Unleashing the Efficacy of PI3K/AKT/mTOR Pathway Inhibitors in B-ALL

描述（申请人提供）：b细胞急性淋巴细胞白血病（B-ALL）是儿童最常见的癌症。最高危的B-ALL患者通常有激活的致癌激酶，如BCR-ABL、PDGFR和JAK。这些激酶聚集在PI3K/AKT/mTOR通路上，促进癌细胞增殖和存活。该通路的活性与预后不良和高复发率相关。该项目的目标是确定该途径的各种抑制剂与当前化疗药物联合使用时的潜在治疗益处。然而，我们的前期研究表明，抑制mTOR实际上会诱导化疗耐药，而PI3K或AKT抑制剂往往会增强B-ALL的杀伤。我们的第一个目标是确定哪种PI3K或AKT抑制剂与化疗结合效果最好，以更好地杀死B-ALL细胞系和原发性患者白血病细胞。此外，我们将确定添加PI3K或AKT抑制剂是否可以降低异种移植模型的复发率。我们的第二个目标是确定mtor诱导的化学耐药机制，以获得如何逆转这种化学耐药的线索。我们的初步数据还显示，BCR- ABL抑制剂达沙替尼可以在达沙替尼也抑制mTOR的细胞系中使细胞对甲氨蝶呤产生耐药性，但在达沙替尼不抑制mTOR的细胞系中则没有。因此，我们最后的目标是确定达沙替尼是否也能保护原代患者细胞免受甲氨蝶呤的侵害，以及达沙替尼mTOR活性的降低是否可以作为一种生物标志物，表明达沙替尼是否应该与甲氨蝶呤联合使用。本研究不仅将指导更有效地使用PI3K/AKT/mTOR抑制剂治疗B-ALL，也将指导目前临床上达沙替尼的使用。

DESCRIPTION (provided by applicant): B-cell acute lymphoblastic leukemia (B-ALL) is the most common cancer in children. The most high-risk B-ALL patients often have activated oncogenic kinases like BCR-ABL, PDGFR and JAK. These kinases converge on the PI3K/AKT/mTOR pathway, which promotes cancer cell proliferation and survival. The activity of this pathway correlates with poor outcome and higher relapse. The goal of this project is to determine the potential therapeutic benefits of various inhibitors of this pathway when combined with the current chemotherapeutic agents. However, our pilot studies have revealed that inhibition of mTOR actually induces chemotherapeutic resistances whereas PI3K or AKT inhibitors tend to enhance B-ALL killing. Our first aim is to determine which PI3K or AKT inhibitors combine best with chemotherapy to better kill B-ALL cell lines and primary patient leukemia cells. Moreover, we will determine if the addition of PI3K or AKT inhibitors can reduce relapse rates in xenograft models. Our second aim is to determine the mechanism of mTOR-induced chemoresistance to gain clues as to how this chemoresistance can be reversed. Our preliminary data also shows that the BCR- ABL inhibitor dasatinib can make cells resistant to methotrexate in cell lines where dasatanib also inhibits mTOR but not in cell lines where dasatinib does not inhibit mTOR. Thus our last aim is to determine if dasatinib also protects primary patient cells from methotrexate and if reduction in mTOR activity by dasatinib can serve as a biomarker to indicate if dasatinib should be combined with methotrexate. This study will not only guide the more effective use of PI3K/AKT/mTOR inhibitors in B-ALL, but also the current use of dasatinib in the clinic.