Targeting the PI3K/AKT/mTOR signaling network in acute myelogenous leukemia

Martelli, Alberto M.; Evangelisti, Camilla; Chiarini, Francesca; Grimaldi, Cecilia; Manzoli, Lucia; McCubrey, James A.

doi:10.1517/14728220903136775

Cited by 105 publications

(125 citation statements)

References 169 publications

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“…1 This review will discuss how this pathway may be aberrantly regulated in leukemia and contribute to therapeutic sensitivity/ resistance, drug resistance and in some cases poor prognosis. 1,2 However, increased activation of this pathway can often be correlated with enhanced sensitivity to targeted therapy. 1,2 Inhibition of PI3K, Akt, mTOR and in some cases Ras or Ras homolog enriched in brain (Rheb) may prove useful in leukemia treatment.…”

Section: Introductionmentioning

confidence: 99%

“…1,2 However, increased activation of this pathway can often be correlated with enhanced sensitivity to targeted therapy. 1,2 Inhibition of PI3K, Akt, mTOR and in some cases Ras or Ras homolog enriched in brain (Rheb) may prove useful in leukemia treatment. These observations have propelled the pharmaceutical industry to develop inhibitors that target important components of these pathways.…”

Section: Introductionmentioning

confidence: 99%

“…PI3K serves to phosphorylate a series of membrane phospholipids, including phosphatidylinositol 4-phosphate (PtdIns(4)P) and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P 2 ), catalyzing the transfer of ATP-derived phosphate to the D-3 position of the inositol ring of membrane phosphoinositides, thereby forming the second messenger lipid phosphatidylinositol 3,4-bisphosphate (PtdIns (3,4)P 2 ) and phosphatidylinositol 3,4,5-trisphosphate (PtdIns (3,4,5)P 3 ). 2 Most often, PI3K is activated via the binding of a ligand to its cognate receptor, whereby p85 associates with phosphorylated tyrosine residues on the receptor via an Src-homology 2 domain. After association with the receptor, the p110 catalytic subunit then transfers phosphate groups to the aforementioned membrane phospholipids.…”

Section: Introductionmentioning

confidence: 99%

“…After association with the receptor, the p110 catalytic subunit then transfers phosphate groups to the aforementioned membrane phospholipids. 2 It is these lipids, specifically PtdIns(3,4,5)P 3 , that attract a series of kinases to the plasma membrane, thereby initiating the signaling cascade. 2 The genes encoding the PI3K catalytic and regulatory chains are members of multi-gene families.…”

Section: Introductionmentioning

confidence: 99%

“…2 It is these lipids, specifically PtdIns(3,4,5)P 3 , that attract a series of kinases to the plasma membrane, thereby initiating the signaling cascade. 2 The genes encoding the PI3K catalytic and regulatory chains are members of multi-gene families. Historically, the p110a isoform has been the best-characterized catalytic subunit; however, it has been recently shown that the p110d isoform may play a larger role in leukemogenesis [3][4][5] and tumor surveillance than expected previously.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

et al. 2011

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

et al. 2011

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Buparlisib, a PI3K inhibitor, demonstrates acceptable tolerability and preliminary activity in a phase I trial of patients with advanced leukemias

et al. 2016

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Phosphatidylinositol-3-kinase (PI3K) signaling plays a crucial role in oncogene-mediated tumor growth and proliferation. Buparlisib (BKM120) is an oral pan-class I PI3K inhibitor. This phase I study was conducted to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of BKM120 in patients (pts) with relapsed/refractory acute leukemias. Fourteen pts (12 acute myeloid leukemia, 1 acute lymphoblastic leukemia, and 1 mixed phenotype leukemia) were enrolled. Twelve pts received BKM-120 80 mg/day and two 100 mg/day. The MTD was 80 mg/day. Of the 14 patients treated, the best response was stable disease in one patient that lasted 82 days. The median survival for all patients was 75 days (range 10–568). Three patients with a 3q26 chromosome abnormality had a significantly improved median survival of 360 days (range 278–568) as compared to a median survival of 57 days (range, 10–125) among the 11 other patients. The most frequent drug-related toxicities included confusion, mucositis, dysphagia, and fatigue. Western blot profiling revealed a decrease in p-pS6K/total pS6K in 5/7 (71%) available patient samples with a mean quantitative inhibition of 65% (range, 32–100%) and a decrease in p-FOXO3/total FOXO3 in 4/6 (67%) samples with a mean quantitative inhibition of 93% (range, 89–100%). BKM120 administered at 80 mg/day showed modest efficacy and was tolerable in advanced acute leukemias.

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Synthesis of SHIP1‐Activating Analogs of the Sponge Meroterpenoid Pelorol

et al. 2012

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Two biomimetic approaches have been used to synthesize analogs of the SHIP1‐activating sponge meroterpenoid pelorol (1). One approach started from the chiral pool plant natural product sclareolide, which has the same absolute configuration as pelorol. The second approach utilized an enantioselective polyene cyclization to efficiently access both absolute configurations of the pelorol meroterpenoid skeleton and to prepare A‐ring functionalized compounds. Selected analogs have been evaluated for water solubility and biological activity. It was found that the undesirable catechol and ester functionalities in 1 could be removed to give MN100 (3), without a decrease in SHIP1‐activating ability. A further refinement led to the resorcinol analog 18, which is the most effective SHIP1‐activating pelorol analog made to date. The HCl salt of ent‐28, a C‐3 amino analog of 18, is about 500,000‐fold more soluble in water than MN100 (3). (±)‐28·HCl activates SHIP1 in vitro, inhibits Akt phosphorylation in stimulated MOLT‐4 (SHIP+) cells, and is active in a dose‐dependent manner in a mouse model of inflammation when administered by oral gavage (ED50 ≈ 0.1 mg/kg). Pelorol analogs ent‐28 or (±)‐28 are promising chemical tools for further preclinical in vivo evaluation of the potential of SHIP1 activators as therapeutics for treating hematopoietic diseases involving aberrant activation of PI3K cell signaling.

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Targeting the PI3K/AKT/mTOR signaling network in acute myelogenous leukemia

Cited by 105 publications

References 169 publications

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

Buparlisib, a PI3K inhibitor, demonstrates acceptable tolerability and preliminary activity in a phase I trial of patients with advanced leukemias

Synthesis of SHIP1‐Activating Analogs of the Sponge Meroterpenoid Pelorol

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