Chemoprevention of Breast Cancer by Targeting Glucose Metabolism with HJC0152

HJC0152 通过靶向葡萄糖代谢来化学预防乳腺癌

基本信息

批准号：
10599984
负责人：
Qiang Shen
金额：
$ 32.96万
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：
2018-04-20 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599984
关键词：
Address Adult Affinity African American Age Animal Model Antineoplastic Agents Aromatase Inhibitors Automobile Driving BRCA1 Mutation BRCA1 gene Binding Biochemical Biological Availability Biotin Blood Breast Breast Cancer Cell Breast Cancer Model Breast Cancer Prevention Breast Cancer Prevention Trial Breast Cancer cell line Breast Cancer survivor Breast Carcinogenesis Cell Proliferation Cells Chemoprevention Chemopreventive Agent Chronic Clinical Complex Contralateral Breast Crystallography Development Dose ERBB2 gene Energy Metabolism Enzymes Estrogen Antagonists Estrogen Receptors Estrogen decline Estrogen receptor negative Estrogen receptor positive Excretory function Fluorescein Fostering Foundations Glucose Goals Hematology Hispanic Histologic Human Immune system In Vitro Incidence Intervention Investigation Investigational Drugs Ipsilateral Knowledge Latina Lesion Ligands Malignant - descriptor Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Mammary gland Metabolic Metabolism Molecular Probes Monitor Mouse Mammary Tumor Virus Mus Oral Oral Administration Organ Outcome Pathway interactions Pharmaceutical Preparations Pilot Projects Polymers Prevention Preventive Preventive therapy Preventive treatment Primary Prevention Production Receptor Signaling Recurrence Research Resistance Risk Role STAT3 gene Selective Estrogen Receptor Modulators Signal Transduction Simian virus 40 Solid Specificity Structure Technology Testing Toxic effect Transgenic Mice Validation Woman Work absorption analog arginase cancer care cancer subtypes cancer therapy carcinogenesis clinical development clinically relevant drug candidate efficacy evaluation energy balance experimental study glucose metabolism high risk population human model in vivo loss of function malignant breast neoplasm mouse model mutant novel pharmacokinetics and pharmacodynamics pre-clinical assessment preclinical development preclinical safety premalignant prevent restoration small molecule specific biomarkers tool translational potential triple-negative invasive breast carcinoma tumor

项目摘要

SUMMARY Chemoprevention of Breast Cancer by Targeting Glucose Metabolism with HJC0152 About 60-70% of breast cancers (BCs) are estrogen receptor (ER)-positive BCs (EPBCs), and the remaining 30-40% are ER-negative BCs (ENBCs). Currently available anti-ER-based chemopreventive therapies, such as selective ER modulators and aromatase inhibitors, are effective in preventing only about half of EPBCs and do not prevent any ENBCs, meaning that almost 60% of BCs cannot be prevented with existing anti-ER-based preventive agents. In particular, the majority of ENBCs are triple-negative BCs (TNBCs), which grow faster, spread earlier, and recur more often than other BC subtypes do, and the incidence of TNBC is higher among young African American and Hispanic/Latina women and women with BRCA1 mutations. BC survivors, particularly ENBC and TNBC survivors are at a predictable increased risk of developing a new BC in the breasts. Thus, the prevention of BC in those “healthy” women and BC survivors represents a huge, urgent but unmet need, since currently available preventive agents are anti-ER-based, and is ineffective to protect women from developing BC. Those women or BC survivors will likely benefit most from effective, non–ER-based preventive drugs. The proposed research will directly address this overarching challenge by defining new intervention points and developing effective agents for preventing all BC subtypes. We recently discovered a small molecule, HJC0152, which can modulate glucose metabolism and effectively block premalignant lesions and ENBC/TNBC formation in transgenic mouse models of human ENBC. We hypothesize that effective modulation, reprograming, and restoration of dysregulated glucose metabolism with HJC0152 will reverse precancerous changes and block BC development. We will test this hypothesis through 3 specific aims. In Aim 1, we will determine the preventive efficacy of HJC0152 in ENBC and TNBC models in various clinically relevant prevention settings. Preclinical assessments and safety profiling will also be performed. In Aim 2, we will identify the physically interacting targets of HJC0152 that are essential to ENBC/TNBC development through multiple approaches including bait-molecule affinity binding to capture potential targets of HJC0152. In preliminary studies, we have identified a list of bona fide targets for HJC0152 for further investigation. In Aim 3, we will characterize and validate the top-ranked high-confidence target of HJC0152, arginase, by performing affinity binding determination, co-complex of ligand-target interaction, gain- /loss-of-function assessments, and expression determination experiments in breast cells and tumors. These studies will elucidate the drivers of BC development and provide a solid foundation for further preclinical and clinical development of HJC0152 as a non-ER-based preventive drug candidate. Given the demonstrated preventive efficacy of HJC0152, low toxicity profiles, identification of high-confidence HJC0152 targets and ongoing validation, and the convenience of oral administration of HJC0152, outcomes from this project will have high translational potential to foster new strategies of chemoprevention for BC, particularly ENBC/TNBC.

