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: 10239256
• 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: 2018-04-20 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10239256
• 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; Hispanics; 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; 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.

概括 HJC0152 通过靶向葡萄糖代谢来化学预防乳腺癌 大约 60-70% 的乳腺癌 (BC) 是雌激素受体 (ER) 阳性 BC (EPBC)， 其余 30-40% 是 ER 阴性 BC（ENBC）。目前可用的基于抗 ER 的化学预防 选择性 ER 调节剂和芳香酶抑制剂等疗法只能有效预防约 一半的 EPBC 并且不能预防任何 ENBC，这意味着几乎 60% 的 BC 无法通过以下方法预防 现有的基于抗ER的预防剂。特别是，大多数 ENBC 都是三阴性 BC (TNBC)，与其他 BC 亚型相比，其生长更快、传播更早、复发更频繁，并且 年轻的非裔美国人和西班牙裔/拉丁裔女性以及患有以下疾病的女性中 TNBC 的发病率较高 BRCA1 突变。 BC 幸存者，特别是 ENBC 和 TNBC 幸存者，可预见的罹患癌症的风险会增加 乳房中形成新的 BC。因此，预防那些“健康”女性和 BC 幸存者的 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药物都是基于抗 ER 的，并且 无法有效保护女性免于罹患 BC。那些女性或 BC 幸存者可能会从中受益最多 有效的、非基于 ER 的预防药物。拟议的研究将直接解决这一总体问题 通过确定新的干预点和开发有效的药物来预防所有 BC 亚型来应对挑战。 我们最近发现了一种小分子HJC0152，它可以调节糖代谢，有效地调节糖代谢。 在人类 ENBC 转基因小鼠模型中阻断癌前病变和 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 将逆转癌前变化并阻止 BC 发展。我们将通过 3 来检验这个假设 具体目标。在目标 1 中，我们将确定 HJC0152 在 ENBC 和 TNBC 模型中的预防功效 各种临床相关的预防设置。临床前评估和安全性分析也将 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 通过多种方法开发 ENBC/TNBC，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 的真实目标清单 以便进一步调查。在目标 3 中，我们将描述并验证排名最高的高置信度目标 HJC0152，精氨酸酶，通过进行亲和力结合测定，配体-靶标相互作用的复合物，获得- /乳腺细胞和肿瘤的功能丧失评估和表达测定实验。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 作为非基于 ER 的预防性候选药物的临床开发。鉴于所证明的 HJC0152的预防功效、低毒性特征、高置信度HJC0152靶标的识别和 持续的验证以及 HJC0152 口服给药的便利性，该项目的成果将 具有很高的转化潜力，可促进 BC 化学预防新策略，特别是 ENBC/TNBC。