Impact of mTOR expression on clinical outcome in paediatric patients with B-cell acute lymphoblastic leukaemia – preliminary report

Ulińska, Edyta; Mycko, Katarzyna; Sałacińska-Łoś, Elżbieta; Pastorczak, Agata; Siwicka, Alicja; Młynarski, Wojciech; Matysiak, Michał

doi:10.5114/wo.2016.61848

Cited by 6 publications

(7 citation statements)

References 16 publications

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“…Increased mTOR expression and/or activation are associated with poor outcomes in ALL [ 9 , 10 ]. Therapeutic effects of the mTOR inhibitor, rapamycin, have been tested in clinical trials [ 8 , 42 – 45 ].…”

Section: Resultsmentioning

confidence: 99%

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Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia

Song

Ding

et al. 2021

Leukemia

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Children of Hispanic/Latino ancestry have increased incidence of high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) with poor prognosis. This leukemia is characterized by a single-copy deletion of the IKZF1 (IKAROS) tumor suppressor and increased activation of the PI3K/AKT/mTOR pathway. This identifies mTOR as an attractive therapeutic target in HR B-ALL. Here, we report that IKAROS represses MTOR transcription and IKAROS’ ability to repress MTOR in leukemia is impaired by oncogenic CK2 kinase. Treatment with the CK2 inhibitor, CX-4945, enhances IKAROS activity as a repressor of MTOR, resulting in reduced expression of MTOR in HR B-ALL. Thus, we designed a novel therapeutic approach that implements dual targeting of mTOR: direct inhibition of the mTOR protein (with rapamycin), in combination with IKAROS-mediated transcriptional repression of the MTOR gene (using the CK2 inhibitor, CX-4945). Combination treatment with rapamycin and CX-4945 shows synergistic therapeutic effects in vitro and in patient-derived xenografts from Hispanic/Latino children with HR B-ALL. These data suggest that such therapy has the potential to reduce the health disparity in HR B-ALL among Hispanic/Latino children. The dual targeting of oncogene transcription, combined with inhibition of the corresponding oncoprotein provides a paradigm for a novel precision medicine approach for treating hematological malignancies.

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Section: Resultsmentioning

confidence: 99%

“…mTOR (mammalian Target of Rapamycin) is a serine/threonine kinase that directly regulates cellular proliferation and metabolism [ 7 , 8 ]. Increased expression and activation of mTOR are associated with poor outcomes in ALL [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia

Song

Ding

et al. 2021

Leukemia

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“… [ 127 ] Leukemia Expression of mTOR and p-mTOR was associated higher risk of paediatric acute lymphoblastic leukaemia (ALL) relapse. [ 128 ] Expression of mTOR was upregulated in more than 50% of cases of ALL, both T- or B-ALL, and it was observed that the mean fold change of mTOR expression was higher in patients that did not respond to chemotherapy. [ 53 ] Multiple Myeloma Expression of mTOR or p-mTOR was observed in 25.8% FFPE samples from MM patients and high mTOR and p-mTOR were associated with male gender and older patients.…”

Section: Methodsmentioning

confidence: 99%

Expression of mTOR in normal and pathological conditions

Marques-Ramos

Cervantes

2023

Mol Cancer

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The mechanistic/mammalian target of rapamycin (mTOR), a protein discovered in 1991, integrates a complex pathway with a key role in maintaining cellular homeostasis. By comprising two functionally distinct complexes, mTOR complex 1 (mTORC1) and mTORC2, it is a central cellular hub that integrates intra- and extracellular signals of energy, nutrient, and hormone availability, modulating the molecular responses to acquire a homeostatic state through the regulation of anabolic and catabolic processes. Accordingly, dysregulation of mTOR pathway has been implicated in a variety of human diseases. While major advances have been made regarding the regulators and effectors of mTOR signaling pathway, insights into the regulation of mTOR gene expression are beginning to emerge. Here, we present the current available data regarding the mTOR expression regulation at the level of transcription, translation and mRNA stability and systematize the current knowledge about the fluctuations of mTOR expression observed in several diseases, both cancerous and non-cancerous. In addition, we discuss whether mTOR expression changes can be used as a biomarker for diagnosis, disease progression, prognosis and/or response to therapeutics. We believe that our study will contribute for the implementation of new disease biomarkers based on mTOR as it gives an exhaustive perspective about the regulation of mTOR gene expression in both normal and pathological conditions.

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“…In the early 2010s, our and others' results confirmed that elevated mTOR activity is characteristic for human lymphoma and leukemia cells. Based on IHC and flow cytometry data, higher mTOR activity, especially in the presence of a high amount of mTORC2 complex, was correlated with worse prognosis and lower OS in lymphoma/leukemia patients [324][325][326][327].…”

Section: Characterization Of Mtor Hyperactivity and Its Correlation W...mentioning

confidence: 99%

The role of metabolic ecosystem in cancer progression — metabolic plasticity and mTOR hyperactivity in tumor tissues

Sebestyén

Dankó

Sztankovics

et al. 2021

Cancer Metastasis Rev

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Despite advancements in cancer management, tumor relapse and metastasis are associated with poor outcomes in many cancers. Over the past decade, oncogene-driven carcinogenesis, dysregulated cellular signaling networks, dynamic changes in the tissue microenvironment, epithelial-mesenchymal transitions, protein expression within regulatory pathways, and their part in tumor progression are described in several studies. However, the complexity of metabolic enzyme expression is considerably under evaluated. Alterations in cellular metabolism determine the individual phenotype and behavior of cells, which is a well-recognized hallmark of cancer progression, especially in the adaptation mechanisms underlying therapy resistance. In metabolic symbiosis, cells compete, communicate, and even feed each other, supervised by tumor cells. Metabolic reprogramming forms a unique fingerprint for each tumor tissue, depending on the cellular content and genetic, epigenetic, and microenvironmental alterations of the developing cancer. Based on its sensing and effector functions, the mechanistic target of rapamycin (mTOR) kinase is considered the master regulator of metabolic adaptation. Moreover, mTOR kinase hyperactivity is associated with poor prognosis in various tumor types. In situ metabolic phenotyping in recent studies highlights the importance of metabolic plasticity, mTOR hyperactivity, and their role in tumor progression. In this review, we update recent developments in metabolic phenotyping of the cancer ecosystem, metabolic symbiosis, and plasticity which could provide new research directions in tumor biology. In addition, we suggest pathomorphological and analytical studies relating to metabolic alterations, mTOR activity, and their associations which are necessary to improve understanding of tumor heterogeneity and expand the therapeutic management of cancer.

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Impact of mTOR expression on clinical outcome in paediatric patients with B-cell acute lymphoblastic leukaemia – preliminary report

Cited by 6 publications

References 16 publications

Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia

Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia

Expression of mTOR in normal and pathological conditions

The role of metabolic ecosystem in cancer progression — metabolic plasticity and mTOR hyperactivity in tumor tissues

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