Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway

Polívka, Jiří; Janků, Filip

doi:10.1016/j.pharmthera.2013.12.004

Cited by 697 publications

(543 citation statements)

References 119 publications

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“…Inhibition of such aberrant signaling components can be a promising targeted therapeutic strategy in GBM (4,22). Protein kinase C (PKC) is an important driver of the signal propagation from several growth factors, such as EGF and PDGF, stimulating glioma cell proliferation.…”

Section: Inhibitors Of Growth Factors and Their Receptors Inhibitorsmentioning

confidence: 99%

“…The novel so-called targeted therapies can affect and inhibit various tumor-specific features, such as altered cellular signaling pathways, aberrant vascularization, or the tumor microenvironment and impaired anticancer immune response (21,22). Genetic and epigenetic studies in GBM have revealed potential new targets in cancer cells and the surrounding tumor microenvironment that can be therapeutically influenced by the small molecules and monoclonal antibodies (4, 23).…”

Section: Perspectives On Novel Therapies For Gbmmentioning

confidence: 99%

“…These are relatively new molecules are able to specifically inhibit various aberrantly activated cell signaling pathways which lead to the formation and progression of cancer (4, 22,26). Such effects can be achieved by inhibiting specific growth factors and their receptors, including the epidermal growth factor family (EGF) and their receptors (EGFR), plateletderived growth factors (PDGF) and their receptors (PDGFR), insulin-like growth factors (IGF), fibroblast growth factor (FGF) and their receptors and others that are overexpressed or mutated in a high proportion of GBMs (9, 27).…”

Section: Inhibitors Of Growth Factors and Their Receptors Inhibitorsmentioning

confidence: 99%

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Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

Polívka

Holubec

Kubíková

et al. 2017

Self Cite

117

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Abstract. Glioblastoma multiforme (GBM) represents the most malignant primary brain tumor in adults with generally dismal prognosis, early clinical deterioration and high mortality. GBM is extremely invasive, characterized by intense and aberrant vascularization and high resistance to multimodal treatment. Standard therapy (surgery, radiotherapy and chemotherapy with temozolomide) has very limited effectiveness, with median overall survival of patients no longer than 15 months. Progress in genetics and epigenetics of GBM over the past decade has revealed various aberrations in cellular signaling pathways, the tumor microenvironment, and pathological angiogenesis. A number of targeted anticancer drugs, such as small-molecule kinase inhibitors and monoclonal antibodies, have been evaluated in clinical trials with newly-diagnosed, as well as recurrent GBM. Unfortunately, to date, only a single antiangiogenic agent, bevacizumab, has been approved for the treatment of recurrent GBM in the USA and Canada. The novel possibilities of cancer immunotherapy, especially immune checkpoint inhibitors, are being evaluated in clinical trials of patients with GBM. The most recent clinical experiences with targeted therapy as well as immunotherapy of GBM are given in this review. The relative lack of success of some of these approaches recently revealed in well-designed randomized clinical trials is also discussed.Glioblastoma multiforme (GBM) belongs to the largest group of primary central nervous system (CNS) tumors, so-called gliomas, which are formed from supporting glial cells in the brain parenchyma (1, 2). GBM represents the most common and most malignant tumor in this class, with an incidence of 3-4/100,000/year (3, 4). GBM is an extremely invasive and difficult to treat tumor, characterized by intense and aberrant vascularization and high resistance to radiotherapy (RT) and chemotherapy (CHT). The current standard of care for patients with newly-diagnosed GBM comprises of neurosurgery and subsequent concomitant chemoradiotherapy by fractionated external-beam RT and systemic temozolomide followed by systemic temozolomide in the adjuvant setting (5). There are only very limited possibilities for the treatment of subsequent recurrences, generally with minimal clinical efficacy (6). Despite intensive multimodal treatment strategies, the median survival of patients with GBM is still 12.1-14.6 months and only 3-5% of patients survive longer than 3 years (7).Enormous progress has been made in the genetics and epigenetics of GBM during the past decade. The Cancer 21Τhis article is freely accessible online.Correspondence to: Jiri Polivka, Department of Neurology, Faculty Hospital Plzen, alej Svobody 80, 304 60, Plzen, Czech Republic. E-mail: polivka@fnplzen.cz Key Words: Glioblastoma multiforme, GBM, targeted therapy, immunotherapy, immune checkpoint inhibitors, PD1 inhibition, CTLA4 inhibition, clinical trials, personalized medicine, review. ANTICANCER RESEARCH 37: 21-34 (2017) [8][9][10][11][12]. The most important genetic...

