Potentiating effects of RAD001 (Everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia

Crazzolara, Roman; Cisterne, Adam; Thien, Marilyn; Hewson, John; Baraz, Rana; Bradstock, Kenneth F.; Bendall, Linda J.

doi:10.1182/blood-2008-02-137752

Cited by 112 publications

(98 citation statements)

References 48 publications

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“…[132] Since that initial report, the activity of a number of rapalogs, including everolimus, sirolimus, and temsirolimus have been extensively studied in ALL in preclinical models by our group and others, establishing activity not only in cell lines and transgenic mouse models, but also against primary human ALL samples supported in vitro with stromal cells and in vivo with immunodeficient mouse strains. [131,132,[134][135][136][137][138][139][140] Our work and the work of others suggest that rapalogs may have the highest degree of activity against ALL types with the worst prognosis, including pre-T, adult, BCR-ABL and Ikaros mutant. [29,135,141,142] Supporting this are recent data demonstrating that early engraftment of pre-B-ALL in immune-deficient mice is associated with the activation of the mTOR pathway and a very high risk of relapse.…”

Section: Acute Lymphoblastic Leukemiamentioning

confidence: 53%

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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: Acute Lymphoblastic Leukemiamentioning

confidence: 53%

“…[136,[144][145][146] An added benefit was not found when rapalogs were combined with vincristine in vitro; however, the combination was found to be more effective than either drug alone in vivo. [136,139,146] Rapalogs have been studied in vivo in combination with methotrexate and corticosteroids.…”

Section: Acute Lymphoblastic Leukemiamentioning

confidence: 99%

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

et al. 2012

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“…9 mTOR inhibitors have significant anti-tumor activity as single agents in vitro and in experimental mouse models of ALL. 6,[10][11][12][13] Furthermore, positive interactions have been demonstrated between mTOR inhibitors and standard chemotherapeutics including vincristine, doxorubicin and methotrexate, 3,[13][14][15] as well as newer growth factor receptor or tyrosine kinase inhibitors with anti-cancer agents targeting growth factor pathways. 16 Indeed we have demonstrated that the survival of mice receiving vincristine and RAD001 is enhanced, while Teachey et al found similar results with the combination of methotrexate and CCI-779.…”

Section: Introductionmentioning

confidence: 99%

The mammalian target of rapamycin inhibitor RAD001 (everolimus) synergizes with chemotherapeutic agents, ionizing radiation and proteasome inhibitors in pre-B acute lymphocytic leukemia

Saunders¹,

Cisterne²,

Weiss³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundDespite incremental improvements in outcomes for patients with acute lymphoblastic leukemia, significant numbers of patients still die from this disease. Mammalian target of rapamycin inhibitors have shown potential in vitro and in vivo as therapeutic agents against a range of tumors including acute lymphoblastic leukemia. Design and MethodsFlow cytometry was used to evaluate drug-induced cell death in acute lymphoblastic leukemia cell lines and patients' samples. Human xenografts in immunocompromised mice were used to assess the in vivo effects of selected combinations. Pharmacological inhibitors and lentiviral small interfering ribonucleic acid knock-down of p53 were used to investigate the mechanism of cell killing involved. ResultsSynergistic interactions between RAD001 and cytotoxic agents were demonstrated in vitro and in vivo, with increased caspase-dependent killing. RAD001 suppressed p53 and p21 responses, while suppression of p53 did not prevent killing, indicating p53 independence. RAD001 and cytotoxic agents activated the JUN N-terminal kinase pathway and the combination further increased JUN N-terminal kinase activation. JUN N-terminal kinase inhibition reduced synergistic cell killing by cytotoxic agents and RAD001 in pre-B acute lymphoblastic leukemia cell lines and patients' samples. Bortezomib and MG132, which activate the JUN N-terminal kinase pathway, also synergized with RAD001 in killing pre-B acute lymphoblastic leukemia cells. Killing was greater when RAD001 was combined with proteasome inhibitors than with cytotoxic drugs. ConclusionsThese observations suggest that combining mammalian target of rapamycin inhibitors with conventional chemotherapy or selected novel agents has the potential to improve clinical responses in patients with pre-B acute lymphoblastic leukemia.Key words: acute lymphoblastic leukemia, proteasome inhibitors, RAD001, mTOR inhibitors, JNK. pre-B acute lymphocytic leukemia. Haematologica 2011;96(1):69-77. doi:10.3324/haematol.2010 This is an open-access paper. Citation: Saunders P, Cisterne A, Weiss J, Bradstock KF, and Bendall LJ. The mammalian target of rapamycin inhibitor RAD001 (everolimus) synergizes with chemotherapeutic agents, ionizing radiation and proteasome inhibitors inThe mammalian target of rapamycin inhibitor RAD001 (everolimus) synergizes with chemotherapeutic agents, ionizing radiation and proteasome inhibitors in pre-B acute lymphocytic leukemia

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“…The use of human ALL cells to engraft immune-deficient mice has been previously exploited to assess the effect of new drugs in the treatment of ALL 42,43 or even to predict the response of a specific patient to standard chemotherapy such as vincristine and dexamethasone. 44 However, our approach differs from those of previous studies as we have developed a model that can be transplanted into multiple generations of animals without significant changes either in their genetic or epigenetic makeup.…”

Section: In Vitro Activity Of Lbh589 In All Cellsmentioning

confidence: 99%

Preclinical activity of LBH589 alone or in combination with chemotherapy in a xenogeneic mouse model of human acute lymphoblastic leukemia

et al. 2012

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Histone deacetylases (HDACs) have been identified as therapeutic targets due to their regulatory function in chromatin structure and organization. Here, we analyzed the therapeutic effect of LBH589, a class I --II HDAC inhibitor, in acute lymphoblastic leukemia (ALL). In vitro, LBH589 induced dose-dependent antiproliferative and apoptotic effects, which were associated with increased H3 and H4 histone acetylation. Intravenous administration of LBH589 in immunodeficient BALB/ c-RAG2 À/À gc À/À mice in which human-derived T and B-ALL cell lines were injected induced a significant reduction in tumor growth. Using primary ALL cells, a xenograft model of human leukemia in BALB/c-RAG2 À/À gc À/À mice was established, allowing continuous passages of transplanted cells to several mouse generations. Treatment of mice engrafted with T or B-ALL cells with LBH589 induced an in vivo increase in the acetylation of H3 and H4, which was accompanied with prolonged survival of LBH589-treated mice in comparison with those receiving vincristine and dexamethasone. Notably, the therapeutic efficacy of LBH589 was significantly enhanced in combination with vincristine and dexamethasone. Our results show the therapeutic activity of LBH589 in combination with standard chemotherapy in pre-clinical models of ALL and suggest that this combination may be of clinical value in the treatment of patients with ALL.

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Potentiating effects of RAD001 (Everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia

Cited by 112 publications

References 48 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

The mammalian target of rapamycin inhibitor RAD001 (everolimus) synergizes with chemotherapeutic agents, ionizing radiation and proteasome inhibitors in pre-B acute lymphocytic leukemia

Preclinical activity of LBH589 alone or in combination with chemotherapy in a xenogeneic mouse model of human acute lymphoblastic leukemia

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