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Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

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Abstract

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.

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Acknowledgements

The work described in this review was supported by grants from the United States Immunodeficiency Network (USIDNET) through the National Institute of Allergy and Infectious Diseases (NIAID) grant numbers N01-A1-30070 and R56A1091791, a Foerderer-Murray Award, the Goldman Philanthropic Partnerships and the Rockefeller Brothers Fund, the Partnership for Cures Patient Impact Initiative, a Larry and Helen Hoag Foundation Clinical Translational Research Career Development Award, and the Leukemia and Lymphoma Society (David Teachey); National Institutes of Health (NIH) 1 K08 CA104882-01A1, grant number IRG-78-002-30 from the American Cancer Society, the Children’s Cancer Fund, the Kimmel Foundation, the Florence R.C. Murray Program at the Children’s Hospital of Philadelphia and W.W. Smith Charitable Trust (Valerie Brown); and NIH CA102646, CA1116660, ACS RSG0507101, and the Weinberg Fund of the Children’s Hospital of Philadelphia (Stephan Grupp). Stephan Grupp and Valerie Brown have a patent covering methods of treatment for ALL, including treatment with rapamycin or a derivative thereof (patent number 7026330). David Barrett has no conflicts of interest to declare that are directly relevant to the content of this review.

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  1. Department of Pediatrics, Division of Oncology, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    David Barrett, Valerie I. Brown, Stephan A. Grupp &  David T. Teachey MD

  2. Department of Pediatrics, Division of Hematology, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, 3008 CTRB, 3501 Civic Center Boulevard, Philadelphia, Pennsylvania, 19104, USA

    David T. Teachey MD

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  1. David Barrett
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  2. Valerie I. Brown
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  3. Stephan A. Grupp
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  4. David T. Teachey MD
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Correspondence to David T. Teachey MD.

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Barrett, D., Brown, V.I., Grupp, S.A. et al. Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies. Pediatr Drugs 14, 299–316 (2012). https://doi.org/10.1007/BF03262236

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