PMID- 22845486
OWN - NLM
STAT- MEDLINE
DCOM- 20130516
LR  - 20240213
IS  - 1179-2019 (Electronic)
IS  - 1174-5878 (Print)
IS  - 1174-5878 (Linking)
VI  - 14
IP  - 5
DP  - 2012 Oct 1
TI  - Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic 
      malignancies.
PG  - 299-316
LID - 10.2165/11594740-000000000-00000 [doi]
AB  - 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-Hodgkin's 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, the agents that are used to target this pathway, and 
      the results of preclinical and clinical trials, using those agents in childhood 
      hematologic cancers.
FAU - Barrett, David
AU  - Barrett D
AD  - Department of Pediatrics, Division of Oncology, Childrens Hospital of 
      Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 
      19104, USA.
FAU - Brown, Valerie I
AU  - Brown VI
FAU - Grupp, Stephan A
AU  - Grupp SA
FAU - Teachey, David T
AU  - Teachey DT
LA  - eng
GR  - K08 CA104882/CA/NCI NIH HHS/United States
GR  - R01 CA116660/CA/NCI NIH HHS/United States
GR  - R01 CA102646/CA/NCI NIH HHS/United States
GR  - 1 K08 CA104882-01A1/CA/NCI NIH HHS/United States
GR  - P30 CA016520/CA/NCI NIH HHS/United States
GR  - CA102646/CA/NCI NIH HHS/United States
GR  - CA1116660/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - Switzerland
TA  - Paediatr Drugs
JT  - Paediatric drugs
JID - 100883685
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology/therapeutic use
MH  - Child
MH  - Hematologic Neoplasms/drug therapy/*metabolism
MH  - Humans
MH  - Lymphoproliferative Disorders/drug therapy/*metabolism
MH  - Molecular Targeted Therapy
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Proto-Oncogene Proteins c-akt/antagonists & inhibitors/*metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism
PMC - PMC4214862
MID - NIHMS607332
EDAT- 2012/08/01 06:00
MHDA- 2013/05/17 06:00
PMCR- 2014/10/30
CRDT- 2012/08/01 06:00
PHST- 2012/08/01 06:00 [entrez]
PHST- 2012/08/01 06:00 [pubmed]
PHST- 2013/05/17 06:00 [medline]
PHST- 2014/10/30 00:00 [pmc-release]
AID - 10.2165/11594740-000000000-00000 [doi]
PST - ppublish
SO  - Paediatr Drugs. 2012 Oct 1;14(5):299-316. doi: 10.2165/11594740-000000000-00000.