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

• 批准号: 10402887
• 负责人: Qiang Shen
• 金额: $ 53.5万
• 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: 2018-04-20 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10402887
• 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 Prevention; Breast Cancer Prevention Trial; Breast Cancer survivor; Breast Carcinogenesis; Cell Line; Cell Proliferation; Cells; Chemoprevention; Chemopreventive Agent; Chronic; Clinical; Complex; Contralateral Breast; Crystallography; Development; Dose; ERBB2 gene; Energy Metabolism; Enzymes; Estrogen Antagonists; Estrogen Receptors; 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; Modeling; 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; Research; Resistance; Risk; Role; STAT3 gene; Selective Estrogen Receptor Modulators; Signal Transduction; Simian virus 40; Solid; Specificity; Structure; Survivors; Technology; Testing; Toxic effect; Transgenic Mice; Validation; Woman; Work; absorption; analog; arginase; base; cancer care; cancer subtypes; cancer therapy; carcinogenesis; clinical development; clinically relevant; drug candidate; 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

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.

摘要 HJC0152靶向葡萄糖代谢预防乳腺癌的研究 大约60%-70%的乳腺癌是雌激素受体(ER)阳性的乳腺癌(EPBC)，而 其余30-40%为ER阴性的BCS(ENBC)。目前可用的基于ER的化学预防药物 选择性雌激素受体调节剂和芳香酶抑制剂等治疗方法只能有效地预防大约 一半的EPBC和不预防任何ENBC，这意味着几乎60%的BBC无法通过 现有的以抗ER为主的预防制剂。特别是，大多数ENBC是三重负的BCS (TNBCs)，比其他BC亚型生长更快，传播更早，复发更频繁，并且 在年轻的非洲裔美国人和西班牙裔/拉丁裔妇女和患有 BRCA1突变。BC幸存者，特别是ENBC和TNBC幸存者面临可预见的增加的风险 在乳房中形成新的BC。因此，在那些健康的妇女和BC幸存者中预防BC 这是一个巨大、紧迫但未得到满足的需求，因为目前可用的预防性药物是以抗ER为基础的， 对于保护女性免受该病的侵袭是无效的。这些妇女或不列颠哥伦比亚省的幸存者可能从 有效的、不含ER的预防性药物。拟议的研究将直接解决这一总体问题。 通过定义新的干预点和开发有效的药物来预防所有BC亚型，以应对挑战。 我们最近发现了一种小分子HJC0152，它可以调节葡萄糖代谢，并有效地 阻断人ENBC转基因小鼠模型的癌前病变和ENBC/TNBC的形成。我们 假设有效地调节、重新编程和恢复失调的葡萄糖代谢 HJC0152将逆转癌前病变并阻止BC的发展。我们将通过3个步骤来检验这一假设 明确的目标。在目标1中，我们将确定HJC0152在ENBC和TNBC模型中的预防效果。 各种临床相关的预防环境。临床前评估和安全性分析也将 已执行。在目标2中，我们将确定HJC0152的物理相互作用目标，这些目标对于 ENBC/TNBC通过多种途径发展，包括诱饵-分子亲和结合捕获 HJC0152的潜在目标。在初步研究中，我们已经确定了HJC0152的真正靶标名单 以作进一步调查。在目标3中，我们将描述和验证排名靠前的高置信度目标 HJC0152，精氨酸酶，通过进行亲和结合测定，配体-靶相互作用的共络合物，获得- /功能丧失评估，以及在乳腺细胞和肿瘤中的表达确定实验。这些 研究将阐明BC发展的驱动因素，并为进一步的临床前和 HJC0152作为非ER预防候选药物的临床研究进展考虑到演示的 HJC0152的预防效果，低毒概况，高置信度HJC0152靶点的识别和 正在进行的验证，以及口服HJC0152的便利性，该项目的结果将 有很高的翻译潜力来促进BC的化学预防新战略，特别是ENBC/TNBC。