Utility of mTOR Inhibition in Hematologic Malignancies

Younes, Anas; Samad, Nousheen

doi:10.1634/theoncologist.2010-0318

Cited by 40 publications

(43 citation statements)

References 64 publications

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“…As neither of these lymphomas present in childhood, except for a few case reports of follicular lymphoma, the role of PI3K/AKT/mTOR signaling and the activity of inhibitors in these diseases will not be discussed; however, it can be found in other reviews. [60,65,193] The PI3K/AKT/mTOR pathway may be dysregulated in three lymphoma types that present in childhood: Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL), and ALK-positive anaplastic largecell lymphoma (ALCL).…”

Section: Lymphomasmentioning

confidence: 99%

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

et al. 2012

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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 malignanc...

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Section: Lymphomasmentioning

confidence: 99%

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

et al. 2012

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“…This article will focus on PI3K inhibitors because mTOR and AKT inhibitors have been extensively reviewed elsewhere. [5][6][7] Herein, we explore the rationale for targeting PI3K in hematologic malignancies and discuss the clinical development of PI3K inhibitors in these diseases.…”

Section: Introductionmentioning

confidence: 99%

Targeting the phosphoinositide 3-kinase pathway in hematologic malignancies

et al. 2014

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The phosphoinositide 3-kinase pathway represents an important anticancer target because it has been implicated in cancer cell growth, survival, and motility. Recent studies show that PI3K may also play a role in the development of resistance to currently available therapies. In a broad range of cancers, various components of the phosphoinositide 3-kinase signaling axis are genetically modified, and the pathway can be activated through many different mechanisms. The frequency of genetic alterations in the phosphoinositide 3-kinase pathway, coupled with the impact in oncogenesis and disease progression, make this signaling axis an attractive target in anticancer therapy. A better understanding of the critical function of the phosphoinositide 3-kinase pathway in leukemias and lymphomas has led to the clinical evaluation of novel rationally designed inhibitors in this setting. Three main categories of phosphoinositide 3-kinase inhibitors have been developed so far: agents that target phosphoinositide 3-kinase and mammalian target of rapamycin (dual inhibitors), pan-phosphoinositide 3-kinase inhibitors that target all class I isoforms, and isoform-specific inhibitors that selectively target the α, -β, -g, or -d isoforms. Emerging data highlight the promise of phosphoinositide 3-kinase inhibitors in combination with other therapies for the treatment of patients with hematologic malignancies. Further evaluation of phosphoinositide 3-kinase inhibitors in first-line or subsequent regimens may improve clinical outcomes. This article reviews the role of phosphoinositide 3-kinase signaling in hematologic malignancies and the potential clinical utility of inhibitors that target this pathway. ABSTRACTE. Jabbour et al. 8 haematologica | 2014; 99 (1) where it activates the AKT serine/threonine kinase by phosphorylating the threonine 308 residue (Figure 1). In turn, AKT phosphorylates many downstream substrates, including forkhead box protein O (FOXO), glycogen synthase kinase-3 (GSK-3), and Bcl-2 associated death promoter (BAD). AKT-mediated phosphorylation also inhibits the proline-rich AKT substrate of 40 kDa (PRAS40) and tuberous sclerosis complex 2 (TSC2), thereby activating mTOR complex 1 (mTORC1). mTORC1 consists of mTOR, mTOR-associated protein LST8 homolog (mLST8), regulatory associated protein of mTOR (RAPTOR), DEP domain TOR-binding protein (DEPTOR), and PRAS40. Activated mTORC1 stimulates protein synthesis by phosphorylating the ribosomal kinase proteins S6K1 (p70S6K/p85S6K) and S6K2 (p54S6K), and the eukaryotic initiation factor 4E-binding proteins (4E-BP1, 4E-BP2, and 4E-BP3). 17,18 mTORC2 is physiologically distinct from mTORC1 and consists of mTOR, mLST8, DEPTOR, rapamycin-insensitive companion of mTOR (RICTOR), protein observed with RIC-TOR (PROTOR), and mammalian stress-activated protein kinase interaction protein 1 (mSIN1). Unlike mTORC1, mTORC2 is considered rapamycin-insensitive because its inhibition requires prolonged drug exposure. While its function is not fully elucidated, mTORC2 is known to phosphoryla...

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“…Thus, the expression of Rheb is associated with increased activation of mTOR. 1 Activation of PI3K is frequently associated with the deletion or mutation of phosphatase and tensin homolog (PTEN) in many tumors. However, in Hodgkin's lymphoma, other mechanisms activate the pathway, including activation of CD30, CD40, and Receptor Activator of Nuclear Factor κ B receptors, mutations in the p85a subunit of PI3K and inactivation of PTEN function through phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

mTOR inhibitor in the treatment of Hodgkin’s lymphoma: a case report

Ibeas¹,

Cantos²,

Provencio³

2011

BLCTT

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Hodgkin's disease is curable in 90% of the cases diagnosed in early stages (I and II) and in 70% of all patients who suffer from the disease. Refractory disease occurs in 10%-15% of cases and is still a clinical challenge. Its treatment is based on intensive chemotherapy regimens with transplantation, but there are patients who relapse after transplantation who have a poor prognosis. At this point in time, there is a lack of effective treatment options with proven efficacy and there is a real need to investigate new treatment drugs with different mechanisms of action. A persistent activation of mTOR signaling has been identified in leukemia, Hodgkin's and non-Hodgkin's lymphoma, and multiple myeloma. Everolimus, an mTOR kinase inhibitor, is being used as an option in these cases with encouraging results. Here, the authors report their experience with a patient treated with everolimus.

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Utility of mTOR Inhibition in Hematologic Malignancies

Abstract: ABSTRACT

Cited by 40 publications

References 64 publications

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

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

Targeting the phosphoinositide 3-kinase pathway in hematologic malignancies

mTOR inhibitor in the treatment of Hodgkin’s lymphoma: a case report

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Utility of mTOR Inhibition in Hematologic Malignancies

Abstract: ABSTRACT

Cited by 40 publications

References 64 publications

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

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

Targeting the phosphoinositide 3-kinase pathway in hematologic malignancies

mTOR inhibitor in the treatment of Hodgkin&rsquo;s lymphoma: a case report

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mTOR inhibitor in the treatment of Hodgkin’s lymphoma: a case report