Unlocking the Potential of PI3K Inhibition in CLL

项目摘要 慢性淋巴细胞性白血病是北美最常见的成人白血病，目前仍无法治愈。最新发现的 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，但 挑战依然存在。就个人而言，这些药物都不能治愈，大约30%的患者停止使用 尽管疾病反应良好，但仍有毒性。PI3K p110δ抑制剂包括第一代fda 批准的药物idelalisib，以及目前正在注册试验的PI3Kγ和δ抑制剂duvelisib。PI3Kδ 抑制剂有一种毒性模式，包括肝炎、结肠炎和肺炎。我们有两个正在进行的 CLL患者的临床试验，一项基于idelalisib的临床试验，一项基于duvelisib的临床试验，我们在其中描述了这些 毒性是由免疫调节的。我们进一步证明，这种毒性与T降低有关。 调节细胞，这也可以提高疗效和降低这些患者实体瘤的风险。在这 在具体目标1中，我们建议深化这些观察，描述T调节和T PI3Kδ抑制剂治疗期间慢性淋巴细胞性白血病的效应曲线与观察到的毒性的关系，目的是 确定毒性和疗效的临床和免疫学预测因子。我们将进一步在体外进行功能测试 检测抑制PI3Kδ对T调节细胞抑制功能、活化功能的影响 T效应细胞的能力和幼稚CD4+T细胞的体外分化潜能。在具体目标2中，我们 将评估PI3Kδ基因敲除对慢性淋巴细胞性白血病Eμ-TCL1小鼠模型的影响 发育、自身免疫毒性和T细胞环境。这些实验将重点放在小鼠死亡的激酶上 基因模型，但也将评估药理抑制剂。因此，目标1和目标2将阐明 在人类和小鼠中PI3Kδ选择性抑制的基础生物学，并使我们能够识别 毒性和疗效，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PI3Kδ抑制的敏感性和抗性机制。我们的初步数据显示基因和/或 对PI3Kδ抑制产生或变得抵抗的患者，ERK通路的生化上调。我们 因此建议对ERK通路激活对PI3Kδ的影响进行直接的机制研究 体外抗药性。我们还将通过研究登记在这两个项目上的患者来进行进一步的发现 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， 转录和信号评估。这些以前未接受治疗的制服患者代表着一种 理想的同质队列，这将使我们能够更有效地理解这些机制 异质性复发队列。因此，该项目将代表着对 抑制PI3Kδ在人体内的生物学作用及其免疫效应和机制 耐药性，所有这些都将使这种疗法的患者选择最佳，甚至可能导致扩大使用 基于其免疫调节功能，研究了PI3Kδ在其他癌症中的抑制作用。

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.