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 i s 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 i s 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.

Public Health Relevance

A group of enzymes known as PI3K/AKT/mTOR are important targets for new cancer drugs since the enzymes control cell growth and survival in various cancer types. The goal of this project is to find which enzyme should be inhibited to best increase leukemia cell killing by chemotherapy drugs, which could improve the therapeutic outcome of leukemia patients. The second goal is to understand why targeting this group of enzymes is not always effective, and how to overcome these shortcomings.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Jakowlew, Sonia B
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University of California Irvine
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Vo, Thanh-Trang T; Lee, J Scott; Nguyen, Duc et al. (2017) mTORC1 Inhibition Induces Resistance to Methotrexate and 6-Mercaptopurine in Ph+ and Ph-like B-ALL. Mol Cancer Ther 16:1942-1953
Lee, Jong-Hoon Scott; Vo, Thanh-Trang; Fruman, David A (2016) Targeting mTOR for the treatment of B cell malignancies. Br J Clin Pharmacol 82:1213-1228
Lee, J Scott; Tang, Sarah S; Ortiz, Veronica et al. (2015) MCL-1-independent mechanisms of synergy between dual PI3K/mTOR and BCL-2 inhibition in diffuse large B cell lymphoma. Oncotarget 6:35202-17
Vo, Thanh-Trang T; Fruman, David A (2015) INPP4B Is a Tumor Suppressor in the Context of PTEN Deficiency. Cancer Discov 5:697-700
Beagle, Brandon R; Nguyen, Duc M; Mallya, Sharmila et al. (2015) mTOR kinase inhibitors synergize with histone deacetylase inhibitors to kill B-cell acute lymphoblastic leukemia cells. Oncotarget 6:2088-100