14 research outputs found
Targeted Therapy Resistance Mediated by Dynamic Regulation of Extrachromosomal Mutant EGFR DNA
Intratumoral heterogeneity contributes to cancer drug resistance, but the underlying mechanisms are not understood. Single-cell analyses of patient-derived models and clinical samples from glioblastoma patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) demonstrate that tumor cells reversibly up-regulate or suppress mutant EGFR expression, conferring distinct cellular phenotypes to reach an optimal equilibrium for growth. Resistance to EGFR TKIs is shown to occur by elimination of mutant EGFR from extrachromosomal DNA. After drug withdrawal, reemergence of clonal EGFR mutations on extrachromosomal DNA follows. These results indicate a highly specific, dynamic, and adaptive route by which cancers can evade therapies that target oncogenes maintained on extrachromosomal DNA
Brain Tumor Stem Cells as Therapeutic Targets in Models of Glioma
At this time, brain tumor stem cells remain a controversial hypothesis while malignant brain tumors continue to present a dire prognosis of severe morbidity and mortality. Yet, brain tumor stem cells may represent an essential cellular target for glioma therapy as they are postulated to be the tumorigenic cells responsible for recurrence. Targeting oncogenic pathways that are essential to the survival and growth of brain tumor stem cells represents a promising area for developing therapeutics. However, due to the multiple oncogenic pathways involved in glioma, it is necessary to determine which pathways are the essential targets for therapy. Furthermore, research still needs to comprehend the morphogenic processes of cell populations involved in tumor formation. Here, we review research and discuss perspectives on models of glioma in order to delineate the current issues in defining brain tumor stem cells as therapeutic targets in models of glioma
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An introduction to statistical issues in High throughput screens
We describe the nature and goals of high-throughput screening experiments, focusing on the challenges they present from the view-point of statistical analysis. We suggest graphical displays to facilitate quality control. We describe sources of systematic variation and methods to correct for it. We consider the problem of ranking compounds with respect to their effects on one cell type and we suggest a couple of procedures, depending on the available number of replicates. Finally, we explore the use of a hierarchical framework for hypothesis testing, to study the effects of compounds in multiple cell lines
Recommended from our members
An introduction to statistical issues in High throughput screens
We describe the nature and goals of high-throughput screening experiments, focusing on the challenges they present from the view-point of statistical analysis. We suggest graphical displays to facilitate quality control. We describe sources of systematic variation and methods to correct for it. We consider the problem of ranking compounds with respect to their effects on one cell type and we suggest a couple of procedures, depending on the available number of replicates. Finally, we explore the use of a hierarchical framework for hypothesis testing, to study the effects of compounds in multiple cell lines
Recommended from our members
An introduction to statistical issues in High throughput screens
We describe the nature and goals of high-throughput screening experiments, focusing on the challenges they present from the view-point of statistical analysis. We suggest graphical displays to facilitate quality control. We describe sources of systematic variation and methods to correct for it. We consider the problem of ranking compounds with respect to their effects on one cell type and we suggest a couple of procedures, depending on the available number of replicates. Finally, we explore the use of a hierarchical framework for hypothesis testing, to study the effects of compounds in multiple cell lines
Recommended from our members
An introduction to statistical issues in High throughput screens
We describe the nature and goals of high-throughput screening experiments, focusing on the challenges they present from the view-point of statistical analysis. We suggest graphical displays to facilitate quality control. We describe sources of systematic variation and methods to correct for it. We consider the problem of ranking compounds with respect to their effects on one cell type and we suggest a couple of procedures, depending on the available number of replicates. Finally, we explore the use of a hierarchical framework for hypothesis testing, to study the effects of compounds in multiple cell lines
Squamous cell carcinoma of the external auditory canal: A case report and review of the literature
A case of groans, moans and stones with malignant undertones: Endometrioid carcinoma-associated hypercalcemia
Humoral hypercalcemia of malignancy is frequently observed in patients with solid tumors. However, few instances have been described involving patients with gynecological malignancies. We report a case of endometrioid carcinoma of the uterine corpus in a patient who initially presented with hypercalcemia. The elevated calcium levels were found to be the result of an increased serum concentration of parathyroid hormone-related peptide (PTHrP). PTHrP is commonly secreted by malignant cells and suppresses PTH. This case demonstrates that endometrial cancer should be considered in the differential diagnosis of patients presenting with symptomatic or asymptomatic hypercalcemia
A Molecular Screening Approach to Identify and Characterize Inhibitors of Glioblastoma Stem Cells
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A molecular cascade modulates MAP1B and confers resistance to mTOR inhibition in human glioblastoma.
BackgroundClinical trials of therapies directed against nodes of the signaling axis of phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin (mTOR) in glioblastoma (GBM) have had disappointing results. Resistance to mTOR inhibitors limits their efficacy.MethodsTo determine mechanisms of resistance to chronic mTOR inhibition, we performed tandem screens on patient-derived GBM cultures.ResultsAn unbiased phosphoproteomic screen quantified phosphorylation changes associated with chronic exposure to the mTOR inhibitor rapamycin, and our analysis implicated a role for glycogen synthase kinase (GSK)3B attenuation in mediating resistance that was confirmed by functional studies. A targeted short hairpin RNA screen and further functional studies both in vitro and in vivo demonstrated that microtubule-associated protein (MAP)1B, previously associated predominantly with neurons, is a downstream effector of GSK3B-mediated resistance. Furthermore, we provide evidence that chronic rapamycin induces microtubule stability in a MAP1B-dependent manner in GBM cells. Additional experiments explicate a signaling pathway wherein combinatorial extracellular signal-regulated kinase (ERK)/mTOR targeting abrogates inhibitory phosphorylation of GSK3B, leads to phosphorylation of MAP1B, and confers sensitization.ConclusionsThese data portray a compensatory molecular signaling network that imparts resistance to chronic mTOR inhibition in primary, human GBM cell cultures and points toward new therapeutic strategies