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

基本信息

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
项目类别：
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&apos 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

项目摘要

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存在的情况下驱动细胞周期进入并进展至G1，在人类癌症中以高频率过度表达。使用首个选择性抑制剂 PD 0332991 (palbociclib) 以 CDK4/6 为靶点，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，与来曲唑联合使用时，无进展生存期增加了两倍以上。在套细胞淋巴瘤 (MCL) 这种无法治愈的非霍奇金淋巴瘤中，CDK4 过度表达和异常的细胞周期蛋白 D1 表达会驱动不受限制的增殖，从而导致疾病进展。在第一个针对复发性 MCL 的 I 期单药临床试验中，我们表明 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，我们现在表明：1) PD 0332991 对 CDK4/6 的抑制导致底物 (Rb) 依赖性早期 G1 停滞； 2) 延长的早期 G1 阻滞 (pG1) 使 Rb+ 癌细胞对多种临床相关药物的杀伤变得敏感； 3) pG1 重编程源于将基因的表达限制为仅在早期 G1 中安排的基因。我们进一步表明，PD 0332991 最初在所有 MCL 患者的肿瘤细胞中诱导 pG1，无论其与硼替佐米 (PD-Btz) 联合使用时的后续临床反应如何。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，并且对 PD-Btz 的耐药性与 MCL 细胞中 pG1 中仅 1% (9 /868) 被抑制的基因的反向激活相关有反应的患者。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 中伙伴代理特异性基因的调节相配合，以重新编程 MCL 细胞以进行细胞毒性杀伤。为了进一步靶向 CDK4，我们将通过将 PD 0332991 与不可逆布鲁顿酪氨酸激酶 (BTK) 抑制剂依鲁替尼结合来测试这一新假设。依鲁替尼在复发性 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，复发通常在一年多一点的时间内，并且常常伴随着肿瘤细胞的侵袭性增殖。我们将研究代谢扰动在 pG1 重编程中抑制 BTK 的作用和机制（目标 1）；确定针对 PI3K 抑制的 pG1 重编程是否可以克服依鲁替尼耐药性（目标 2）；并通过纵向功能基因组学发现最能区分 CDK4 和 BTK 治疗靶向的敏感性和耐药性的关键中心基因（目标 3）。 PD 0332991 和 ibrutinib 均获得 FDA 突破性疗法认定。这项研究的成功完成预计将揭示癌症代谢的细胞周期控制，并显着推进 MCL 及其他疾病中基于机制的 CDK4/CDK6 和 BTK 靶向。