Genetic Alterations and Aberrant Expression of Genes Related to the Phosphatidyl‐lnositol‐3′‐Kinase/Protein Kinase B (Akt) Signal Transduction Pathway in Glioblastomas

Knobbe, Christiane B.; Reifenberger, Guido

doi:10.1111/j.1750-3639.2003.tb00481.x

Cited by 215 publications

(167 citation statements)

References 46 publications

Supporting

Mentioning

153

Contrasting

Unclassified

Order By: Relevance

“…Mizoguchi et al (24) investigated 10 glioblastoma samples with fluorescence in situ hybridization and reported one case with an extra copy of PIK3CA. No amplification of PIK3CA, however, was detected in glioblastoma samples using a duplex PCR assay (12,25). In our study and the study reported by Broderick et al (3), no evidence of significant PIK3CA gene amplification was observed in 73 and 50 glioblastoma samples by quantitative PCR analysis, respectively.…”

Section: Discussionmentioning

confidence: 29%

PIK3CA Gene Mutations in Pediatric and Adult Glioblastoma Multiforme

Gallia¹,

Rand²,

Siu³

et al. 2006

Molecular Cancer Research

150

View full text Add to dashboard Cite

The phosphatidylinositol 3-kinases (PI3K) are a family of enzymes that relay important cellular growth control signals. Recently, a large-scale mutational analysis of eight PI3K and eight PI3K-like genes revealed somatic mutations in PIK3CA, which encodes the p110A catalytic subunit of class IA PI3K, in several types of cancer, including glioblastoma multiforme. In that report, 4 of 15 (27%) glioblastomas contained potentially oncogenic PIK3CA mutations. Subsequent studies, however, showed a significantly lower mutation rate ranging from 0% to 7%. Given this disparity and to address the relation of patient age to mutation frequency, we examined 10 exons of PIK3CA in 73 glioblastoma samples by PCR amplification followed by direct DNA sequencing. Overall, PIK3CA mutations were found in 11 (15%) samples, including several novel mutations. PIK3CA mutations were distributed in all sample types, with 18%, 9%, and 13% of primary tumors, xenografts, and cell lines containing mutations, respectively. Of the primary tumors, PIK3CA mutations were identified in 21% and 17% of pediatric and adult samples, respectively. No evidence of PIK3CA gene amplification was detected by quantitative real-time PCR in any of the samples. This study confirms that PIK3CA mutations occur in a significant number of human glioblastomas, further indicating that therapeutic targeting of this pathway in glioblastomas is of value.Moreover, this is the first study showing PIK3CA mutations in pediatric glioblastomas, thus providing a molecular target in this important pediatric malignancy.

show abstract

Section: Discussionmentioning

confidence: 29%

PIK3CA Gene Mutations in Pediatric and Adult Glioblastoma Multiforme

Gallia¹,

Rand²,

Siu³

et al. 2006

Molecular Cancer Research

150

View full text Add to dashboard Cite

show abstract

“…[7,[42][43][44] No mutations have been identified in any AKT isoform in childhood cancer; however, chromosomal gains amplifying the AKT1 gene have been described recently in rare cases of childhood AML, T-cell ALL, and gliosarcoma. [45][46][47] Amplification of eIF4E, S6K1, and cyclin D have been reported in adult cancers, including breast and mantle cell lymphomas but not in pediatric tumors. [48][49][50][51] mTOR-specific mutations in human cancer are extremely rare, with only two reported cases in adult carcinomas.…”

Section: Pi3k/akt/mtor Signaling In Cancermentioning

confidence: 99%

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

et al. 2012

View full text Add to dashboard Cite

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...

show abstract

“…In fact, activating mutations in the gene PIK3CA, which encodes the p110a catalytic subunit of PI3K, have been observed in anaplastic oligodendrogliomas, anaplastic astrocytomas, GBM and medulloblastomas, as well as other common malignancies such as prostate, breast and colon carcinoma (Broderick et al, 2004;Samuels et al, 2004). Another study investigating all three genes that encode the catalytic subunits of PI3K (PIK3CA, PIK3CD and PIK3C2B) did not find PIK3CA mutations but did observe PIK3C2B amplification and PIK3CD mRNA overexpression in GBM (Knobbe and Reifenberger, 2003). Interestingly, PIK3CA and PTEN mutations have been observed to occur simultaneously in endometrial tumors and GBM indicating a potential additive effect of both mutations on pathway activation (Broderick et al, 2004;Oda et al, 2005;Hartmann et al, 2005a;Hayes et al, 2006).…”

Section: Pi3k Pathway Involvement In Brain Tumorsmentioning

confidence: 99%

“…Although elevation of AKT activity is seen more frequently than PTEN mutation in gliomas and medulloblastomas (Schlegel et al, 2002;Hartmann et al, 2006), mutations causing increased activity of any AKT isoform have not been observed frequently. AKT1 amplification has been reported in various human cancers, including a single case of gliosarcoma (Knobbe and Reifenberger, 2003) and AKT3 mutation has been reported in a single case of glioma (Hunter et al, 2006); however, the consequence of this missense mutation (G171R) on the activity of the enzyme is unknown. While AKT2 amplification has been observed frequently in head and neck tumors, as well as pancreatic, ovarian and breast cancers (Bellacosa et al, 1995;Cheng et al, 1996;Pedrero et al, 2005;Nakayama et al, 2006), it has not yet been described in primary human brain tumors, although studies indicate it may be overexpressed and drive tumorigenicity in some glioma cell lines (Pu et al, 2006).…”

Section: Pi3k Pathway Involvement In Brain Tumorsmentioning

confidence: 99%