Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas

Bhatt, Aadra P.; Bhende, Prasanna M.; Sin, Sang-Hoon; Roy, Debasmita; Dittmer, Dirk P.; Damania, Blossom

doi:10.1182/blood-2009-10-251082

Cited by 131 publications

(131 citation statements)

References 48 publications

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“…PEL displays activated PI3K, Akt and mTOR. Although single modulation of the mTOR pathway inhibited PEL proliferation, it has been reported that dual inhibition of PI3K and mTOR was significantly more efficacious in culture and in a PEL xenograft tumour model [59]. These data provide important preclinical proof-of-concept on the suitability of targeting the PI3K/mTOR axis with specific inhibitors for the treatment of PEL in HIV-infected patients [59].…”

Section: Lymphomasmentioning

confidence: 79%

mTOR as a multifunctional therapeutic target in HIV infection

Nicoletti

Fagone

Meroni

et al. 2011

Drug Discovery Today

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Section: Lymphomasmentioning

confidence: 79%

mTOR as a multifunctional therapeutic target in HIV infection

Nicoletti

Fagone

Meroni

et al. 2011

Drug Discovery Today

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“…Targeting multiple intermediates along the PI3K/AKT/mTOR axis may overcome this potential problem. [75][76][77] Most of the small molecule inhibitors that target mTORC1/2 also target other proteins in the PI3K/AKT/ mTOR signaling pathway, including PI3K, and are discussed in section 4.3. As with many kinase inhibitors, these agents can also affect other kinase pathways at higher concentrations, but the half maximal inhibitory concentration (IC50) values for mTOR kinase for many of these drugs, including PP242, are nearly 100-fold lower than their affinity for other kinases.…”

Section: Mtor Kinase Inhibitors (Mtorc1/2 Inhibitors)mentioning

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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“…NVP-BEZ235 is a pan-PI3K inhibitor that acts against all of the isoforms of PI3K and PI3K mutants. Previous studies have demonstrated the efficacy of NVP-BEZ235 as an antitumor agent in vitro and in vivo in glioblastoma, multiple myeloma, melanoma, lymphoma, www.nature.com/aps Pal I et al Acta Pharmacologica Sinica npg sarcoma, breast, lung, and ovarian cancer models [84][85][86][87][88][89][90][91][92][93] . In the case of colon cancer, NVP-BEZ23 decreases cellular proliferation and causes sustained inhibition of mTORC1 and mTORC2 with a transient PI3K blockade with no subsequent effect on apoptosis either in vitro or in vivo in a GEM model.…”

Section: Current Progress In Clinical Trialsmentioning

confidence: 99%

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

2012

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The PI3K-Akt pathway is a vital regulator of cell proliferation and survival. Alterations in the PIK3CA gene that lead to enhanced PI3K kinase activity have been reported in many human cancer types, including cancers of the colon, breast, brain, liver, stomach and lung. Deregulation of PI3K causes aberrant Akt activity. Therefore targeting this pathway could have implications for cancer treatment. The first generation PI3K-Akt inhibitors were proven to be highly effective with a low IC 50 , but later, they were shown to have toxic side effects and poor pharmacological properties and selectivity. Thus, these inhibitors were only effective in preclinical models. However, derivatives of these first generation inhibitors are much more selective and are quite effective in targeting the PI3K-Akt pathway, either alone or in combination. These second-generation inhibitors are essentially a specific chemical moiety that helps to form a strong hydrogen bond interaction with the PI3K/Akt molecule. The goal of this review is to delineate the current efforts that have been undertaken to inhibit the various components of the PI3K and Akt pathway in different types of cancer both in vitro and in vivo. Our focus here is on these novel therapies and their inhibitory effects that depend upon their chemical nature, as well as their development towards clinical trials.

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Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas

Cited by 131 publications

References 48 publications

mTOR as a multifunctional therapeutic target in HIV infection

mTOR as a multifunctional therapeutic target in HIV infection

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

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

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