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: 10543989
• 负责人: Dai Horiuchi
• 金额: $ 33.66万
• 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/10543989
• 关键词: Acute; Address; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Cell Death; Cell Survival; Cells; 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 Inhibition; Protein Isoforms; Proteins; Radiation; Reactive Oxygen Species; Recurrent tumor; Reporting; Research; Resistance; Sampling; Solid; Solid Neoplasm; Stress; Testing; Translating; Up-Regulation; Validation; Xenograft Model; antitumor effect; biological adaptation to stress; cancer stem cell; cancer subtypes; cancer type; chemotherapy; 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.

项目摘要/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 立即有吸毒的分子，例如雌激素和孕激素受体和人表皮 生长因子受体2。目前尚未批准绝大多数TNBC患者的靶向治疗。 TNBC 接受了当前护理标准的患者，包括化学疗法，放射和手术， 通常会出现早期肿瘤复发，死亡率明显较差。因此，识别至关重要 并验证针对TNBC患者的临床可行，挽救生命的靶向疗法。我们以前报道了 与非TNBC病例相比 MYC水平与TNBC患者的结局差有关。不幸的是，临床发展 直接针对MYC活动的抑制剂仍然挑战。为了克服这一挑战，我们以前 采用了一种称为合成致命筛查方法的替代方法，以识别可容易吸毒的方法 MYC驱动的肿瘤生存能力所需的靶标，但在非肿瘤细胞中并不是必需的。我们的屏幕确定了 激酶的PIM家族，由密切相关的非必需激酶同工型PIM1，-2和 -3（Pim Herelafter），作为MYC驱动的TNBC的承诺目标。我们发现PIM表达在 临床样本中的三阴性（TN）肿瘤，与患者不良结局有关。临床相关 PAN-PIM抑制剂在TNBC的各种实验模型中显示了活性。但是，我们的单一效率 使用临床前PIM抑制剂的研究表明，尽管PIM抑制作用显着减慢了TN的生长 肿瘤，它仅诱导体内肿瘤细胞死亡和消退，表明需要组合 疗法。我们采取了强有力的药物筛查方法，并意外地发现该药物 靶向PIM激酶和蛋白酶体的组合可以急性诱导有毒水平的蛋白质毒性应激水平 在过表达MYC的TNBC细胞中有选择地。从机械上讲，我们的初步观察表明PIM 抑制作用，它与蛋白酶体抑制作用相结合时，可以提高活性氧的水平， 淹没了TNBC细胞连续降解损伤蛋白的能力，导致蛋白毒性危机。 这就是我们的观察结果提高了可能性的可能性，我们的研究将检验PIM抑制的假设 代表了一种独特且临床上可行的工具，可将TNBC肿瘤感知到蛋白酶体抑制作用。成功 这项研究的执行将允许识别和审问临床可剥削的脆弱性 在MYC驱动的固体类型中，例如TNBC。这项研究的结果也可以鼓励FDA- 批准的蛋白酶体抑制剂（例如Carfilzomib），尚未成功使用液体肿瘤。 类型，将与PAN-PIM激酶抑制剂结合迅速评估 肿瘤试验。