概括通过用HJC0152靶向葡萄糖代谢，对乳腺癌进行化学预防约60-70％的乳腺癌（BC）是雌激素受体（ER）阳性BCS（EPBC），并且剩余的30-40％是ER阴性BCS（ENBC）。目前可用的基于反ER的化学预防疗法，例如选择性ER调节剂和芳香化酶抑制剂，可有效防止一半的EPBC，并且不能阻止任何ENBC，这意味着几乎60％的BC无法阻止现有的基于反ER的预防剂。特别是，大多数ENBC是三阴性BC （TNBC），比其他BC亚型更快地生长，更早地传播，并且复发的频率更高，并且在非裔美国人和西班牙裔/拉丁裔妇女和妇女中，TNBC的发病率更高 BRCA1突变。卑诗省的存活，尤其是ENBC和TNBC存活率，可预测的增加风险在乳房中开发新的卑诗省。这是在那些“健康”妇女和卑诗省幸存者中预防BC的代表了一个巨大，紧急但未满足的需求，因为当前可用的预防剂是基于反ER的，并且无效保护妇女免受卑诗省的发展。那些妇女或卑诗省幸存者可能会从中受益最大有效的，非ER的预防性药物。拟议的研究将直接解决这个总体通过定义新的干预点并开发有效的代理来防止所有BC亚型来挑战。我们最近发现了一个小分子HJC0152，该分子可以调节葡萄糖代谢并有效地调节人ENBC的转基因小鼠模型中的阻滞前病变和ENBC/TNBC形成。我们假设有效调节，重编程和恢复失调的葡萄糖代谢 HJC0152将逆转癌前的变化并阻止BC的发展。我们将通过3来检验这一假设具体目标。在AIM 1中，我们将确定HJC0152在ENBC和TNBC模型中的预防效率各种临床相关的预防环境。临床前评估和安全概况也将是执行。在AIM 2中，我们将确定HJC0152的物理相互作用目标，这对于 ENBC/TNBC通过多种方法开发包括诱饵 - 分子亲和力结合以捕获 HJC0152的潜在目标。在初步研究中，我们确定了HJC0152的真正目标列表进行进一步研究。在AIM 3中，我们将表征和验证最高的高信心目标 HJC0152，精氨酸酶，通过执行亲和力结合确定，配体 - 靶标相互作用的共复合，增益 - /功能丧失评估以及乳腺细胞和肿瘤中的表达测定实验。这些研究将阐明卑诗省开发的驱动力，并为进一步的临床前和 HJC0152作为非ER基于预防药物的临床发展。给定证明 HJC0152的预防效率，低毒性特征，高信心HJC0152目标和正在进行的验证以及HJC0152口服管理的便利性，该项目的结果将具有很高的翻译潜力，可以为BC（特别是ENBC/TNBC）培养新的化学预防策略。