Glioblastoma (GBM) is the most common malignant primary brain tumor of adults and one of the most lethal of all cancers. EGFR mutations (EGFRvIII) and PI3K hyperactivation are common in GBM, promoting tumor growth and survival, including through SREBP-1-dependent-lipogenesis. The role of cholesterol metabolism in GBM pathogenesis, its association with EGFR/PI3K signaling, and its potential therapeutic targetability are unknown. Here, studies in GBM cell lines, xenograft models and GBM clinical samples, including from patients treated with the EGFR tyrosine kinase inhibitor lapatinib, uncovered an EGFRvIII-activated, PI3K/SREBP-1-dependent tumor survival pathway through the LDL receptor. Targeting LDLR with the Liver X Receptor (LXR) agonist GW3965 caused IDOL (Inducible Degrader Of LDLR)-mediated LDLR degradation and increased expression of the ABCA1 cholesterol efflux transporter, potently promoting tumor cell death in an in vivo GBM model. These results demonstrate that EGFRvIII can promote tumor survival through PI3K-SREBP-1 dependent up-regulation of LDLR, and suggest a role for LXR agonists in the treatment of GBM patients.
Although it is known that mTOR complex 2 (mTORC2) functions upstream of Akt, the role of this protein kinase complex in cancer is not well understood. Through an integrated analysis of cell lines, in vivo models and clinical samples, we demonstrate that mTORC2 is frequently activated in glioblastoma (GBM), the most common malignant primary brain tumor of adults. We show that the common activating epidermal growth factor receptor (EGFR) mutation (EGFRvIII) stimulates mTORC2 kinase activity, which is partially suppressed by PTEN. mTORC2 signaling promotes GBM growth and survival, and activates NF-κB. Importantly, this mTORC2-NF-κB pathway renders GBM cells and tumors resistant to chemotherapy in a manner independent of Akt. These results highlight the critical role of mTORC2 in GBM pathogenesis, including through activation of NF-κB downstream of mutant EGFR, leading to a previously unrecognized function in cancer chemotherapy resistance. These findings suggest that therapeutic strategies targeting mTORC2, alone or in combination with chemotherapy, will be effective in cancer.
Acquired resistance to tyrosine kinase inhibitors (TKI) represents a major challenge for personalized cancer therapy. Multiple genetic mechanisms of acquired TKI resistance have been identified in several types of human cancer. However, the possibility that cancer cells may also evade treatment by co-opting physiologically regulated receptors has not been addressed. Here we demonstrate the first example of this alternate mechanism in brain tumors by showing that EGFR-mutant glioblastomas (GBMs) evade EGFR TKIs by transcriptionally de-repressing PDGFRβ. Mechanistic studies demonstrate that EGFRvIII signaling actively suppresses PDGFRβ transcription in an mTORC1 and ERK-dependent manner. Genetic or pharmacologic inhibition of oncogenic EGFR renders GBMs dependent on the consequently de-repressed PDGFRβ signaling for growth and survival. Importantly, combined inhibition of EGFR and PDGFRβ signaling potently suppresses tumor growth in vivo. These data identify a novel, non-genetic TKI resistance mechanism in brain tumors and provide compelling rationale for combination therapy.
