Cell cycle reprogramming for therapeutic targeting of BTK in lymphoma

淋巴瘤中 BTK 治疗靶向的细胞周期重编程

• 批准号: 9117498
• 负责人: SELINA Y CHEN-KIANG
• 金额: $ 35.17万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9117498
• 关键词: Address; Agammaglobulinaemia tyrosine kinase; Binding Sites; Biopsy; Bortezomib; CDK4 gene; Cell Cycle; Cell Cycle Regulation; Cell Line; Cell Proliferation; Cell division; Cells; Clinical; Clinical Trials; Combined Modality Therapy; Coupled; Cyclin D1; DNA Sequence; Development; Disease Progression; Frequencies; G1 Arrest; Gene Expression; Genes; Glucose Transporter; Glycolysis; Health; Homeostasis; Human; Lead; Letrozole; Light; Lymphoma; Malignant Neoplasms; Mantle Cell Lymphoma; Metabolic; Mutation; Natural Killer Cells; Non-Hodgkin' s Lymphoma; Oxidation-Reduction; Oxidative Stress; Patients; Pharmaceutical Preparations; Phase; Progression-Free Survivals; Proteasome Inhibitor; Recurrence; Regulation; Relapse; Resistance; Role; S Phase; SLC2A1 gene; Schedule; Sequence Analysis; TXNIP gene; Testing; Time; Tyrosine Kinase Inhibitor; Validation; Withdrawal; base; cancer cell; cancer therapy; cell killing; clinical efficacy; clinically relevant; exome sequencing; functional genomics; glucose metabolism; glucose transport; improved; in vivo; inhibitor/antagonist; killings; malignant breast neoplasm; metabolomics; neoplastic cell; novel; overexpression; response; restoration; small molecule inhibitor; stem; therapeutic target; transcriptome sequencing; tumor; tumor metabolism

DESCRIPTION (provided by applicant): CDK4 and CDK6, which drive cell cycle entry and progression through G1 in the presence of cyclin D, are overexpressed at a high frequency in human cancers. Targeting CDK4/6 with the first selective inhibitor, PD 0332991 (palbociclib), has recently achieved unprecedented clinical efficacy in human cancers, especially in breast cancer, where it more than tripled the progression free survival when combined with letrozole. In mantle cell lymphoma (MCL), an incurable non-Hodgkin lymphoma, CDK4 overexpression and aberrant cyclin D1 expression drive unrestrained proliferation that underlies disease progression. In the first Phase I single-agent clinical trial in recurrent MCL, we showed that PD 0332991 resulted in a durable clinical response with tumor regression in some MCL patients; but the mechanism that differentiates sensitivity and resistance is unknown. To address this question, we have now shown that 1) Inhibition of CDK4/6 by PD 0332991 leads to substrate (Rb)-dependent early G1 arrest; 2) prolonged early G1 arrest (pG1) sensitizes Rb+ cancer cells for killing by diverse clinically-relevant agents; 3) pG1 reprogramming stems from restricting the expression of genes to those scheduled for early G1 only. We further showed that PD 0332991 induced pG1 in tumor cells of all MCL patients initially, regardless of their subsequent clinical response when used in combination with bortezomib (PD-Btz). Longitudinal RNA and exome sequencing revealed that selective genes in glycolysis and redox homeostasis were regulated in pG1 and that resistance to PD-Btz was associated with converse activation of only 1% (9 /868) of the genes that were repressed in pG1 in MCL cells of responding-patients. On this basis, we propose that perturbation of glycolysis and redox homeostasis in pG1 cooperates with regulation of partner agent-specific genes in pG1 to reprogram MCL cells for cytotoxic killing. To advance targeting CDK4, we will test this novel hypothesis by combining PD 0332991 with ibrutinib, an irreversible Bruton's tyrosine kinase (BTK) inhibitor. Ibrutinib has achieved a remarkable overall clinical response rate of 68% in a Phase I/II single-agent clinical trial in recurrent MCL patients. However, relapse is common in slightly over a year, and is often accompanied by aggressive proliferation of tumor cells. We will investigate the role and mechanism of metabolic perturbation in pG1 reprogramming for BTK inhibition (Aim 1); determine if pG1 reprogramming for PI3K inhibition can override ibrutinib resistance (Aim 2); and discover key hub genes that best discriminate sensitivity and resistance to therapeutic targeting of CDK4 and BTK by longitudinal functional genomics (Aim 3). PD 0332991 and ibrutinib have both attained the Breakthrough Therapy Designation by the FDA. Successful completion of this study is anticipated to shed light on cell cycle control of cancer metabolism and significantly advance mechanism-based targeting of CDK4/CDK6 and BTK in MCL and beyond.

描述（由申请人提供）：CDK4和CDK6在细胞周期蛋白D的存在下驱动细胞周期进入和通过G1的进展，在人类癌症中高频率过表达。用第一种选择性抑制剂PD 0332991 （palbociclib）靶向CDK4/6，最近在人类癌症中取得了前所未有的临床疗效，特别是在乳腺癌中，当与来曲唑联合使用时，无进展生存期增加了三倍以上。套细胞淋巴瘤（MCL）是一种无法治愈的非霍奇金淋巴瘤，CDK4过表达和异常的细胞周期蛋白D1表达驱动无限制的增殖，这是疾病进展的基础。在复发性MCL的首个I期单药临床试验中，我们发现PD 0332991在一些MCL患者中产生了持久的临床反应，肿瘤消退；但区分敏感性和耐药性的机制尚不清楚。为了解决这个问题，我们现在已经证明1)PD 0332991对CDK4/6的抑制导致底物（Rb）依赖性的早期G1阻滞；2)延长早期G1阻滞（pG1）使Rb+癌细胞对多种临床相关药物的杀伤增敏；3) pG1重编程源于将基因的表达限制在G1早期。我们进一步发现，PD 0332991在最初诱导所有MCL患者肿瘤细胞中的pG1，而不考虑与硼替佐米（PD- btz）联合使用后的临床反应。纵向RNA和外显子组测序显示，糖酵解和氧化还原稳态中的选择性基因在pG1中受到调节，对PD-Btz的耐药性与MCL细胞中pG1中被抑制的基因中只有1%（9 /868）的反向激活相关。在此基础上，我们提出pG1中糖酵解和氧化还原稳态的扰动与pG1中伴侣剂特异性基因的调控合作，以重新编程MCL细胞进行细胞毒性杀伤。为了推进靶向CDK4，我们将通过PD 0332991联合ibrutinib（一种不可逆的布鲁顿酪氨酸激酶（BTK）抑制剂）来验证这一新的假设。伊鲁替尼在复发性MCL患者的I/II期单药临床试验中取得了68%的显着总体临床缓解率。然而，复发是常见的在一年多一点，往往伴随着肿瘤细胞的侵袭性增殖。我们将研究代谢扰动在pG1重编程抑制BTK中的作用和机制（目的1）；确定pG1重编程抑制PI3K是否可以克服伊鲁替尼耐药性（Aim 2）；并通过纵向功能基因组学发现最能区分CDK4和BTK治疗靶向敏感性和耐药性的关键枢纽基因（目标3）。PD 0332991和ibrutinib都获得了FDA的突破性治疗指定。这项研究的成功完成有望揭示细胞周期对癌症代谢的控制，并显著推进基于机制的靶向CDK4/CDK6和BTK在MCL及其他疾病中的应用。