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

• 批准号: 10017168
• 负责人: Qiang Shen
• 金额: --
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 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/10017168
• 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; Proliferating; Proteins; Resistance; Role; Selective Estrogen Receptor Modulators; Specificity; Survival Rate; Time; Toxic effect; Treatment Efficacy; Work; 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; outcome forecast; preclinical development; response; targeted agent; targeted treatment; tool; triple-negative invasive breast carcinoma; tumor; tumor progression; tumor xenograft

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）相关死亡是浸润性进展的直接结果， 在其他器官如脑、骨、肺或其他器官中发生转移。据估计， 侵袭性BC患者会发生转移，导致5年生存率从99%急剧下降， 在远处转移患者中，局限性BCs的患者为27%。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）和芳香化酶抑制剂 (AIs)，仅对约一半的ER阳性BC患者有效。目前没有其他可用的 无应答/耐药ER阳性BC和所有ER阴性BC的靶向治疗。这些事实表明， 迫切需要确定非ER为基础的分子靶点，并开发靶向治疗，以阻止 BC的各种亚型进展为转移性疾病。BC细胞有异常的糖酵解， 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。三重- 阴性BC（TNBC），最具侵袭性和高转移性的BC亚型，被发现增加了 葡萄糖摄取，从而支持葡萄糖代谢紊乱与TNBC相关的观点 致癌作用因此，开发针对异常葡萄糖代谢的药物可能提供替代治疗方案。 并且是治疗转移性BC（MBC）的潜在更有效的方法。为了满足这一迫切需求，我们 最近开发的HJC 0152作为推定的葡萄糖代谢调节剂用于治疗MBC，并且作为分子生物学调节剂用于治疗MBC。 工具来阐明转移决定因素和相关机制，推动BC转移进展。在 初步研究发现，HJC 0152可抑制癌症进展，抑制癌细胞运动，阻断肺 转移发展，抑制肿瘤局部侵袭。我们的中心假设是HJC 0152靶向关键的 代谢酶来调节葡萄糖代谢并抑制BC细胞运动性和BC转移 进展提出了三个具体目标。在目标1中，我们将评估HJC 0152在回归 抑制MBC的生长，阻断MBC的肺转移发展，并延长MBC的寿命- 在活体内繁殖动物。在目标2中，我们将评估HJC 0152靶向的转移决定因子蛋白，并优化 HJC 0152，以增强整体药物开发概况。在初步研究中，我们发现高- 置信度目标包括可能与HJC 0152直接交互的ARG。在目标3中，我们将定义和验证 介导HJC 0152抗转移作用的关键转移决定蛋白。最终目标是 开发一种创新的，非ER为基础的治疗，以抑制现有的转移和减少/阻断新的转移， 显著改善MBC患者的预后。在该项目完成后，预计 HJC 0152的抗转移和延长生命的疗效将被确定， 将在MBC中进行识别和验证，从而使HJC 0152准备进入研究阶段 新药（IND）注册，用于治疗MBC的进一步临床前和临床开发。