Novel use of PI3K inhibition to prevent recurrence of B-cell acute lymphoblastic leukemia

PI3K 抑制预防 B 细胞急性淋巴细胞白血病复发的新用途

基本信息

批准号：
10289183
负责人：
Dorothy A Sipkins
金额：
$ 18.82万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10289183
关键词：
1-Phosphatidylinositol 3-Kinase Acute Lymphocytic Leukemia Address Adult Precursor B Lymphoblastic Leukemia Apoptotic Ara-C Area B-Cell Acute Lymphoblastic Leukemia B-Cell Antigen Receptor Basement membrane Binding Biological Markers Blast Cell Blood - brain barrier anatomy Bone Marrow Calvaria Cell Cycle Cell Cycle Arrest Cell surface Cells Central Nervous System Leukemia Central Nervous System Prophylaxis Cerebrospinal Fluid Cessation of life Chemosensitization Clinical Clinical Trials Cytostatics Cytotoxic Chemotherapy Data Disease Disease remission Dose Drug Design Drug Targeting Extracellular Matrix Foundations Future Hematogenous Spread Human In Vitro Institutional Review Boards Integrin alpha6 Integrins Intrathecal Injections Investigation Laminin Laminin Receptor Leptomeninges Leukemic Cell Light Maintenance Malignant Neoplasms Membrane Proteins Metastatic Neoplasm to the Central Nervous System Metastatic Neoplasm to the Leptomeninges Microscopic Modeling Molecular Molecular Target Mus Neoadjuvant Therapy Neoplasm Metastasis Neuraxis Pathway interactions Patients Phase II Clinical Trials Pre-Clinical Model Prognosis Prognostic Marker Prophylactic treatment Protein Isoforms Protocols documentation Recurrence Recurrent disease Refractory Regimen Relapse Research Research Proposals Residual Neoplasm Resistance Role Route Sampling Signal Pathway Signal Transduction Site Surface Systemic disease Therapeutic Therapeutic Effect Translating Treatment Protocols Vertebral Bone Work Xenograft procedure acute lymphoblastic leukemia cell base burden of illness cell killing chemotherapy cohort combat cortical bone design disorder later incidence prevention drug development druggable target effective therapy experience experimental study falls improved in vivo indexing inhibitor/antagonist innovation irradiation kinase inhibitor leukemia leukemia relapse leukemia treatment migration mouse model neurotoxic neurotropic novel pharmacodynamic biomarker phase 2 study prevent prophylactic relapse patients response side effect spine bone structure targeted treatment transcriptome trial design

项目摘要

ABSTRACT Central nervous system (CNS) metastasis and relapse occurs in up to 10% of patients with acute lymphoblastic leukemia (ALL), despite CNS-directed prophylaxis with cytotoxic chemotherapy or craniospinal irradiation. With no uniformly effective treatment options, CNS relapse carries a grim prognosis of less than 6 months. Until now, the molecular mechanism of ALL invasion into the CNS has been poorly understood, preventing targeted drug development. Our lab recently discovered a previously unknown mechanism used by B-ALL cells to enter the CNS. This invasion pathway is dependent on key molecular interactions between 6 integrin, a surface protein expressed on ALL blasts, and its receptor laminin, expressed on the basement membrane of vessels connecting the calvarial and vertebral bone marrow to the CNS leptomeninges. We further demonstrated that B-ALL 6 integrin expression is regulated by PI3K signaling, and that PI3K isoform inhibition in vivo in mouse models of leukemia blocks CNS metastasis. Using in vitro and in vivo mouse models of B-ALL, we now show that treatment with the pan-PI3K isoform inhibitor copanlisib has additional therapeutic effects including cell cycle arrest and chemosensitization of ALL blasts. These translate to decreased CNS metastasis, reduced systemic disease burden and prolonged survival in leukemic mice. Based on these data, we have designed a novel window-of- opportunity (WoO) clinical trial to characterize molecular responses to pan-PI3K inhibition in ALL in humans. We have also designed mouse models to study the impact of PI3Ki on the persistence of minimal residual disease (MRD) following chemotherapy, a key prognostic indicator of disease relapse. In the current research proposal, we aim to: 1) Perform detailed correlative analyses of B-ALL cell molecular responses in patient samples pre- and post-copanlisib dosing in our WoO trial, and 2) Determine whether pan-PI3K inhibition by copanlisib combined with salvage chemotherapy can decrease MRD in our preclinical models of B-ALL. The therapeutic role of PI3K inhibition in ALL has not yet been established; therefore, data gathered from our WoO protocol and the experiments described within this research proposal will critically inform trial design of a potential follow-on phase II study of copanlisib incorporated into existing ALL treatment regimens. If successful, our work will represent a novel breakthrough in CNS prophylactic therapy for ALL, addressing an area of substantial unmet clinical need for patients.

抽象的高达 10% 的急性淋巴细胞白血病患者会出现中枢神经系统 (CNS) 转移和复发尽管采用细胞毒性化疗或颅脊髓照射进行中枢神经系统定向预防，但仍可能导致白血病（ALL）。目前尚无统一有效的治疗方案，中枢神经系统复发的预后很差，不到 6 个月。 ALL 侵袭中枢神经系统的分子机制尚不清楚，阻碍了靶向药物我们的实验室最近发现了一种以前未知的 B-ALL 细胞进入细胞的机制。这种入侵途径依赖于 α6 整合素（一种表面蛋白）之间的关键分子相互作用。在所有原始细胞上表达，其受体层粘连蛋白在连接血管的基底膜上表达我们进一步证明了 B-ALL 6。整合素表达受 PI3K 信号传导调节，并且在小鼠模型中体内 PI3K 亚型抑制我们现在利用 B-ALL 的体外和体内小鼠模型证明了白血病可以阻止 CNS 转移。与泛 PI3K 同工型抑制剂 copanlisib 一起使用具有额外的治疗作用，包括细胞周期停滞和 ALL 母细胞的化学增敏可以减少中枢神经系统转移，减少全身性疾病。根据这些数据，我们设计了一种新的窗口- 白血病小鼠的负担和延长的生存期。我们开展了一项临床试验，旨在表征人类 ALL 对泛 PI3K 抑制的分子反应。还设计了小鼠模型来研究 PI3Ki 对微小残留病持续存在的影响 (MRD) 化疗后，疾病复发的一个关键预后指标。我们的目标是： 1) 对患者样本中的 B-ALL 细胞分子反应进行详细的相关分析以及在我们的 WoO 试验中 copanlisib 后给药，以及 2) 确定 copanlisib 是否抑制 pan-PI3K 与挽救性化疗相结合可以降低 B-ALL 临床前模型中的 MRD。 PI3K 抑制在 ALL 中的作用尚未确定；因此，从我们的 WoO 方案中收集的数据和本研究提案中描述的实验将为潜在后续试验设计提供重要信息将 copanlisib 纳入现有 ALL 治疗方案的 II 期研究如果成功，我们的工作将。代表了 ALL 中枢神经系统预防性治疗的新突破，解决了一个尚未满足的领域患者的临床需要。