Two acute myeloid leukemia patient subsets are identified based on the constitutive PI3K-Akt-mTOR signaling of their leukemic cells; a functional, proteomic, and transcriptomic comparison

Nepstad, Ina; Hatfield, Kimberley Joanne; Aasebø, Elise; Hernandez-Valladares, Maria; Brenner, Annette K.; Bartaula-Brevik, Sushma; Berven, Frode S.; Selheim, Frode; Skavland, Jørn; Gjertsen, Bjørn Tore; Reikvam, Håkon; Bruserud, Øystein

doi:10.1080/14728222.2018.1487401

Cited by 16 publications

(16 citation statements)

References 196 publications

(236 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While therapeutic targeting of the PI3K/Akt/mTOR signaling cascade at multiple molecular levels has been shown preclinically to provide better antitumor effects than selective inhibition of only individual components of this pathway, a priori identification of leukemias likely to respond has so far proven elusive. In AML, constitutive PI3K-Akt-mTOR activation was shown to differ between patients with high constitutive pathway activation [44,45]. Being associated with less monocytic differentiation and increased frequency of adverse karyotypes, indicating that activation level may depend on complex phenotypic differences [44,45].…”

Section: Discussionmentioning

confidence: 99%

A phase I study of a dual PI3-kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia

Lang

Wunderle

Badura

et al. 2020

BMC Pharmacol Toxicol

View full text Add to dashboard Cite

Background Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The primary objective of this phase I single center open label study was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the dual pan-class I PI3K and mTOR inhibitor BEZ235 in patients with advanced leukemia. Methods Herein patients > 18 years of age who had relapsed or showed refractory leukemia were treated with BEZ235 (orally at 300–400 mg BID (cohort − 1/1)) to assess safety, tolerability, preliminary efficacy and pharmacokinetic (PK). Adverse events data and serious adverse events were analyzed and haematological and clinical biochemistry toxicities were assessed from laboratory test parameters. Response was assessed for the first time at the end of cycle 1 (day 29) and after every subsequent cycle. Pharmacokinetic and pharmacodynamic analyses of BEZ235 were also included (BEZ235 plasma levels, phosphorylation of AKT, S6 and 4EBP1). On statistics this trial is a multiple ascending dose study in which a following variant of the 3 + 3 rule (“Rolling Six”), a minimum of 6 and a maximum of 12 patients was recruited for the dose escalation and another 5 were planned for the expansion phase. Results Twenty-four patients with ALL (n = 11) or AML (n = 12) or CML-BP (n = 1) were enrolled. All patients had failed one (n = 5) or more lines of therapy (n = 5) and 14 patients were in refractory / refractory relapse. No formal MTD was defined, stomatitis and gastrointestinal toxicity at 400 mg BID dose was considered incompatible with prolonged treatment. The RP2D of BEZ235 was defined as 300 mg BID. Four of 24 patients showed clinical benefit. Twenty-two of 24 patients discontinued because of progression, (median time to progression 27 days (4d-112d). There was no association between PK parameters and efficacy or tolerability. Conclusions Combined inhibition of PI3K and mTOR inhibits a clinically meaningful driver pathway in a small subset of patients with ALL, with no benefit in patients with AML. Trial registration ClinicalTrials.gov, identifier NCT01756118. retrospectively registered 19th December 2012, https://clinicaltrials.gov/ct2/show/NCT01756118.

show abstract

Section: Discussionmentioning

confidence: 99%

A phase I study of a dual PI3-kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia

Lang

Wunderle

Badura

et al. 2020

BMC Pharmacol Toxicol

View full text Add to dashboard Cite

show abstract

“…Mutations in membrane bound-proteins, such as RTKs or GTPases, are major causes of dysregulated PI3K-Akt-mTOR signaling and are observed in 55% of AML cases [13,66]. However, no available data indicate that PI3K-Akt-mTOR activity is related to specific etiology of the disease, i.e., de novo, secondary or refractory/relapsed AML, nor to specific molecular subtypes, i.e., nucleophosmin 1 (NPM1) or fms like tyrosine kinase 3 (FLT3) mutations or other cytogenetic or molecular genetic alterations [84][85][86].…”

Section: Pi3k-akt-mtor Signaling In Amlmentioning

confidence: 99%

The PI3K-Akt-mTOR Signaling Pathway in Human Acute Myeloid Leukemia (AML) Cells

Nepstad

Hatfield

Grønningsæter

et al. 2020

IJMS

Self Cite

185

113

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) is a heterogeneous group of diseases characterized by uncontrolled proliferation of hematopoietic stem cells in the bone marrow. Malignant cell growth is characterized by disruption of normal intracellular signaling, caused by mutations or aberrant external signaling. The phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway (PI3K-Akt-mTOR pathway) is among one of the intracellular pathways aberrantly upregulated in cancers including AML. Activation of this pathway seems important in leukemogenesis, and given the central role of this pathway in metabolism, the bioenergetics of AML cells may depend on downstream signaling within this pathway. Furthermore, observations suggest that constitutive activation of the PI3K-Akt-mTOR pathway differs between patients, and that increased activity within this pathway is an adverse prognostic parameter in AML. Pharmacological targeting of the PI3K-Akt-mTOR pathway with specific inhibitors results in suppression of leukemic cell growth. However, AML patients seem to differ regarding their susceptibility to various small-molecule inhibitors, reflecting biological heterogeneity in the intracellular signaling status. These findings should be further investigated in both preclinical and clinical settings, along with the potential use of this pathway as a prognostic biomarker, both in patients receiving intensive curative AML treatment and in elderly/unfit receiving AML-stabilizing treatment.

