Investigating Rational Combination Therapies for Triple-Negative Breast Cancer

研究三阴性乳腺癌的合理联合疗法

• 批准号: 10367060
• 负责人: Dai Horiuchi
• 金额: $ 34.35万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367060
• 关键词: Acute; Address; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Cell Death; Cell Survival; Cells; Chemotherapy and/or radiation; Clinical; Clinical Investigator; Collaborations; Collection; Combined Modality Therapy; Disease; Disease Progression; Drug Combinations; Drug Screening; Drug Synergism; Epidermal Growth Factor Receptor; Estrogen Receptors; Excision; Experimental Models; FDA approved; Family; Goals; Growth; Human; Impairment; In Vitro; Life; Liquid substance; Malignant Neoplasms; Mammary Neoplasms; Multiple Myeloma; Oncogenic; Oncoproteins; Operative Surgical Procedures; Outcome; Outcomes Research; Oxidative Stress; PIM1 gene; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Phosphotransferases; Pre-Clinical Model; Progesterone Receptors; Proteasome Inhibition; Proteasome Inhibitor; Protein Isoforms; Proteins; Reactive Oxygen Species; Recurrence; Reporting; Research; Resistance; Sampling; Savings; Solid; Solid Neoplasm; Stress; Testing; Translating; Up-Regulation; Validation; Xenograft Model; antitumor effect; base; biological adaptation to stress; cancer stem cell; cancer subtypes; cancer type; clinical development; clinically relevant; cytotoxicity; drug testing; druggable target; early experience; efficacy evaluation; efficacy study; human model; in vivo; inhibitor; kinase inhibitor; malignant breast neoplasm; misfolded protein; molecular targeted therapies; mortality; mouse model; multicatalytic endopeptidase complex; neoplastic cell; novel; overexpression; oxidative damage; pre-clinical; proteotoxicity; proto-oncogene protein pim; rational design; receptor; research clinical testing; resistance mechanism; screening; small molecule inhibitor; standard of care; stem-like cell; targeted treatment; therapy resistant; tool; transcription factor; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor xenograft

PROJECT SUMMARY/ABSTRACT Triple-negative breast cancer (TNBC) refers to a collection of heterogeneous breast tumors that lack expression of immediately druggable molecules, such as the estrogen and progesterone receptors and human epidermal growth factor receptor 2. No targeted therapy is currently approved for the vast majority of TNBC patients. TNBC patients who have received the current standard of care, consisting of chemotherapy, radiation, and surgery, often experience early tumor recurrence and a significantly worse mortality rate. Therefore, it is critical to identify and validate clinically viable, life-saving targeted therapies for patients with TNBC. We previously reported that the oncogenic MYC pathways were activated in ~50% of TNBC cases compared with non-TNBC cases and that MYC levels were associated with poor outcomes among TNBC patients. Unfortunately, clinical development of inhibitors that directly target MYC activity has remained challenging. To overcome this challenge, we previously took an alternative approach known as the synthetic lethal screening approach to identify readily druggable targets required for MYC-driven tumor viability but that are not essential in non-tumor cells. Our screen identified the PIM family of kinases, which is composed of the closely related nonessential kinase isoforms PIM1, -2, and -3 (PIM hereafter), as a promising target in MYC-driven TNBC. We found that PIM expression was elevated in triple-negative (TN) tumors in clinical samples and was associated with poor patient outcomes. Clinically relevant pan-PIM inhibitors showed activity in various experimental models of TNBC. However, our single-agent efficacy studies using preclinical PIM inhibitors showed that although PIM inhibition significantly slowed the growth of TN tumors, it induced only modest in vivo tumor cell death and regression, suggesting the need for combination therapies. We have taken robust drug screening approaches and have unexpectedly found that the drug combination that targets PIM kinases and the proteasome can acutely induce toxic levels of proteotoxic stress selectively in MYC-overexpressing TNBC cells. Mechanistically, our preliminary observations indicate that PIM inhibition, which elevates the levels of reactive oxygen species, when combined with proteasome inhibition, overwhelms the capacity of TNBC cells to continuously degrade damaged proteins, resulting in proteotoxic crisis. Thus, our observations raise the possibility—and our study will test the hypothesis—that PIM inhibition represents a unique and clinically viable tool to sensitize TNBC tumors to proteasome inhibition. The successful execution of this research will allow for the identification and interrogation of clinically exploitable vulnerabilities in MYC-driven solid-cancer types such as TNBC. The outcomes of this research could also encourage the FDA- approved proteasome inhibitors (e.g., carfilzomib), which have not been successfully used outside of liquid tumor types, to be rapidly evaluated in combination with pan-PIM kinase inhibitors in early-stage MYC-driven solid- tumor trials.

项目概要/摘要 三阴性乳腺癌（TNBC）是指缺乏表达的异质乳腺肿瘤的集合 立即可成药的分子，例如雌激素和孕激素受体以及人类表皮 生长因子受体2。目前还没有批准针对绝大多数TNBC患者的靶向治疗。三全国广播公司 接受当前标准护理（包括化疗、放疗和手术）的患者， 经常经历早期肿瘤复发和显着更差的死亡率。因此，识别至关重要 并验证针对 TNBC 患者的临床可行、挽救生命的靶向治疗。我们之前报道过 与非 TNBC 病例相比，大约 50% 的 TNBC 病例中致癌 MYC 通路被激活 MYC 水平与 TNBC 患者的不良预后相关。不幸的是，临床发展 直接靶向 MYC 活性的抑制剂仍然具有挑战性。为了克服这一挑战，我们之前 采用了一种称为合成致死筛选方法的替代方法来识别易于药物化的方法 MYC 驱动的肿瘤活力所需的靶标，但对于非肿瘤细胞来说并不是必需的。我们的屏幕已识别 PIM 激酶家族，由密切相关的非必需激酶亚型 PIM1、-2 和 -3（以下简称 PIM），作为 MYC 驱动的 TNBC 中一个有前途的目标。我们发现 PIM 表达升高 临床样本中存在三阴性（TN）肿瘤，并与患者预后不良相关。临床相关 pan-PIM 抑制剂在 TNBC 的各种实验模型中显示出活性。然而，我们的单药疗效 使用临床前 PIM 抑制剂的研究表明，尽管 PIM 抑制显着减缓了 TN 的生长 肿瘤，它仅诱导适度的体内肿瘤细胞死亡和消退，表明需要联合使用 疗法。我们采取了强有力的药物筛选方法，并意外地发现该药物 针对 PIM 激酶和蛋白酶体的组合可以急性诱导毒性水平的蛋白毒性应激 选择性地作用于 MYC 过表达的 TNBC 细胞。从机制上讲，我们的初步观察表明 PIM 当与蛋白酶体抑制相结合时，抑制作用会提高活性氧的水平， 压倒了 TNBC 细胞持续降解受损蛋白质的能力，导致蛋白毒性危机。 因此，我们的观察提出了一种可能性——并且我们的研究将检验这一假设——PIM 抑制 代表了一种独特且临床上可行的工具，可以使 TNBC 肿瘤对蛋白酶体抑制敏感。成功者 这项研究的执行将允许识别和询问临床可利用的漏洞 MYC 驱动的实体癌类型，如 TNBC。这项研究的结果也可能鼓励 FDA—— 已批准的蛋白酶体抑制剂（例如卡非佐米），但尚未成功用于液体肿瘤之外 类型，与早期 MYC 驱动的固体-泛 PIM 激酶抑制剂联合进行快速评估 肿瘤试验。