Lineage-specific signaling and targeting of PI3K gamma in myeloid malignancies

项目概要/摘要 骨髓恶性肿瘤是一组通常致命的癌症，其来源于骨髓细胞的骨髓谱系细胞。 包括急性髓性白血病（AML）和多种骨髓增生异常综合征 (MDS)和骨髓增生性肿瘤（MPN），后者包括慢性骨髓性白血病 (CML)和原发性骨髓纤维化AML是成人中最常见的急性白血病， 显著的癌症相关死亡率，5年生存率为28.9%。虽然最近的进展， 基因组学和其他领域的研究极大地提高了我们对 AML发病机制，这些进展尚未转化为总体结局的显著改善 在过去的40年里，这种疾病的患者人数相对保持不变。 与AML的情况形成鲜明对比的是，被诊断患有不同白血病、慢性白血病和其他白血病的患者的结局 淋巴细胞白血病（CLL），近几十年来已经被靶向蛋白质的药物所改变， 布鲁顿酪氨酸激酶（BTK）、PI 3 Kd和CD 20，其表达和功能是B细胞所特有的 这些癌症的起源。因此，这些表现出窄副作用特征的药剂可以被施用。 长期使用，单独使用或与另一种药物或其他药物联合使用，以产生非常长期的疾病 控制在靶向具有谱系特异性表达谱的蛋白质方面的类似进展， 依赖性导致了乳腺、前列腺和前列腺癌患者治疗的实质性改善， 神经嵴源性肿瘤 最近，我们发现PI 3 Kg全酶由催化性p110 g和调节性p101组成， 亚基，是AML中AKT信号传导、存活和化疗敏感性的重要调节因子，其表达与AML中的AKT信号传导、存活和化疗敏感性相关。 仅限于造血细胞，特别是髓系细胞。因此，针对这一关键 信号传导节点在AML细胞系、患者源性培养物和PDX模型中产生显著的抗肿瘤作用 没有历史上与泛或a/B亚型特异性PI 3 K抑制相关的全身毒性。在这 建议，我们描述了研究，以全面表征PI 3 Kg的表达和功能，在所有 主要AML亚型以及造血系统的正常细胞类型。此外，我们建议定义 AML中PI 3 Kg表达的基本机制，然后评估治疗效果， 在金标准异种移植物、人源化小鼠和遗传学上靶向该信号传导轴的安全性 AML的工程小鼠模型。总之，这些研究将定义一个新的，谱系限制的信号轴 调节髓系恶性肿瘤的存活，其选择性靶向可显著增加治疗效果， 急性髓细胞白血病的治疗

Project Summary/Abstract Myeloid malignancies are a group of often lethal cancers that derive from cells of the myeloid lineage of the hematopoietic system and include acute myeloid leukemia (AML) and diverse myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), the latter of which include chronic myelogenous leukemia (CML) and primary myelofibrosis. AML, the most common acute leukemia in adults, is responsible for significant cancer-related mortality, with a five-year survival rate of 28.9%. Although recent advances in genomics and other areas have significantly improved our understanding of the molecular events that underlie AML pathogenesis, these advances have yet to translate to significant improvements in the overall outcomes of patients with the disease, which have remained relatively unchanged over the last 40 years. In notable contrast to the scenario for AML, outcomes in patients diagnosed with a different leukemia, chronic lymphocytic leukemia (CLL), have been transformed in recent decades by drugs that target proteins such as Bruton’s tyrosine kinase (BTK), PI3Kd, and CD20, whose expression and function are unique to the B cell lineage from which these cancers arise. These agents, which exhibit narrow side effect profiles, can thus be used chronically, alone or in combination with one another or additional agents to yield very long term disease control. Similar advances in the targeting of proteins with lineage-specific expression profiles and dependencies have led to substantial improvements in the treatment of patients with breast, prostate, and neural crest-derived tumors. Recently, we discovered that the PI3Kg holoenzyme, comprised of the catalytic p110g and regulatory p101 subunits, is a profound regulator of AKT signaling, survival, and chemosensitivity in AML whose expression is restricted to hematopoietic cells, and particularly those of the myeloid lineage. Thus, targeting this critical signaling node leads to marked antitumor effects in AML cell lines, patient-derived cultures, and PDX models without the systemic toxicities historically associated with pan- or a/b isoform-specific PI3K inhibition. In this proposal, we describe studies to comprehensively characterize the expression and function of PI3Kg across all major AML subtypes as well the normal cell types of the hematopoietic system. Further, we propose to define the fundamental mechanisms governing PI3Kg expression in AML, then evaluate the therapeutic efficacy and safety of targeting this signaling axis in gold standard xenograft, humanized mouse, and genetically engineered mouse models of AML. Together, these studies will define a novel, lineage-restricted signaling axis regulating survival in myeloid malignancies whose selective targeting may add substantially to the therapeutic armamentarium in AML.