Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene expression profiling has provided insights into different cancer types and revealed tissue-specific expression signatures. Alterations in microRNA expression contribute to the pathogenesis of many types of human diseases. Few studies have integrated all levels of gene expression, miRNA and methylation to uncover correlations between these data types. We performed an integrated profiling to discover instances of miRNAs associated with a gene expression and DNA methylation signature across multiple cancer types. Using data from The Cancer Genome Atlas (TCGA), we revealed a concordant gene expression and methylation signature associated with the microRNA hsa-miR-142 across the same samples. In all cancer types examined, we found a signature of co-expression of a gene set R and methylated sites M, which correlate positively (M+) or negatively (M-) with the expression of hsa-miR-142. The set R consistently contains many genes, such as TRAF3IP3, NCKAP1L, CD53, LAPTM5, PTPRC, EVI2B, DOCK2, LCP2, CYBB and FYB. The signature is preserved across glioblastoma, ovarian, breast, colon, kidney, lung, uterine and rectum cancer. There is 28% overlap of methylation sites in M between glioblastoma (GBM) and ovarian cancer. There is 60% overlap of genes in R between GBM and ovarian (P = 1.3e(-11)). Most of the genes in R are known to be expressed in lymphocytes and haematopoietic stem cells, while M reflects membrane proteins involved in cell-cell adhesion functions. We speculate that the hsa-miR-142 associated signature may signal haematopoietic-specific processes and an accumulation of methylation events triggering a progressive loss of cell-cell adhesion. We also observed that GBM samples belonging to the proneural subtype tend to have underexpressed hsa-miR-142 and R genes, hypomethylated M+ and hypermethylated M-, while the mesenchymal samples have the opposite profile.
 ...
PMID:Integrated Analysis Reveals hsa-miR-142 as a Representative of a Lymphocyte-Specific Gene Expression and Methylation Signature. 2257 May 37

Radiation therapy or the combination of radiation and chemotherapy is an important component in the local control of many tumor types including glioblastoma, rectal cancer, and pancreatic cancer. The addition of anti-angiogenic agents to chemotherapy is now standard treatment for a variety of metastatic cancers including colorectal cancer and non-squamous cell lung cancer. Anti-angiogenic agents can increase the efficacy of radiation or chemoradiation for primary tumors through mechanisms such as vascular normalization and augmentation of endothelial cell injury. The most commonly used anti-angiogenic drug, bevacizumab, is a humanized monoclonal antibody that binds and neutralizes vascular endothelial growth factor A (VEGF-A). Dozens of preclinical studies nearly uniformly demonstrate that inhibition of VEGF-A or its receptors potentiates the effects of radiation therapy against solid tumors, and this potentiation is generally independent of the type or schedule of radiation and timing of VEGF-A inhibitor delivery. There are now several clinical trials combining bevacizumab with radiation or chemoradiation for the local control of various primary, recurrent, and metastatic tumors, and many of these early trials show encouraging results. Some added toxicities occur with the delivery of bevacizumab but common toxicities such as hypertension and proteinuria are generally easily managed while severe toxicities are rare. In the future, bevacizumab and other anti-angiogenic agents may become common additions to radiation and chemoradiation regimens for tumors that are difficult to locally control.
 ...
PMID:Combining Bevacizumab with Radiation or Chemoradiation for Solid Tumors: A Review of the Scientific Rationale, and Clinical Trials. 2497 13