Despite their nearly universal activation of mammalian target of rapamycin (mTOR) signaling, glioblastomas (GBMs) are strikingly resistant to mTOR-targeted therapy. We analyzed GBM cell lines, patient-derived tumor cell cultures, and clinical samples from patients in phase 1 clinical trials, and find that the promyelocytic leukemia (PML) gene mediates resistance to mTOR-targeted therapies. Direct mTOR inhibitors and EGF receptor (EGFR) inhibitors that block downstream mTOR signaling promote nuclear PML expression in GBMs, and genetic overexpression and knockdown approaches demonstrate that PML prevents mTOR and EGFR inhibitor-dependent cell death. Low doses of the PML inhibitor, arsenic trioxide, abrogate PML expression and reverse mTOR kinase inhibitor resistance in vivo, thus markedly inhibiting tumor growth and promoting tumor cell death in mice. These results identify a unique role for PML in mTOR and EGFR inhibitor resistance and provide a strong rationale for a combination therapeutic strategy to overcome it. mTORC1 | glioma
Background: Study utility of seven automated VCS parameters (V-volume, Cconductivity and S-scatter) in leukocytes as an objective read-out of dysplasia in Myelodysplastic Syndromes (MDS). Methods: Peripheral blood was analyzed by Beckman-Coulter DxH800 hematology analyzer in 43 patients with low-grade, high-grade MDS and 21 control individuals. The differences in mean (MN) and standard deviation (SD) of each parameter were examined. The optimal sensitivity and specificity to predict MDS were determined by statistical analysis. Results: In neutrophils, all means of the light scatters were significantly lower in highgrade MDS than in the control group. Mean median angle light scatter (MN-MALS-NE) and mean upper median angle light scatter (MN-UMALS-NE) were significantly different between low-grade MDS and control patients. MN-MALS-NE as a MDSpredictor revealed 63% sensitivity and 67% specificity with a cutoff value of ≤133.SDs of each parameter in neutrophils differed significantly among three groups. SD of neutrophil upper median angle light scatter (SD-UMALS-NE) had 77% sensitivity and 82% specificity (cutoff value of ≥11.16) to predict MDS.Conclusions: MDS patients have a significant decrease with a linear trend in VCS parameters in neutrophils, indicating cell dysplasia. The degree of the heterogeneity measured by SD is the most predictive of MDS.
To investigate a high spatial resolution peripheral contrast-enhanced MR angiography (CE-MRA) protocol, applying a dedicated multi-channel array coil and accelerated parallel acquisition at 3.0T in evaluation of patients with peripheral vascular disease. Twenty patients with peripheral vascular disease underwent multi-station high spatial resolution peripheral CE-MRA at 3T. The image quality, presence of venous contamination, image noise, and artifact were evaluated by 2 radiologists independently. Assessment of arterial disease for 540 arterial segments was performed, and findings were correlated with conventional catheter angiography in 10 patients. All studies were yielded high diagnostic image quality. Venous contamination and artifact were minimal and never interfered with diagnosis. Sixty seven arterial segments with significant stenoses (>0%) were detected by observers with excellent interobserver agreement (kappa = 0.82; 95% CI: 0.76, 0.88). There was a significant correlation between CE-MRA and conventional angiography (Rs = 0.91 and 0.94 for reader 1 and 2, respectively) for the assessment of the degree of stenosis. Higher available SNR at 3T in combination with multi-coil technology and accelerated parallel acquisition, result in acquisition of nearly isotropic submillimeter 3D voxels throughout the entire peripheral arterial tree with diagnostic image quality and favorable comparative analysis with catheter angiography.
Thyroid-like follicular carcinoma of the kidney (TLFCK) is a rare histological variant of renal cell carcinoma not currently included in the World Health Organization classification of renal tumors. Only 24 previous cases of TLFCK have been reported to date. We report a case of TLFCK in a 19-year-old woman with history of pediatric acute lymphoblastic leukemia. This patient is the youngest with TLFCK to be reported to date and the first with history of lymphoblastic leukemia. The development of TLFCK in a young patient with history of lymphoblastic leukemia is interesting and suggests that genes involved in leukemogenesis may also be important for TLFCK pathogenesis. Recognition of TLFCK is important to distinguish it from other conditions that show thyroid-like features, as a misdiagnosis can result in adverse patient care.
Idiopathic Infantile Arterial Calcification is a rare autosome recessive disease characterized by extensive calcification of medium and large arteries. Loss-of-function mutations in ectonucleotide pyrophosphatase/phosphodiesterase 1 gene have been described in more than 80% of the cases. Although the diagnosis is usually made at autopsy, it is possible to identify cases based on clinical presentation, radiology findings, and molecular studies. Appropriate treatment can be initiated and has been shown to successfully induce permanent remission. We report a 4-week-old neonate who initially presented with respiratory distress, heart failure, and Coxsackie B viremia suggestive of viral induced cardiomyopathy. His symptoms progressed to multiple organ failure and he eventually expired at four weeks of age. On autopsy, diffuse calcium deposition within the internal elastic lamina of medium and large arteries was identified, as well as narrowing of lumen due to myointimal proliferation. This case report will emphasize the importance of taking this rare curable disease into consideration in all cases of infants with cardiopulmonary failure.
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