Chemoprevention of Breast Cancer by Targeting Glucose Metabolism with HJC0152

总结 HJC 0152靶向糖代谢对乳腺癌的化学预防作用 约60-70%的乳腺癌（BC）是雌激素受体（ER）阳性BC（EPBC），并且乳腺癌患者中的大多数是女性。 其余30-40%是ER阴性BC（ENBC）。目前可用的基于抗ER的化学预防 治疗，如选择性ER调节剂和芳香酶抑制剂，仅有效预防约 EPBC的一半，不能预防任何ENBC，这意味着几乎60%的BC不能预防， 现有的基于抗ER的预防剂。特别是，大多数ENBC是三阴性BC （TNBC），其生长更快，传播更早，并且比其他BC亚型更经常复发， TNBC的发病率在年轻的非洲裔美国人和西班牙裔/拉丁裔妇女和患有 BRCA 1突变。BC幸存者，特别是ENBC和TNBC幸存者， 在乳房中形成新的BC。因此，在那些“健康”妇女和BC幸存者中预防BC 代表了巨大的、紧迫的但未满足的需求，因为目前可用的预防剂是基于抗ER的，并且 不能有效保护妇女免受BC的侵害。这些女性或BC幸存者可能会从以下方面受益最多： 有效的，非ER为基础的预防药物。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，这是一项挑战。 我们最近发现了一种小分子HJC 0152，它可以调节葡萄糖代谢， 阻断人ENBC转基因小鼠模型中的癌前病变和ENBC/TNBC形成。我们 假设葡萄糖代谢失调有效调节、重编程和恢复， HJC 0152将逆转癌前病变并阻断BC发展。我们将通过3来验证这个假设。 具体目标。在目标1中，我们将确定HJC 0152在ENBC和TNBC模型中的预防功效， 各种临床相关的预防设置。还将进行临床前评估和安全性分析， 执行。在目标2中，我们将确定HJC 0152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以捕获 HJC 0152的潜在目标。在初步研究中，我们已经确定了HJC 0152的真实目标列表 以作进一步调查。在目标3中，我们将描述和验证排名第一的高置信度目标， HJC 0152，酶，通过进行亲和结合测定，配体-靶标相互作用的共复合物，获得- /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BC开发的驱动因素，并为进一步的临床前和 HJC 0152作为一种非ER预防性候选药物的临床开发。鉴于所展示的 HJC 0152的预防功效、低毒性特征、高置信度HJC 0152靶点的鉴定以及 正在进行的验证，以及HJC 0152口服给药的便利性，该项目的结果将 具有很高的转化潜力，以促进BC，特别是ENBC/TNBC的化学预防新策略。

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.