Mechanism-Based Targeting of Mantle Cell Lymphoma

套细胞淋巴瘤（MCL）是一种非霍奇金淋巴瘤，由于发展为恶性淋巴瘤， 耐药性，尽管有大量的治疗方法。每次连续治疗失败都与 疾病扩散更快，实际治疗选择更少。例如，BTK抑制剂 （BTKi）伊曲替尼最初具有前所未有的疗效，但失败几乎是普遍的，并与 令人沮丧的结果。因此，了解MCL耐药的基因组基础和机制， 迫切需要。我们的目标是为MCL开发有效、持久、耐受性好的上级疗法 并通过定义药物治疗的基因组和分子机制， 阻力靶向细胞周期代表了MCL治疗的合理方法，因为CDK 4 和细胞周期蛋白D1表达是疾病进展中无限制增殖的基础。我们已经证明 palbociclib通过抑制CDK 4诱导延长的早期G1期阻滞（pG 1）， 原代MCL细胞的增殖，但也重新编程它们以通过临床相关的靶向剂杀死 包括伊曲替尼和PI 3 K抑制剂（PI 3 Ki）。MCL系列活检的纵向功能基因组学 接受palbociclib或ibocicinib治疗的患者进一步发现， PI 3 K的应答和失活以及肿瘤抑制转录因子FOXO 1的激活。 此外，染色质重塑似乎是MCL细胞重编程的近端事件， CDK 4抑制。总的来说，我们的研究结果表明，通过调节PI 3 K，FOXO 1和 表观基因组，通过CDK 4抑制诱导pG 1重新编程MCL，以实现更深入，更持久的临床治疗。 对BTKi和PI 3 Ki的反应。支持这一假设的是，在我们的palbociclib + ibocinib的I期临床试验中， （PALIBR）在复发MCL中，总有效率为67%，完全缓解率为43%。的答复 快速且持久;自试验开始以来的32个月内，只有2名有反应的患者出现进展。 为了进一步加速靶向MCL疗法的发展，我们开发了一种新型抑制剂， 蛋白质精氨酸甲基转移酶5（PRMT 5），其在MCL和许多其他人类肿瘤中失调。 癌的PRMT 5的抑制逆转PRMT 5催化的表观遗传标记，恢复调节途径， 杀死伊替尼耐药原代MCL细胞。在这些新发现的基础上， 在复发性MCL的多中心2期PALIBR中，我们建议使用三种整合的特异性 目的：1）确定联合治疗中靶向CDK 4的临床反应机制，并确定 2）确定FOXO 1和染色质重塑在细胞周期中的作用 治疗;和3）靶向MCL中的PRMT 5。总的来说，这些工具和知识 创新和及时的研究应该大大推进细胞周期和细胞周期的治疗靶向， 表观基因组在MCL和提供新的见解耐药机制MCL和超越。

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.