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Targeting the PI3K/mTOR Pathway in Pediatric Hematologic Malignancies.

ABSTRACT: A complex interplay of intracellular signaling networks orchestrates normal cell growth and survival, including translation, transcription, proliferation, and cell cycle progression. Dysregulation of such signals occurs commonly in many malignancies, thereby giving the cancer cell a survival advantage, but also providing possible targets for therapeutic intervention. Activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway contributes to the proliferative advantage of malignant cells and may confer resistance to chemotherapy in various hematologic malignancies. The initial mTOR inhibitor, sirolimus (also known as rapamycin), was first discovered in 1975 in the soil of Easter Island. Sirolimus was originally developed as an anti-fungal agent given its macrolide properties, but was approved by the Food and Drug Administration (FDA) in 1999 as an immunosuppressive agent for renal transplantation patients once its T cell suppression characteristics were recognized. Shortly thereafter, recognition of sirolimus's ability to inhibit cellular proliferation and cell cycle progression brought sirolimus to the forefront as a possible inhibitor of mTOR. In the subsequent decade, the functional roles of the mTOR protein have been more fully elucidated, and this protein is now known to be a key regulator in a highly complex signaling pathway that controls cell growth, proliferation, metabolism, and apoptosis. This article discusses the dysregulation of PI3K/mTOR signaling in hematologic malignancies, including acute and chronic leukemias, lymphomas, and lymphoproliferative disorders. The current repertoire of PI3K/mTOR pathway inhibitors in development and clinical trials to date are described with emphasis upon pediatric hematologic malignancies (Figure 1). Investigation of small molecule inhibitors of this complex signaling network is an active area of oncology drug development.

SUBMITTER: Tasian SK

PROVIDER: S-EPMC4032892 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Targeting the PI3K/mTOR Pathway in Pediatric Hematologic Malignancies.

Tasian Sarah K SK Teachey David T DT Rheingold Susan R SR

Frontiers in oncology 20140516

A complex interplay of intracellular signaling networks orchestrates normal cell growth and survival, including translation, transcription, proliferation, and cell cycle progression. Dysregulation of such signals occurs commonly in many malignancies, thereby giving the cancer cell a survival advantage, but also providing possible targets for therapeutic intervention. Activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathw ...[more]

PMID: 24904824

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Project description: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.

Project description:BackgroundMesothelioma is a notoriously chemotherapy-resistant neoplasm, as is evident in the dismal overall survival for patients with those of asbestos-associated disease. We previously demonstrated co-activation of multiple receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR), MET, and AXL in mesothelioma cell lines, suggesting that these kinases could serve as novel therapeutic targets. Although clinical trials have not shown activity for EGFR inhibitors in mesothelioma, concurrent inhibition of various activated RTKs has pro-apoptotic and anti-proliferative effects in mesothelioma cell lines. Thus, we hypothesised that a coordinated network of multi-RTK activation contributes to mesothelioma tumorigenesis.MethodsActivation of PI3K/AKT/mTOR, Raf/MAPK, and co-activation of RTKs were evaluated in mesotheliomas. Effects of RTK and downstream inhibitors/shRNAs were assessed by measuring mesothelioma cell viability/growth, apoptosis, activation of signalling intermediates, expression of cell-cycle checkpoints, and cell-cycle alterations.ResultsWe demonstrate activation of the PI3K/AKT/p70S6K and RAF/MEK/MAPK pathways in mesothelioma, but not in non-neoplastic mesothelial cells. The AKT activation, but not MAPK activation, was dependent on coordinated activation of RTKs EGFR, MET, and AXL. In addition, PI3K/AKT/mTOR pathway inhibition recapitulated the anti-proliferative effects of concurrent inhibition of EGFR, MET, and AXL. Dual targeting of PI3K/mTOR by BEZ235 or a combination of RAD001 and AKT knockdown had a greater effect on mesothelioma proliferation and viability than inhibition of individual activated RTKs or downstream signalling intermediates. Inhibition of PI3K/AKT was also associated with MDM2-p53 cell-cycle regulation.ConclusionsThese findings show that PI3K/AKT/mTOR is a crucial survival pathway downstream of multiple activated RTKs in mesothelioma, underscoring that PI3K/mTOR is a compelling target for therapeutic intervention.

Dataset Information

Targeting the PI3K/mTOR Pathway in Pediatric Hematologic Malignancies.

Publications

Targeting the PI3K/mTOR Pathway in Pediatric Hematologic Malignancies.

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