Project 1: Therapeutic targeting of CDK4 in Mantle Cell Lymphoma

项目1：套细胞淋巴瘤中CDK4的治疗靶向

基本信息

批准号：
10249086
负责人：
SELINA Y CHEN-KIANG
金额：
$ 34.46万
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：
2018
资助国家：
美国
起止时间：
2018-09-18 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10249086
关键词：
Advanced Malignant Neoplasm Animal Model B-Lymphocytes Biological Assay Biological Markers Breast Cancer Treatment CDK4 gene CDKN2A gene Cell Cycle Cell Cycle Regulation Cell Line Cell Therapy Chromatin Clinical Clinical Trials Collaborations Combined Modality Therapy Copy Number Polymorphism Cyclin D1 Development Disease Drug resistance E2F transcription factors EZH2 gene Event FDA approved Failure G1 Arrest Gene Expression Genes Genetic Genetic Transcription Genomics Growth Human IRF4 gene In complete remission Lymphoma Lymphoma cell Malignant Neoplasms Mantle Cell Lymphoma Mediating Outcome Patients Pharmaceutical Preparations Phase Phase I Clinical Trials Phase II Clinical Trials Phosphorylation Proliferating RB1 gene Recurrence Repression Resistance Role Schedule Testing Therapeutic Transposase Treatment Failure base cancer therapy chromatin remodeling drug development exome sequencing functional genomics gain of function histone methyltransferase individual patient inhibitor/antagonist molecular marker novel novel therapeutics patient stratification promoter response side effect single-cell RNA sequencing targeted treatment therapeutic target transcriptional reprogramming transcriptome virtual

项目摘要

Mantle cell lymphoma (MCL) remains incurable due to the development of drug resistance despite advances in targeted therapy. Each successive treatment failure is associated with a more rapidly proliferating disease and fewer practical treatment options. For example, the BTK inhibitor (BTKi) ibrutinib has unprecedented activity but failure is virtually universal and is associated with dismal outcomes. Understanding the mechanism and genomic basis for therapy resistance is thus fundamental to developing superior durable therapies that are also amenable to patient stratification in MCL. As dysregulation of CDK4 (CDK6 is not expressed in MCL) and aberrant cyclin D1 expression underlie MCL proliferation, targeting CDK4 represents a rational approach to developing novel therapies that circumvent ibrutinib resistance in MCL. We have previously demonstrated that the clinical response to ibrutinib was tightly associated with PI3K inactivation in MCL patients. Induction of prolonged early G1 arrest (pG1) by inhibiting CDK4 with palbociclib (selective CDK4/6 inhibitor) restricts the expression of genes to those scheduled for early G1 only. This led to an imbalance in gene expression that reprogrammed MCL cells for therapeutic vulnerability, including BTK and PI3K inhibition. On this basis, we hypothesize that targeting CDK4 will both restrict the expansion of resistant clones and reprogram MCL cells for a deeper, and more durable clinical response to BTKi or PI3Ki. Supporting this hypothesis, our phase I clinical trial of palbociclib in combination with ibrutinib for patients with recurrent MCL (PALIBR) revealed a promising 67% overall response rate with 43% complete response (N=27), Moreover the response was rapid and durable; only 14% responding patients have progressed in ~32 months since the trial opened. Capitalizing on these exciting findings and the upcoming phase 2 PALIBR clinical trial, we propose to define the mechanism of pG1 reprograming for therapeutic vulnerability and the molecular biomarkers that discriminate sensitivity from resistance to targeting CDK4 in MCL with two specific aims: 1) to determine the genomic basis for resistance to targeting CDK4 in combination therapy. We will determine if composite copy number variation (CNV) and clonal selection causes resistance to PALIBR by longitudinal functional genomics and develop strategies to circumvent PALIBR resistance by targeting the therapeutic vulnerability conferred by resistance biomarkers; 2) to elucidate the mechanism for pG1 reprogramming in MCL cells. We will test our hypothesis that by reinforcing Rb sequestration of E2F1, CDK4 inhibition disrupts the E2F1- EZH2 regulatory circuitry, which sustains the pG1 state needed for a durable clinical response and reprograms MCL cells for therapy vulnerability through chromatin remodeling, repression of IRF4 and inactivation of PI3K. Targeting CDK4/6 is now FDA-approved for treatment of breast cancer and is being actively investigated in diverse human cancers, yet the underlying mechanism remains unknown. Successful completion of the proposed studies should both advance MCL therapy and have a profound impact on targeting the cell cycle in human cancer.

尽管取得了进展，但由于耐药性的发展，套细胞淋巴瘤（MCL）仍然无法治愈靶向治疗。每次连续的治疗失败都与更快增殖的疾病有关，并且实际治疗选择较少。例如，BTK抑制剂（BTKi）依鲁替尼具有前所未有的活性但失败实际上是普遍存在的，并且会带来惨淡的结果。了解机制和因此，治疗耐药性的基因组基础对于开发卓越的持久疗法至关重要。也适合 MCL 患者分层。由于 CDK4 失调（CDK6 在 MCL 中不表达）和异常的细胞周期蛋白 D1 表达是 MCL 增殖的基础，靶向 CDK4 是一种合理的方法开发新疗法来规避 MCL 中的依鲁替尼耐药性。我们之前已经证明了 MCL 患者对依鲁替尼的临床反应与 PI3K 失活密切相关。感应通过用 palbociclib（选择性 CDK4/6 抑制剂）抑制 CDK4 来延长早期 G1 停滞 (pG1)，限制了基因的表达仅限于 G1 早期。这导致了基因表达的不平衡重新编程 MCL 细胞以应对治疗脆弱性，包括 BTK 和 PI3K 抑制。在此基础上，我们假设靶向 CDK4 将限制耐药克隆的扩增并重新编程 MCL 细胞对 BTKi 或 PI3Ki 产生更深入、更持久的临床反应。支持这一假设，我们的第一阶段 palbociclib 联合依鲁替尼治疗复发性 MCL (PALIBR) 患者的临床试验显示，承诺 67% 的总体缓解率，43% 的完全缓解 (N=27)，而且缓解速度很快且耐用；自试验开始以来，只有 14% 的患者在约 32 个月内出现了进展。大写根据这些令人兴奋的发现和即将进行的 2 期 PALIBR 临床试验，我们建议定义 pG1重编程治疗脆弱性的机制和区分的分子生物标志物 MCL 中对靶向 CDK4 的耐药性的敏感性有两个具体目的：1) 确定基因组基础联合治疗中针对 CDK4 的耐药性。我们将确定复合拷贝数是否变异 (CNV) 和克隆选择通过纵向功能基因组学导致对 PALIBR 的抗性并发展通过针对耐药性带来的治疗脆弱性来规避 PALIBR 耐药性的策略生物标志物； 2）阐明MCL细胞中pG1重编程的机制。我们将检验我们的假设通过加强 E2F1 的 Rb 隔离，CDK4 抑制会破坏 E2F1-EZH2 调节电路，它维持持久临床反应所需的 pG1 状态，并重新编程 MCL 细胞以进行治疗染色质重塑、IRF4 抑制和 PI3K 失活导致的脆弱性。靶向 CDK4/6 是现已获得 FDA 批准用于治疗乳腺癌，并正在积极研究多种人类癌症，但其根本机制仍不清楚。成功完成拟议的研究应该推进 MCL 疗法并对靶向人类癌症的细胞周期产生深远影响。