Mechanism-Based Targeting of Mantle Cell Lymphoma

基于机制的套细胞淋巴瘤靶向治疗

基本信息

批准号：
10249085
负责人：
SELINA Y CHEN-KIANG
金额：
$ 178.84万
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/10249085
关键词：
Arginine Bioinformatics Biopsy Biostatistics Core CDK4 gene Cell Cycle Clinical Combined Modality Therapy Cyclin D1 Development Disease Disease Progression Drug resistance Ensure Epigenetic Process Event FOXO1A gene Failure G1 Arrest Genetic Genomics Goals Human In complete remission Knowledge Lymphoma cell Malignant Neoplasms Mantle Cell Lymphoma Molecular Non-Hodgkin&apos s Lymphoma Outcome Pathology Patients Phase Phase I Clinical Trials Proliferating Protein Inhibition Proteins Recurrence Regulation Regulatory Pathway Research Personnel Resistance Role Time Transferase Treatment Failure Tumor Suppressor Proteins base chromatin remodeling clinically relevant drug development epigenome functional genomics genomic biomarker inhibitor/antagonist innovation insight novel novel therapeutics patient stratification prevent programs response synergism targeted agent therapeutic target tool transcription factor virtual

项目摘要

Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma that remains incurable due to the development of drug resistance, despite the plethora of therapies available. Each successive treatment failure is associated with a more rapidly proliferating disease and fewer practical treatment options. For example, the BTK inhibitor (BTKi) ibrutinib initially has unprecedented efficacy, but failure is virtually universal and is associated with dismal outcomes. Understanding the genomic basis and mechanisms for drug resistance in MCL is therefore urgently needed. Our goal is to develop superior therapies for MCL that are effective, durable, well tolerated and amenable to patient stratification, by defining the genomic and molecular mechanisms for drug resistance. Targeting the cell cycle represents a rational approach to MCL therapy, as dysregulation of CDK4 and cyclin D1 expression underlie unrestrained proliferation in disease progression. We have demonstrated that induction of prolonged early G1 arrest (pG1) by inhibiting CDK4 with palbociclib not only prevents proliferation of primary MCL cells but also reprograms them for killing by clinically relevant targeting agents including ibrutinib and PI3K inhibitors (PI3Ki)s. Longitudinal functional genomics of serial biopsies from MCL patients treated with either palbociclib or ibrutinib further uncovered a close association between clinical response and inactivation of PI3K as well as activation of the tumor suppressor transcription factor FOXO1. Moreover, chromatin remodeling appeared to be the proximal event that reprograms MCL cells in response to CDK4 inhibition. Collectively, our findings suggest that through regulation of PI3K, FOXO1 and the epigenome, induction of pG1 by CDK4 inhibition reprograms MCL for a deeper, more durable clinical response to BTKi and PI3Ki. Supporting this hypothesis, in our phase 1 clinical trial of palbociclib + ibrutinib (PALIBR) in recurrent MCL, the overall response rate was 67% with 43% complete responses. The responses were rapid and durable; only 2 responding patients have progressed in the 32 months since the trial opened. To further accelerate the development of targeted MCL therapies, we have developed a novel inhibitor for protein arginine methyl transferase 5 (PRMT5), which is dysregulated in MCL and many other human cancers. Inhibition of PRMT5 reverses PRMT5-catalyzed epigenetic marks, restores regulatory pathways and kills ibrutinib-resistant primary MCL cells. Building on these novel findings and capitalizing on the upcoming multi-center phase 2 PALIBR in recurrent MCL, we propose to achieve our goals with three integrated specific aims: 1) to define the mechanism for clinical response to targeting CDK4 in combination therapy and identify the resistance genomic markers; 2) to determine the role of FOXO1 and chromatin remodeling in cell cycle therapy; and 3) to target PRMT5 in MCL. Collectively, the tools and knowledge assembled from these innovative and timely studies should significantly advance therapeutic targeting of the cell cycle and the epigenome in MCL and provide new insights into the mechanism of drug resistance in MCL and beyond.

套细胞淋巴瘤 (MCL) 是一种非霍奇金淋巴瘤，由于尽管有大量可用的治疗方法，但仍存在耐药性。每次连续的治疗失败都与疾病增殖速度更快，实际治疗选择更少。例如，BTK抑制剂 (BTKi) 伊布替尼最初具有前所未有的功效，但失败几乎是普遍的，并且与惨淡的结果。因此，了解 MCL 耐药性的基因组基础和机制至关重要急需。我们的目标是开发有效、持久、耐受性良好的 MCL 优质疗法并通过定义药物的基因组和分子机制来适应患者分层反抗。靶向细胞周期代表了 MCL 治疗的合理方法，因为 CDK4 失调细胞周期蛋白 D1 的表达是疾病进展中不受限制的增殖的基础。我们已经证明了通过用哌柏西利抑制 CDK4 来诱导延长早期 G1 停滞 (pG1) 不仅可以预防原代 MCL 细胞的增殖，但也会对它们进行重新编程，以便被临床相关的靶向剂杀死包括依鲁替尼和 PI3K 抑制剂 (PI3Ki)。 MCL 连续活检的纵向功能基因组学使用 palbociclib 或 ibrutinib 治疗的患者进一步发现临床 PI3K 的反应和失活以及肿瘤抑制转录因子 FOXO1 的激活。此外，染色质重塑似乎是响应 MCL 细胞重新编程的最近事件。 CDK4 抑制。总的来说，我们的研究结果表明，通过调节 PI3K、FOXO1 和表观基因组，通过 CDK4 抑制诱导 pG1 重新编程 MCL，以获得更深入、更持久的临床效果对 BTKi 和 PI3Ki 的响应。在我们的 palbociclib + ibrutinib 的 1 期临床试验中支持了这一假设 (PALIBR) 在复发性 MCL 中，总体缓解率为 67%，其中完全缓解率为 43%。回应快速且持久；自试验开始以来的 32 个月内，只有 2 名有反应的患者病情有所进展。为了进一步加速MCL靶向疗法的开发，我们开发了一种新型抑制剂蛋白精氨酸甲基转移酶 5 (PRMT5)，在 MCL 和许多其他人类中失调癌症。 PRMT5 的抑制可逆转 PRMT5 催化的表观遗传标记，恢复调控途径并杀死依鲁替尼耐药的原代 MCL 细胞。以这些新颖的发现为基础，并利用即将到来的对于复发性 MCL 的多中心 2 期 PALIBR，我们建议通过三个集成的特定目标来实现我们的目标目标：1) 明确联合治疗中针对 CDK4 的临床反应机制并确定抗性基因组标记； 2) 确定FOXO1和染色质重塑在细胞周期中的作用治疗; 3) 以 MCL 中的 PRMT5 为目标。总的来说，这些工具和知识汇集在一起创新和及时的研究应显着推进细胞周期和细胞的治疗靶向 MCL 的表观基因组，并为 MCL 及其他耐药机制提供新的见解。