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Gene expression data of diagnostic childhood T-ALL samples

ABSTRACT: The PI3K pathway is frequently hyperactivated in primary T-cell acute lymphoblastic leukemia (T-ALL) cells. Activation of the PI3K pathway has been suggested as one mechanism of glucocorticoid resistance in T-ALL, and patients harboring mutations in the PI3K negative regulator PTEN may be at increased risk of induction failure and relapse. In this study, we identified Myc as an important downstream integrator of PI3K pathway activity in T-ALL and we provide data supportive of an association of higher PI3K activity with glucocorticoid resistance and worse clinical outcome. The PI3K inhibitor AS605240 showed anti-leukemic activity and strong synergism with glucocorticoids both in vitro and in a NOD/SCID xenograft model of T-ALL. In contrast, PI3K inhibition showed antagonism with methotrexate and daunorubicin, drugs that preferentially target dividing cells. This antagonistic interaction, however, could be circumvented by the use of correct drug scheduling schemes. Our data indicate the potential benefits and difficulties for the incorporation of PI3K inhibitors in T-ALL therapy. Global gene expression data of diagnostic T-ALL samples were used to analyse whether a gene expression signature of higher PI3K pathway activity is associated with worse prognosis. Patients entered treatment from 2000 to 2007 at Centro Infantil Boldrini. Risk classification and treatment was performed according to the Brazilian Childhood Cooperative Group-Protocol ALL-99.

ORGANISM(S): Homo sapiens

PROVIDER: GSE50999 | GEO | 2015/04/30

SECONDARY ACCESSION(S): PRJNA219727

REPOSITORIES: GEO

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Gene expression signature of primary T-ALL cells treated with the PI3K inhibitor AS605240

Project description:The PI3K pathway is frequently hyperactivated in primary T-cell acute lymphoblastic leukemia (T-ALL) cells. Activation of the PI3K pathway has been suggested as one mechanism of glucocorticoid resistance in T-ALL, and patients harboring mutations in the PI3K negative regulator PTEN may be at increased risk of induction failure and relapse. In this study, we identified Myc as an important downstream integrator of PI3K pathway activity in T-ALL and we provide data supportive of an association of higher PI3K activity with glucocorticoid resistance and worse clinical outcome. The PI3K inhibitor AS605240 showed anti-leukemic activity and strong synergism with glucocorticoids both in vitro and in a NOD/SCID xenograft model of T-ALL. In contrast, PI3K inhibition showed antagonism with methotrexate and daunorubicin, drugs that preferentially target dividing cells. This antagonistic interaction, however, could be circumvented by the use of correct drug scheduling schemes. Our data indicate the potential benefits and difficulties for the incorporation of PI3K inhibitors in T-ALL therapy.

2015-04-30 | GSE51000 | GEO

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Project description:The PTEN tumor suppressor controls cell death and survival by regulating functions of various molecular targets. Whilst the role of PTEN lipid-phosphatase activity on PtdIns(3,4,5)P3 and inhibition of PI3K pathway is well characterized, the biological relevance of PTEN protein-phosphatase activity remains undefined. Using knock-in (KI) mice harbouring cancer-associated and functionally relevant missense mutations, we show that although loss of PTEN lipid-phosphatase function cooperates with oncogenic PI3K to promote rapid mammary tumorigenesis, the additional loss of PTEN protein-phosphatase activity triggered an extensive cell death response evident in early and advanced mammary tumors. Omics and drug-targeting studies revealed that PI3Ks act to reduce glucocorticoid receptor (GR) levels, which are rescued by loss of PTEN protein-phosphatase activity to restrain cell survival. The dual regulation of GR by PI3K and PTEN functions as a rheostat that can be exploited for the treatment of PTEN-loss driven cancers.

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Project description:<p>Putative oncogenic pathways in squamous cell lung cancer have been recently characterized, although their biologic repercussions in patients is largely unknown. This study sought to discover potential clinical manifestations of major pathways in squamous cell lung cancer, particularly the PI3K pathway. Two key findings emerged: patients with stage IV squamous cell lung cancer whose tumors harbored upstream PI3K aberrations had significantly worse survival and a higher burden of metastatic disease. In addition, brain metastases were significantly more common in these patients than in others. Paired lung primary/brain metastasis genotyping, including RNA sequencing and whole exome sequencing, uncovered a high degree of genetic heterogeneity between lung/brain pairs, and identified potential regulators of the metastatic process to brain.</p>

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Transcription profiling of human breast tumors to identify age-specific differences of oncogenic pathway deregulation

Project description:Breast cancer arising in young women has a poorer prognosis, is less likely to be hormone sensitive, and represents a particularly challenging clinical entity. The biology driving the aggressive nature of breast cancer arising in young women has yet to be defined. Among 784 patients with early stage breast cancer, using prospectively-defined, age-specific cohorts (young <= 45 years; older >= 65 years), 411 eligible patients (n = 200 < 45 years; n = 211 >= 65 years) with clinically-annotated Affymetrix microarray data were identified. Gene set enrichment analyses, signatures of oncogenic pathway deregulation and predictors of chemotherapy sensitivity were evaluated within the two age-defined cohorts. In comparing deregulation of oncogenic pathways between age groups, a statistically higher probability of PI3K (p = 0.006) and Myc (p = 0.03) pathway deregulation was observed in the tumors of younger women. When evaluating unique patterns of pathway deregulation, a low probability of Src and E2F deregulation in tumors of younger women, concurrent with activation of PI3K, Myc, and beta-catenin, conferred a worse prognosis (HR = 4.15; p = 0.008). In contrast, a higher probability of Src and E2F pathway activation in tumors of older women, concurrent low probability of PI3K, Myc and beta-catenin deregulation, was associated with a poorer outcome (HR = 2.7; p = 0.006). Similar pathway differences were identified using gene set enrichment analysis. Importantly, in multivariate analyses including clinico-pathologic variables, genomic clusters of pathway deregulation were identified to be independent predictors of disease-free survival. Finally, a significant relationship (p = 0.02) between anthracycline sensitivity and genomic clusters was observed among women aged >= 65 years. Submitters do not have approval to publish the .CEL files Experiment Overall Design: n=78

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2015-12-07 | E-GEOD-64704 | biostudies-arrayexpress

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