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) 相关死亡是侵袭性进展和侵袭性进展的直接结果估计 50 -80% 发生在其他器官，如脑、骨骼、肺或其他器官中。侵袭性BC患者会发生转移，导致5年生存率从99%急剧下降局部 BC 患者中 27% 是远处转移患者唯一可用的靶向治疗。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 (AI)，仅对大约一半 ER 阳性 BC 患者有效，目前没有其他可用的药物。针对无反应/耐药 ER 阳性 BC 和所有 ER 阴性 BC 的靶向治疗这些事实表明了这一点。迫切需要确定非基于 ER 的分子靶点并开发靶向疗法来阻断 BC 各种亚型的 BC 细胞向转移性疾病的进展 BC 细胞具有异常的糖酵解和异常的糖酵解。增殖的 BC 细胞依赖于糖酵解失调，因此对糖酵解的抑制敏感。阴性 BC (TNBC) 是 BC 中最具侵袭性和高度转移性的亚型，被发现增加葡萄糖摄取，从而支持葡萄糖代谢紊乱与 TNBC 相关的观点因此，针对异常葡萄糖代谢的药物的开发可能提供替代方案。以及治疗转移性 BC (MBC) 的潜在更有效方法为了满足这一迫切需求，我们。最近开发了 HJC0152 作为治疗 MBC 的假定葡萄糖代谢调节剂和分子阐明驱动 BC 转移进展的转移决定因素和相关机制的工具。初步研究发现HJC0152可抑制癌症进展、抑制癌细胞运动、阻断肺我们的中心假设是 HJC0152 靶向关键。代谢酶调节葡萄糖代谢并抑制 BC 细胞运动和 BC 转移在目标 1 中，我们将评估 HJC0152 在回归方面的功效。 MBC的生长，阻断MBC的肺转移发展，并延长MBC的寿命 - 在目标 2 中，我们将评估 HJC0152 靶向的转移决定蛋白并进行优化。 HJC0152 增强了整体药物开发概况在初步研究中，我们已经确定了高 - 在目标 3 中，我们将定义和验证包括可能与 HJC0152 直接相互作用的 ARG 的置信度目标。介导 HJC0152 抗转移作用的关键转移决定蛋白的最终目标是开发一种创新的、非基于 ER 的疗法来抑制现有转移并减少/阻止新的转移预计该项目完成后，将显着改善 MBC 患者的预后。 HJC0152的抗转移和延长生命功效将被确定，高可信度目标将在 MBC 中进行鉴定和验证，从而使 HJC0152 做好进入研究阶段的准备新药 (IND) 注册，用于治疗 MBC 的进一步临床前和临床开发。