The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of
rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in
disorders of cell growth and survival, including a number of pediatric
hematologic malignancies. The pathway can be abnormally activated in childhood
acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and
chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and
lymphoproliferative disorders. Most commonly, this abnormal activation occurs as
a consequence of constitutive activation of AKT, providing a compelling
rationale to target this pathway in many of these conditions.
A variety of agents, beginning with the rapamycin analogue (rapalog)
sirolimus, have been used successfully to target this pathway in a number of
pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical
activity against ALL, which has led to a number of clinical trials. Moreover,
rapalogs can synergize with a number of conventional cytotoxic agents and
overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL
treatment, including methotrexate and corticosteroids. Based on preclinical
data, rapalogs are also being studied in AML, CML, and non-Hodgkinâs
lymphoma. Recently, significant progress has been made using rapalogs to treat
pre-malignant lymphoproliferative disorders, including the autoimmune
lymphoproliferative syndrome (ALPS); complete remissions in children with
otherwise therapy-resistant disease have been seen.
Rapalogs only block one component of the pathway (mTORC1), and newer
agents are under preclinical and clinical development that can target different
and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these
agents have been tolerated in early-phase clinical trials. A number of PI3K
inhibitors are under investigation. Of note, most of these also target other
protein kinases. Newer agents are under development that target both mTORC1 and
mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical
data suggest these dual- and multi-kinase inhibitors are more potent than
rapalogs against many of the aforementioned hematologic malignancies.
Two classes of AKT inhibitors are under development, the
alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes
have agents currently in clinical trials. A number of drugs are in development
that target other components of the pathway, including eukaryotic translation
initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase
1 (PDK1). Finally, a number of other key signaling pathways interact with
PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These
alternative pathways are being targeted alone and in combination with
PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric
hematologic malignancies. This review provides a comprehensive overview of the
abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic
malignancies, t...