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Other targeted inhibitors (MDM2, MEK, STAT3, PIM kinase, JAK2)

Leukemia Insights - Spring 2010

Phase I study of RO5045337

In pediatric ALL, overexpression of murine double minute (MDM2) protein by lymphoblasts is typically associated with a wild-type p53 phenotype and chemoresistance. A small molecule antagonist of MDM2, 2nutlin-3 inhibits the MDM2-p53 interaction, resulting in induction of p53 activity and apoptosis. Potent in vitro killing of lymphoblasts derived from several primary leukemia samples and more than 30 cell lines has been reported after exposure to nutlin-3. In this study, RO5045337, an oral formulation of nutlin-3, is administered either daily for 10 days or every other day for 11 days of every 28 day cycle. The dose escalation phase of this study is ongoing with preliminary clinical activity observed both in lymphoid and myeloid malignancies [M. Andreeff, personal communication].

MEK Inhibitors: Phase II study of AS703026; Phase I/II study of GSK1120212

The Ras/Raf/MEK/ERK cascade modulates the activity of nuclear factors, which in turn regulate the transcription of genes required for proliferation and differentiation. Mitogen-activated protein kinase (MEK) activation is known to confer proliferative and survival advantages to leukemia cells. MEK inhibitors have increasingly been recognized as potential therapeutic agents which target this pathway. In vitro data suggest multiple interactions of MEK/ERK with apoptosis pathways. For example, BIM (BCL-2 interacting mediator of cell death) is inactivated by ERK-mediated phosphorylation. In vitro data also suggest synergistic enhancement of dexamethasone-induced apoptosis of lymphoblasts when administered with MEK inhibitors. In the phase II study of the MEK inhibitor AS703026, therapy is administered orally twice daily 5 days each week or twice daily for 21 days of a 28-day cycle. In the phase I-II study of the MEK inhibitor GSK1120212, therapy is given orally once daily continuously. Both studies are actively accruing.

Phase I study of OPB-31121

Multiple counterregulatory mechanisms have been identified in B-cell precursors that operate to regulate cell survival and growth, thereby encuring the orderly development and differentiation of B-cells. Inappropriate apoptosis may underlie the pathogenesis of resistance in leukemias, which makes control of apoptosis an important potential target for therapeutic interventions. Bruton’s tyrosine kinase (BTK) is the first tyrosine kinase to be identified as a dual-function regulator of apoptosis, which promotes radiation-induced apoptosis but inhibits Fas-activated apoptosis in B-cells. BTK functions in a pro-apoptotic manner when B-cells are exposed to reactive oxygen intermediates, at least in part by down-regulating the anti-apoptotic activity of STAT-3, which is a member of the signal transducer and activator of transcription (STAT) family of proteins. OPB-31121 appears to strongly inhibit IL-6 induced phosphorylation of STAT-3. Blockade of aberrant STAT-3 signaling in vitro can induce tumor cell apoptosis and regression. In this phase I dose escalation study, OPB-31121 is administered orally once daily for 7 days of a 21-day cycle. Preliminary clinical activity has been observed [G. Borthakur, personal communication].

Phase I study of SGI-1776

The serine/threonine PIM kinases are up-regulated in several hematological malignancies, and play an important role in key signal transduction pathways, including those regulated by MYC, MYCN, FLT-3, BCR-ABL, HOX9 and EWS fusions. In vitro, T-lymphoblastic leukemia/lymphoma cell lines have been exquisitely sensitive to inhibitors of PIM kinases. SGI-1776 is an orally bioavailable inhibitor of PIM1 kinase. In this dose escation study, SGI-1776 is given twice a day on a continuous basis. Accrual is planned within the upcoming months.

Phase II study of INCB018424

Dysregulation of the Janus kinase (JAK)/STAT pathway has been shown to be involved in the pathophysiology of several hematological malignancies. Activating JAK mutations (JAK1, JAK2, and JAK3) have been reported in pediatric ALL, particularly in association with Down’s syndrome. JAK1 and JAK2 mutations involve highly conserved residues in the kinase and pseudokinase domains and result in constitutive JAK-STAT activation and growth factor independence. The JAK-mutated cases had a gene expression signature similar to BCR-ABL1 pediatric ALL. Mutations of JAK2 were associated with over-expression of CRLF2 (type I cytokine receptor subunit). INCB018424 is an oral inhibitor of the JAKs (including JAK1) that is currently under development for myeloproliferative disorders, but has potential for therapeutic efficacy in ALL owing to the association of JAK mutations with poor outcome. In this phase II trial, INCB018424 is administered orally twice daily on a continuous basis.

© 2014 The University of Texas MD Anderson Cancer Center