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Section: Inhibitors Of Growth Factors and Their Receptors Inhibitorsmentioning

confidence: 99%

Section: Perspectives On Novel Therapies For Gbmmentioning

confidence: 99%

Section: Inhibitors Of Growth Factors and Their Receptors Inhibitorsmentioning

confidence: 99%

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Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

Polívka

Holubec

Kubíková

et al. 2017

Self Cite

117

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“…21 Interestingly, also intervention on the PI3K-AKT pathway has been shown to have positive effects: AKT phosphorylation is known to be elevated in PTPN11-induced JMML, and also mTOR inhibitors have been shown to be effective in in vitro studies. [21][22][23][24] This intriguing observation has been confirmed by animal studies. In line with the in vitro data, there is evidence that hypertrophic cardiomyopathy caused by specific Ptpn11 variants in cell lines and mouse models of LEOPARD syndrome can be successfully treated by mTOR inhibition (rather than MEK inhibition).…”

Section: Ptpn11 Variant and Mcap Syndrome D Döcker Et Almentioning

confidence: 52%

Germline PTPN11 and somatic PIK3CA variant in a boy with megalencephaly-capillary malformation syndrome (MCAP) - pure coincidence?

et al. 2014

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Megalencephaly-capillary malformation (MCAP) syndrome is an overgrowth syndrome that is diagnosed by clinical criteria. Recently, somatic and germline variants in genes that are involved in the PI3K-AKT pathway (AKT3, PIK3R2 and PIK3CA) have been described to be associated with MCAP and/or other related megalencephaly syndromes. We performed trio-exome sequencing in a 6-year-old boy and his healthy parents. Clinical features were macrocephaly, cutis marmorata, angiomata, asymmetric overgrowth, developmental delay, discrete midline facial nevus flammeus, toe syndactyly and postaxial polydactylythus, clearly an MCAP phenotype. Exome sequencing revealed a pathogenic de novo germline variant in the PTPN11 gene (c.1529A4G; p.(Gln510Arg)), which has so far been associated with Noonan, as well as LEOPARD syndrome. Whole-exome sequencing (4100 Â coverage) did not reveal any alteration in the known megalencephaly genes. However, ultra-deep sequencing results from saliva (41000 Â coverage) revealed a 22% mosaic variant in PIK3CA (c.2740G4A; p. (Gly914Arg)). To our knowledge, this report is the first description of a PTPN11 germline variant in an MCAP patient. Data from experimental studies show a complex interaction of SHP2 (gene product of PTPN11) and the PI3K-AKT pathway. We hypothesize that certain PTPN11 germline variants might drive toward additional second-hit alterations.

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“…The essential and well-studied PI3K/AKT/mTOR signaling pathway serves important roles in tumorigenesis (26,27). This signaling pathway contributes to cell proliferation, differentiation, metabolism, cytoskeletal reorganization and apoptosis (28). Activation of the PI3K/AKT/mTOR signaling pathway promotes cancer cell survival and therapy resistance (29)(30)(31).…”

Section: Discussionmentioning

confidence: 99%

AXIN1 protects against testicular germ cell tumors via the PI3K/AKT/mTOR signaling pathway

Yan

Jia

et al. 2017

Oncology Letters

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Abstract. Axis inhibition protein 1 (AXIN1) is characterized as a tumor suppressor in numerous types of cancer. However, the functional role of AXIN1 in the testicular germ cell tumors (TGCTs) remains unclear. The human embryonal carcinoma-derived cell line NTera2 was transfected with a recombinant AXIN1 expression vector (pcDNA3.1-AXIN1) and/or a small interfering RNA (siRNA) directed against AXIN1 (siAXIN). Following transfection, the mRNA and protein levels of AXIN1 were determined via reverse transcription-quantitative polymerase chain reaction analysis and western blotting, respectively. In addition, cell viability, apoptosis and the expression of apoptosis-associated proteins [apoptosis regulator Bax (Bax) and B-cell lymphoma (Bcl)-2] and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway proteins [phosphorylated (p)-mTOR, mTOR, p-AKT, AKT, P-70S ribosomal protein S6 (S6) and S6] were assessed. AXIN1 mRNA and protein levels were increased following transfection with pcDNA3.1-AXIN1 and decreased following transfection with siAXIN1 compared with their respective control groups. After overexpression of AXIN1, NTera2 cell viability and expression of Bcl-2, p-mTOR p-AKT and p-S6 protein was decreased, while apoptosis and Bax protein levels were increased, compared with the control group. However, there was no significant difference in AXIN1 mRNA expression, apoptosis or Bax/Bcl-2 protein expression when NTera2 cells were simultaneously transfected with pcDNA3.1-AXIN1+siAXIN1. In conclusion, the results of the present study indicate that overexpression of AXIN1 protects against TGCTs via inhibiting the PI3K/AKT/mTOR signaling pathway, suggesting that AXIN1 may be a potential target for gene therapy in TGCTs.

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Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway

Cited by 697 publications

References 119 publications

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

Advances in Experimental Targeted Therapy and Immunotherapy for Patients with Glioblastoma Multiforme

Germline PTPN11 and somatic PIK3CA variant in a boy with megalencephaly-capillary malformation syndrome (MCAP) - pure coincidence?

AXIN1 protects against testicular germ cell tumors via the PI3K/AKT/mTOR signaling pathway

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