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 抗药性，尽管有过多的治疗方法可用。每个连续的治疗失败都与 疾病扩散更快，实际治疗选择更少。例如，BTK抑制剂 (BTKi)伊布鲁替尼最初具有前所未有的疗效，但失败几乎是普遍的，与 惨淡的结局。因此，了解MCL耐药的基因组基础和机制是 急需之物。我们的目标是开发有效、持久、耐受性好的治疗MCL的高级疗法。 并通过定义药物的基因组和分子机制，服从患者分层 抵抗。靶向细胞周期是MCL治疗的一种合理方法，因为CDK4的调节失调 而细胞周期蛋白D1的表达是疾病进展过程中不受抑制的增殖的基础。我们已经证明了 通过用Palbociclib抑制CDK4来诱导延长的早期G1期停滞(PG1)不仅可以防止 对原代MCL细胞的增殖，但也对它们进行重新编程，以用于临床相关靶向药物的杀伤 包括伊布鲁替尼和PI3K抑制剂(PI3Ki)S。微淋巴细胞性淋巴瘤系列活检组织的纵向功能基因组学 接受帕波西利或伊布鲁替尼治疗的患者进一步揭示了临床上 PI3K的反应和失活以及肿瘤抑制转录因子FOXO1的激活。 此外，染色质重塑似乎是对MCL细胞重新编程的近端事件 CDK4的抑制作用。总而言之，我们的发现表明，通过调节PI3K、FOXO1和 表观基因组，CDK4抑制诱导pG1重编MCL程序，使临床更深入、更持久 对BTKi和PI3Ki的回应。支持这一假设的是，在我们的Palbociclib+ibrutinib的第一阶段临床试验中 (PALIBR)复发的MCL，总有效率为67%，完全有效率为43%。回应： 试验迅速而持久；自试验开始以来的32个月中，只有2名有反应的患者取得进展。 为了进一步加快MCL靶向治疗的发展，我们开发了一种新的抑制MCL的药物 蛋白精氨酸甲基转移酶5(PRMT5)，它在MCL和许多其他人类中调节失调 癌症。抑制PRMT5逆转PRMT5催化的表观遗传标记，恢复调节通路和 杀死对伊布鲁替尼耐药的原代MCL细胞。以这些新发现为基础，并利用即将到来的 多中心2期PALIBR治疗复发的MCL，我们建议通过三个综合的特异性来实现我们的目标 目的：1)明确联合治疗中靶向CDK4的临床反应机制，并确定 2)FOXO1和染色质重塑在细胞周期中的作用 治疗；3)靶向MCL中的PRMT5。总而言之，从这些集合而来的工具和知识 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 MCL中的表观基因组，为MCL的耐药机制及其他机制提供新的见解。

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.