Unlocking the Potential of PI3K Inhibition in CLL

项目摘要 CLL是北美成人最常见的白血病，并且仍然无法治愈。最近发现的 B细胞受体信号通路的靶向口服激酶抑制剂正在改变CLL的治疗， 挑战依然存在。这些药物中没有一种是治愈性的，大约30%的患者会停药 尽管疾病反应良好，但仍存在毒性。PI 3 K p110δ抑制剂包括第一代FDA 已批准的药物艾代拉里斯以及duvelisib，目前正在注册试验中的PI 3 K γ和δ抑制剂。PI3Kδ 抑制剂具有包括肝炎、结肠炎和肺炎的毒性模式。我们有两个 在CLL患者中进行的临床试验，一项基于艾代拉里斯，一项基于杜维利西，其中我们描述了这些 免疫介导的毒性。我们进一步表明，这种毒性与T细胞减少有关。 调节细胞，这也可以提高疗效，降低这些患者的实体瘤风险。在这 在具体目标1中，我们建议深化这些观察，描述T监管和T PI 3 K δ抑制剂治疗期间CLL的效应器景观与观察到的毒性相关，目的是 确定毒性和疗效的临床和免疫学预测因子。我们将进一步进行体外功能性 评估PI 3 K δ抑制对调节性T细胞的抑制功能的影响的测定， T效应细胞的能力和幼稚CD 4 + T细胞的体外分化潜力。具体目标2 将评估PI 3 K δ敲低对CLL的Eμ-TCL 1小鼠模型的疾病影响 发育、自身免疫毒性和T细胞环境。这些实验将集中在小鼠激酶死亡 遗传模型，但也将评估药理学抑制剂。因此，目标1和2将阐明 人类和小鼠中PI 3 K δ选择性抑制的基础生物学，使我们能够识别PI 3 K δ的预测因子 毒性和疗效，这将优化这些药物的患者选择。在具体目标3中，我们将描述 对PI 3 K δ抑制的敏感性和抵抗机制。我们的初步数据表明 在对PI 3 K δ抑制有抗性或变得对PI 3 K δ抑制有抗性的患者中ERK途径的生物化学上调。我们 因此，建议对ERK通路激活对PI 3 K δ的影响进行直接的机制研究 体外抗性。我们还将通过研究这两种药物的患者进行额外的发现 基线、缓解期和获得性耐药时的前瞻性临床试验，包括基因组， 转录组学和信号转导评估。这一先前未经治疗的统一患者群体代表了 理想的同质队列，这将使我们能够更有效地了解这些机制，而不是一个 异质性复发队列。因此，该项目将代表对以下问题的理解的重大进展： 在人类中PI 3 K δ抑制的生物学，就其显著的免疫学效应和 耐药性，所有这些都将允许为这种疗法选择最佳患者，甚至可能导致扩大使用 PI 3 K δ在其他癌症中的抑制作用，基于其免疫调节功能。

Project Summary CLL is the most common leukemia of adults in North America and remains incurable. Recent discovery of targeted oral kinase inhibitors of the B cell receptor signaling pathway is transforming the therapy of CLL, but challenges remain. Individually none of these drugs is curative, and approximately 30% of patients discontinue for toxicity despite good disease response. The PI3K p110δ inhibitors include the first generation FDA approved drug idelalisib, as well as duvelisib, a PI3K γ and δ inhibitor currently in registration trials. The PI3Kδ inhibitors have a pattern of toxicity that includes hepatitis, colitis and pneumonitis. We have two ongoing clinical trials in CLL patients, one idelalisib based and one duvelisib based, in which we have described these toxicities to be immune-mediated. We have further shown that this toxicity associates with a decrease in T regulatory cells, which could also enhance efficacy and decrease risk of solid tumors in these patients. In this grant in Specific Aim 1 we propose to deepen these observations, characterizing the T regulatory and T effector landscape of CLL during therapy with PI3Kδ inhibitors in relation to observed toxicities, with the goal of identifying clinical and immunologic predictors of toxicity and efficacy. We will further perform in vitro functional assays to assess the impact of PI3Kδ inhibition on the suppressive function of T regulatory cells, the activation capacity of T effector cells and the in vitro differentiation potential of naïve CD4+ T cells. In Specific Aim 2 we will assess the impact of PI3Kδ knockdown on the Eμ-TCL1 mouse model of CLL in terms of disease development, autoimmune toxicity and T cell milieu. These experiments will focus on the mouse kinase dead genetic model but will also assess pharmacologic inhibitors. Aims 1 and 2 will therefore elucidate the fundamental biology of PI3Kδ selective inhibition in humans and mice and enable us to identify predictors of toxicity and efficacy that will optimize patient selection for these drugs. In Specific Aim 3, we will characterize the mechanisms of sensitivity and resistance to PI3Kδ inhibition. Our preliminary data implicate genetic and/or biochemical upregulation of the ERK pathway in patients who are or become resistant to PI3Kδ inhibition. We therefore propose to perform direct mechanistic studies of the impact of ERK pathway activation on PI3Kδ resistance in vitro. We will also perform additional discovery by studying patients enrolled on these two prospective clinical trials at baseline, during remission and at time of acquired resistance, including genomic, transcriptomic and signaling evaluation. This previously untreated uniform patient population represents an ideal homogeneous cohort that will allow us to understand these mechanisms much more effectively than a heterogeneous relapsed cohort. This project will therefore represent a major advance in the understanding of the biology of PI3Kδ inhibition in humans, in terms of its significant immunologic effects and mechanisms of resistance, all of which will allow optimal patient selection for this therapy and may even lead to expanded use of PI3Kδ inhibition in other cancers, based on its immunoregulatory function.