Glioblastoma multiforme is the most common and most malignant primary brain tumor, with a yearly incidence of 2.5 in 100,000. It has a very dismal prognosis, since the medium overall survival of untreated patients is as low as 3 months. Location in the central nervous system, high aggressiveness, spreading alongside blood vessels and white matter, cause a lot of therapeutic challenges. The blood-brain barrier unables most of the systemic drugs to reach the tumor and complete resection is usually impossible. Because of that, effects of the standard treatment remain unsatisfying. It forces to search for novel treatment options. Regarding pharmacotherapy a lot of attention is brought to antiangiogenic therapies, where the most common drug is bevacizumab. In Europe it is registered to use in diffuse breast cancer, non-small cell lung cancer, colon and rectal cancer with metastases, but for glioblastoma it's use is still considered to be experimental. Inhibition of integrins, extracellular matrix metalloproteinases and EGFR are among other therapeutic goals. There is a broad range of studies on breaking the resistance of cancer stem cells, modifying the niche of cancer cells, active immunotherapy and the use of microRNAs. The field of stereotactic radiosurgery is also under constant improvement. Methods of both genetic and biomedical engineering, such as nanotubes or liposomes, can be helpful to overcome the blood-brain barrier and insert the drugs directly and even selectively into the tumor.
 ...
PMID:[The newest perspectives on the treatment of glioblastoma multiforme]. 2525 49

Background: Concurrent chemoradiotherapy (CCRT) has now become the standard of treatments for advanced rectal cancer before surgery. To search the biological molecules with prognostic and therapeutic potential of CCRT could be beneficial for these patients. Recently, aberrant expression of chloride channels has been linked to radio-resistance in glioblastoma; however, its clinical implication has not been well-studied in rectal cancers. Therefore, we examined the clinical significance of targetable drivers associated with chloride channel activity in patients with rectal cancer receiving CCRT. Methods: After datamining from a published transcriptome of rectal cancers, upregulation of CLCA1 gene was recognized to be significantly correlated with non-responders of CCRT. In validation cohort of rectal cancers, the expression levels of CLCA1 were accessed by using immunohistochemistry assays in 172 tumor specimens that were obtained before any treatment. Expression levels of CLCA1 were statistically analyzed with principal clinicopathological features and survival outcomes in this substantial cohort. Results: In validation cohort, high expression of CLCA1 was significantly associated with higher pre-treatment tumor nodal stages (P=0.032), vascular invasion (P=0.028), and inferior tumor regression grade (P=0.042). In survival evaluations, high expression of CLCA1 was significantly correlated with worse local recurrence-free survival (LRFS; P=0.0012), metastasis-free survival (MeFS; P =0.0114), and disease-specific survival (DSS; P=0.0041). Furthermore, high expression of CLCA1 remained an independent prognosticator of shorter LRFS (P=0.029, hazard ratio=2.555), MeFS (P=0.044, hazard ratio=2.125) and DSS (P=0.044, hazard ratio=2.172). Conclusions: High expression of CLCA1 is significantly associated with poor therapeutic response and survival outcomes in rectal cancer patients with CCRT treatment before surgery. With the development of specific inhibitors, our findings indicate not only prognostic but also therapeutic potential of CLCA1 in rectal cancers.
 ...
PMID:High chloride channel accessory 1 expression predicts poor prognoses in patients with rectal cancer receiving chemoradiotherapy. 3012 54

Despite the existence of differences in gene expression across numerous genes between males and females having been known for a long time, these have been mostly ignored in many studies, including drug development and its therapeutic use. In fact, the consequences of such differences over the disease mechanisms or the drug action mechanisms are completely unknown. Here we applied mechanistic mathematical models of signaling activity to reveal the ultimate functional consequences that gender-specific gene expression activities have over cell functionality and fate. Moreover, we also used the mechanistic modeling framework to simulate the drug interventions and unravel how drug action mechanisms are affected by gender-specific differential gene expression. Interestingly, some cancers have many biological processes significantly affected by these gender-specific differences (e.g., bladder or head and neck carcinomas), while others (e.g., glioblastoma or rectum cancer) are almost insensitive to them. We found that many of these gender-specific differences affect cancer-specific pathways or in physiological signaling pathways, also involved in cancer origin and development. Finally, mechanistic models have the potential to be used for finding alternative therapeutic interventions on the pathways targeted by the drug, which lead to similar results compensating the downstream consequences of gender-specific differences in gene expression.
 ...
PMID:Mechanistic Models of Signaling Pathways Reveal the Drug Action Mechanisms behind Gender-Specific Gene Expression for Cancer Treatments. 3261 Jun 26