Targeting the PI3K/Akt/mTOR pathway: Effective combinations and clinical considerations

LoPiccolo, Jaclyn; Blumenthal, Gideon M.; Bernstein, Wendy B.; Dennis, Phillip A.

doi:10.1016/j.drup.2007.11.003

Cited by 709 publications

(582 citation statements)

References 213 publications

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“…43,44 Some therapeutics have targeted the PIP3/AKT cascade due to the constitutive activation of the pathway in a variety of cancers. 45,46 Hence, WA which affects this pathway may also be a key small molecule for cancers that depend on enhanced Akt activity.…”

Section: Discussionmentioning

confidence: 99%

Anti-cancer activity of withaferin A in B-cell lymphoma

McKenna

Gachuki

Alhakeem

et al. 2015

Cancer Biology & Therapy

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Abbreviations: WA, Withaferin A; DLBCL, Diffuse large B cell lymphoma.Withaferin A (WA), a withanolide from the plant, Ashwagandha (Withania somnifera) used in Ayurvedic medicine, has been found to be valuable in the treatment of several medical ailments. WA has been found to have anticancer activity against various solid tumors, but its effects on hematological malignancies have not been studied in detail. WA strongly inhibited the survival of several human and murine B cell lymphoma cell lines. Additionally, in vivo studies with syngeneic-graft lymphoma cells suggest that WA inhibits the growth of tumor but does not affect other proliferative tissues. We demonstrate that WA inhibits the efficiency of NF-kB nuclear translocation in diffuse large B cell lymphomas and found that WA treatment resulted in a significant decrease in protein levels involved in B cell receptor signaling and cell cycle regulation. WA inhibited the activity of heat shock protein (Hsp) 90 as reflected by a sharp increase in Hsp70 expression levels. Hence, we propose that the anti-cancer effects of WA in lymphomas are likely due to its ability to inhibit Hsp90 function and subsequent reduction of critical kinases and cell cycle regulators that are clients of Hsp90.

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Section: Discussionmentioning

confidence: 99%

Anti-cancer activity of withaferin A in B-cell lymphoma

McKenna

Gachuki

Alhakeem

et al. 2015

Cancer Biology & Therapy

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“…Subsequently, drugs were developed that can target PI3K and AKT as well as a number of intermediates in the PI3K/AKT/mTOR signaling pathway, including agents that target individual protein kinases and drugs that target multiple kinases in the pathway. [3,4] Clinical trials investigating a number of agents are ongoing in pediatric ALL, lymphoblastic lymphoma, fibromatosis, and neuroblastoma, as well as a variety of childhood sarcomas, brain tumors, and lymphoproliferative disorders. In addition, there are promising preclinical data demonstrating activity of different agents against acute myelogenous leukemia (AML), CML, and a number of lymphomas.…”

Section: Introductionmentioning

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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“…Alterations in this pathway have been linked with increased neovascular formation, metastasis, and chemotherapy resistance. In addition, blocking PI3K/AKT/mTOR pathway activation leads to apoptosis or cell-cycle arrest in several different models (8)(9)(10)(11)(12). Consequently, this pathway has become a focus of anticancer drug development.…”

Section: Introductionmentioning

confidence: 99%

“…Numerous inhibitors of the PI3K/AKT/mTOR pathwayranging from allosteric inhibitors of mTORC1 (rapalogs) and AKT to ATP-competitive inhibitors of AKT, PI3K (pan-and isoform-specific), PI3K/mTOR, mTOR, S6K, and AKT/S6K-are being evaluated in clinical trials (9,11,25). Though generally tolerable with manageable adverse events, none has shown more than modest single-agent antitumor activity except for the recently approved PI3Kd inhibitor idelalisib (formerly CAL-101), which showed activity in lymphoid malignancies (26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%