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: 10703216
• 负责人: Qiang Shen
• 金额: $ 24.06万
• 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/10703216
• 关键词: Address; Affinity; Animal Experiments; Animal Model; Animals; 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; Induction of Apoptosis; Invaded; 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; 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; Toxic effect; Treatment Efficacy; Work; aggressive breast cancer; analog; 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; patient prognosis; 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.

大多数与乳腺癌(BC)相关的死亡是浸润性进展和 转移瘤发生在其他器官，如脑、骨、肺或其他器官。估计有50%-80%的 侵袭性BC患者将发生转移，导致5年生存率从99%急剧下降。 局限于BCS的患者中27%为远处转移的患者。唯一可用的靶向治疗 转移性BCS(MBCs)是选择性雌激素受体(ER)调节剂(SERM)和芳香酶抑制剂 (AIS)，只对大约一半ER阳性的BC患者有效。目前没有其他可用的 对无反应/耐药的ER阳性BC和所有ER阴性BC的靶向治疗。这些事实证明了 迫切需要确定非内质网分子靶点并开发靶向疗法来阻断 BCS各亚型向转移性疾病的进展。BC细胞糖酵解异常， 增殖的BC细胞依赖于失调的糖酵解，因此对糖酵解的抑制很敏感。三重- 最具侵袭性和高转移性的BC亚型--阴性BC(TNBC)被发现增加 葡萄糖摄取，从而支持了糖代谢障碍与TNBC有关的观点 致癌。因此，针对糖代谢异常的药物的开发可能提供替代方案。 可能是治疗转移性BC(MBC)的更有效的方法。为了解决这一迫切需要，我们 新近开发的HJC0152作为一种可能的糖代谢调节剂用于治疗MBCs和AS分子 工具，阐明转移决定因素和相关的机制，推动乳腺癌转移进展。在……里面 初步研究发现，HJC0152可抑制癌症进展，抑制癌细胞运动，阻断肺 发展转移，抑制肿瘤局部侵袭。我们的中心假设是HJC0152以关键字为目标 代谢酶(S)调节糖代谢，抑制BC细胞运动和BC转移 进步。提出了三个具体目标。在目标1中，我们将评估HJC0152的S对退行性脑损伤的疗效。 MBC的生长，阻断MBC的肺转移发展，延长MBC的寿命 在活体内生育动物。在目标2中，我们将评估HJC0152靶向转移决定蛋白并优化 HJC0152，以提升整体药物开发概况。在初步研究中，我们已经确定了高- 信心目标，包括可能直接与HJC0152相互作用的ARG。在目标3中，我们将定义和验证 HJC0152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为基础的疗法，以抑制现有的转移并减少/阻止新的转移 可显著改善多发性骨髓细胞癌患者的预后。在这个项目完成后，预计 HJC0152的抗转移和延长生命的功效将被确定和高可信的靶点 将在MBCS中进行识别和验证，从而使HJC0152准备进入调查阶段 新药(IND)注册，以进一步开发治疗多发性骨髓瘤的临床前和临床应用。

项目成果

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• DOI: 10.1016/j.ejmech.2022.114229
• 发表时间: 2022-04-15
• 期刊: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 6.7
• 作者: Xu, Jimin;Kim, Hyejin;Dong, Jiabin;Chen, Haiying;Xu, Junhai;Ma, Ruixia;Zhou, Mingxiang;Wang, Tianzhi;Shen, Qiang;Zhou, Jia
• 通讯作者: Zhou, Jia

Oridonin and its derivatives for cancer treatment and overcoming therapeutic resistance.

• DOI: 10.1016/j.gendis.2020.06.010
• 发表时间: 2021-07
• 期刊: Genes & diseases
• 影响因子: 6.8
• 作者: Liu X;Xu J;Zhou J;Shen Q
• 通讯作者: Shen Q