uptake, thus supporting the notion that disturbance in glucose metabolism is linked to TNBC carcinogenesis. Therefore, development of agents targeting aberrant glucose metabolism may offer alternative and potentially more effective approach for treating metastatic BC (MBC). To address this pressing need, we recently developed HJC0152 as a putative glucose metabolism modulator for treating MBCs and as molecular tool to elucidate the metastasis determinants and associated mechanisms that drive BC metastatic progression. In preliminary studies, HJC0152 was found to suppress cancer progression, inhibit cancer cell motility, block lung metastasis development, and inhibit tumor local invasion. Our central hypothesis is that HJC0152 targets key metabolism enzyme(s) to modulate glucose metabolism and suppress BC cell motility and BC metastatic progression. Three specific aims are proposed. In Aim 1, we will assess HJC0152’s efficacy in regressing the growth of MBCs, blocking lung metastasis development from MBCs, and prolonging the lifespan of MBC - bearing animals in vivo. In Aim 2, we will assess HJC0152-targeted metastasis determinant proteins and optimize HJC0152 to enhance the overall drug development profiles. In preliminary studies, we have identified high - confidence targets including ARG that may directly interact with HJC0152. In Aim 3, we will define and validate key metastasis determinant proteins mediating the anti-metastatic effect of HJC0152. The ultimate goal is to develop an innovative, non–ER-based therapy to inhibit existing metastasis and reduce/block new metastasis to achieve significantly improved prognosis for patients with MBCs. At the completion of this project, it is expected that the anti-metastasis and life-prolonging efficacy of HJC0152 will be determined and high-confidence target will be identified and validated in MBCs, thereby making HJC0152 ready to be advanced into Investigational New Drug (IND) registration for further preclinical and clinical development for treating MBCs.

大多数乳腺癌（BC）相关的死亡是侵入性进展和转移在其他器官，例如大脑，骨骼，肺或其他器官中发展。估计有50-80％侵入性BC患者将发展转移，导致5年生存率从99％降低远处转移患者的BCS局部局部为27％。唯一可用的目标疗法转移性BC（MBC）是选择性雌激素受体（ER）调节剂（SERM）和芳香酶抑制剂（AIS），仅在大约一半的ER阳性BC患者中有效。目前没有其他可用无反应/抗性ER阳性BC和所有ER阴性BC的靶向疗法。这些事实表明了迫切需要鉴定非基于基于非ER的分子靶标并开发靶向疗法以阻止 BC的各种亚型向转移性疾病的进展。 BC细胞具有异常的糖酵解和增殖的BC细胞依赖于失调的糖酵解，因此对糖酵解的抑制敏感。三倍- BC负BC（TNBC）是BC的最具侵略性和高度转移性亚型葡萄糖吸收，因此支持葡萄糖代谢中灾难与TNBC有关的观念致癌作用。因此，针对异常葡萄糖代谢的代理的发展可能会提供替代并可能更有效地治疗转移性BC（MBC）。为了满足这种紧迫的需求，我们最近开发了HJC0152作为推定的葡萄糖代谢调节剂，用于治疗MBC和分子阐明转移的工具决定了驱动BC转移进展的相关机制。在初步研究，HJC0152被发现抑制癌症的进展，抑制癌细胞运动，阻断肺转移发展并抑制肿瘤局部侵袭。我们的中心假设是HJC0152针对关键代谢酶（S）调节葡萄糖代谢并抑制BC细胞运动和BC转移性进展。提出了三个具体目标。在AIM 1中，我们将评估HJC0152在回归方面的效率 MBC的生长，阻断MBC的肺转移发展，并延长MBC的寿命在体内轴承动物。在AIM 2中，我们将评估HJC0152靶向转移蛋白蛋白并进行优化 HJC0152增强了整体药物发育概况。在初步研究中，我们已经确定了很高的 - 置信度目标包括可能直接与HJC0152相互作用的ARG。在AIM 3中，我们将定义和验证关键转移确定蛋白介导HJC0152的抗转移性作用。最终目标是开发一种创新的，非ER的疗法，以抑制现有转移并减少/阻止新的转移到对于MBC患者，可显着改善预后。该项目完成后，预计将确定HJC0152的抗阵营和寿命效率将在MBC中识别和验证，从而使HJC0152随时准备好进行研究用于进一步治疗MBC的临床前和临床发育的新药（IND）注册。