show abstract

“…In AML, constitutive PI3K-Akt-mTOR activation was shown to differ between patients with high constitutive pathway activation. 46,47 Being associated with less monocytic differentiation and increased frequency of adverse karyotypes, indicating that activation level may depend on complex phenotypic differences. 46,47 In B cell precursor ALL, we previously showed that combined suppression of PI3K, mTORC1 and mTORC2 displayed greater antileukemic activity than selective inhibitors of PI3K, mTORC1 or mTORC1 and mTORC2 irrespective of their genetic subtype and in case of BCR-ABL1 positive ALL their responsiveness to ABL-directed kinase inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…46,47 Being associated with less monocytic differentiation and increased frequency of adverse karyotypes, indicating that activation level may depend on complex phenotypic differences. 46,47 In B cell precursor ALL, we previously showed that combined suppression of PI3K, mTORC1 and mTORC2 displayed greater antileukemic activity than selective inhibitors of PI3K, mTORC1 or mTORC1 and mTORC2 irrespective of their genetic subtype and in case of BCR-ABL1 positive ALL their responsiveness to ABL-directed kinase inhibitors. 48 In T-ALL, a vital role in Notch-driven thymocyte differentiation and leukemia has been assigned to mTOR complex 2, suggesting a potential role of mTOR C2 inhibition in undifferentiated T-ALL; 49,50 however, activation of the PI3K axis is a common feature among T-ALL independent of differentiation stage.…”

Section: Discussionmentioning

confidence: 99%

A phase I study of a dual PI3-Kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia

Lang

Wunderle

Badura

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The primary objective of this phase I single center open label study was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the dual pan-class I PI3K and mTOR inhibitor BEZ235 in patients with advanced leukemia. Methods Herein patients > 18 years of age who had relapsed or showed refractory leukemia were treated with BEZ235 (orally at 300-400 mg BID (cohort -1/1)) to assess safety, tolerability, preliminary efficacy and pharmacokinetic (PK). Adverse events data and serious adverse events were analyzed and haematological and clinical biochemistry toxicities were assessed from laboratory test parameters. Response was assessed for the first time at the end of cycle 1 (day 29) and after every subsequent cycle. Pharmacokinetic and pharmacodynamic analyses of BEZ235 were also included (BEZ235 plasma levels, phosphorylation of AKT, S6 and 4EBP1). On statistics this trial is a multiple ascending dose study in which a following variant of the 3+3 rule (“Rolling Six”), a minimum of 6 and a maximum of 12 patients was recruited for the dose escalation and another 5 were planned for the expansion phase.Results Twenty-four patients with ALL (n=11) or AML (n=12) or CML-BP (n=1) were enrolled. All patients had failed one (n=5) or more lines of therapy (n=5) and 14 patients were in refractory / refractory relapse. No formal MTD was defined, stomatitis and gastrointestinal toxicity at 400 mg BID dose was considered incompatible with prolonged treatment. The RP2D of BEZ235 was defined as 300 mg BID. Four of 24 patients showed clinical benefit. Twenty-two of 24 patients discontinued because of progression, (median time to progression 27 days (4d-112d). There was no association between PK parameters and efficacy or tolerability. Conclusions Combined inhibition of PI3K and mTOR inhibits a clinically meaningful driver pathway in a small subset of patients with ALL, with no benefit in patients with AML.Trial registration ClinicalTrials.gov, identifier NCT01756118. retrospectively registered 19th December 2012, https://clinicaltrials.gov/ct2/show/NCT01756118.

show abstract

Two acute myeloid leukemia patient subsets are identified based on the constitutive PI3K-Akt-mTOR signaling of their leukemic cells; a functional, proteomic, and transcriptomic comparison

Abstract: The constitutive PI3K-Akt-mTOR activation differed between patients; this difference appears to be a part of complex phenotypic differences including cell communication, intracellular signaling through other pathways, and transcriptional regulation.

Cited by 16 publications

References 196 publications

A phase I study of a dual PI3-kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia

A phase I study of a dual PI3-kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia

The PI3K-Akt-mTOR Signaling Pathway in Human Acute Myeloid Leukemia (AML) Cells

A phase I study of a dual PI3-Kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia

Contact Info

Product

Resources

About