Glioblastoma multiforme is the most common primary malignant brain tumor and despite treatment with surgery, radiation, and chemotherapy, the median survival of patients with glioblastoma multiforme is approximately 1 year. Glioblastoma multiforme explants and cell lines have been reported to overexpress the interleukin-13 receptor alpha2 subunit (IL13Ralpha2) relative to nonneoplastic brain. Based on this finding, a recombinant cytotoxin composed of IL13 ligand and a truncated form of Pseudomonas aeruginosa exotoxin A (IL13-PE38QQR) was developed for the targeted treatment of glioblastoma multiforme tumors. In a recently completed phase III clinical trial, however, IL13-PE38QQR was found to be no more effective than an existing therapy in prolonging survival. To determine possible explanations for this result, we analyzed the relative expression levels of IL13Ralpha2 in glioblastoma multiforme and nonneoplastic brain specimens using publicly available oligonucleotide microarray databases, quantitative real-time reverse transcription PCR, and immunohistochemical staining. Increased expression of the IL13Ralpha2 gene relative to nonneoplastic brain was observed in 36 of 81 (44%) and 8 of 17 (47%) tumor specimens by microarray and quantitative real-time reverse transcription PCR analyses, respectively. Immunohistochemical staining of tumor specimens showed highly variable expression of IL13Ralpha2 protein both within and across specimens. These data indicate that prescreening of subjects may be of benefit in future trials of IL13Ralpha2 targeting therapies.
"IL-13 receptor alpha 2 (IL13Rα2), human epidermal growth factor receptor 2 (HER2), and Ephrin type A receptor 2 (EphA2) are all glioma-specific antigens that provide targets for CAR-based immunotherapy (76–78). The former is currently being explored in a clinical trial infusion autologous CAR T cells clones into resection cavities of GBM (79). "
[Show abstract][Hide abstract] ABSTRACT: Glioblastoma (GBM) is the most common and most aggressive primary brain malignancy and, as it stands, is virtually incurable. With the current standard of care, maximum feasible surgical resection followed by radical radiotherapy and adjuvant temozolomide, survival rates are at a median of 14.6 months from diagnosis in molecularly unselected patients (1). Collectively, the current knowledge suggests that the continued tumor growth and survival is in part due to failure to mount an effective immune response. While this tolerance is subtended by the tumor being utterly "self," it is to a great extent due to local and systemic immune compromise mediated by the tumor. Different cell modalities including lymphokine-activated killer cells, natural killer cells, cytotoxic T lymphocytes, and transgenic chimeric antigen receptor or αβ T cell receptor grafted T cells are being explored to recover and or redirect the specificity of the cellular arm of the immune system toward the tumor complex. Promising phase I/II trials of such modalities have shown early indications of potential efficacy while maintaining a favorable toxicity profile. Efficacy will need to be formally tested in phase II/III clinical trials. Given the high morbidity and mortality of GBM, it is imperative to further investigate and possibly integrate such novel cell-based therapies into the current standards-of-care and herein we collectively assess and critique the state-of-the-knowledge pertaining to these efforts.
Frontiers in Oncology 11/2013; 3:275. DOI:10.3389/fonc.2013.00275
"While GBMs are known to be heterogeneous tumors with substantial histopathological and interpatient variability,15 single-cell antigen coexpression within individual tumors has not been well characterized. We therefore studied the simultaneous expression pattern of three established glioma-restricted antigens (HER2, IL-13Rα2, and EphA2) in primary GBM samples.16,17,18,19,20 "
[Show abstract][Hide abstract] ABSTRACT: Preclinical and early clinical studies have demonstrated that chimeric antigen receptor (CAR)-redirected T cells are highly promising in cancer therapy. We observed that targeting HER2 in a Glioblastoma cell line results in the emergence of HER2-null tumor cells that maintain the expression of non-targeted tumor associated antigens (TAA). Combinational targeting of these TAAs could thus offset this escape mechanism. We studied the single-cell co-expression patterns of HER2, IL-13Rα2 and EphA2 in primary Glioblastoma samples using multicolor flow cytometry and immunofluorescence, and applied a binomial routine to the permutations of antigen expression and the related odds of complete tumor elimination. This mathematical model demonstrated that co-targeting HER2 and IL-13Rα2 could maximally expand the therapeutic reach of the T cell product in all primary tumors studied. Targeting a third antigen did not predict an added advantage in the tumor cohort studied. We thus generated bispecific T cell products from healthy donors and from GBM patients by pooling T cells individually expressing HER2 and IL-13Rα2-specific CARs and by making individual T cells to co-express both molecules. Both HER2/IL-13Rα2-bispecific T cell products offset antigen escape, producing enhanced effector activity in vitro immunoassays (against autologous glioma cells in the case of GBM patient products) and in an orthotopic xenogeneic murine model. Further, T cells co-expressing HER2- and IL-13Rα2-CARs exhibited accentuated yet antigen-dependent downstream signaling and a particularly enhanced antitumor activity.Molecular Therapy (2013); doi:10.1038/mt.2013.185.
"CT (cycle threshold) values were standardized to CT values of GAPDH. Samples obtained from three independent experiments were used for analysis of relative gene expression using the 2-ΔΔCT method as previously described. Each PCR was performed in triplicate with controls. "
[Show abstract][Hide abstract] ABSTRACT: Background:
Aberrant activation of Hedgehog (Hh) signaling pathway has been reported to be related to malignant biological behavior of pancreatic cancer but its mechanism is unclear yet. Since IGF pathway and Bcl-2 family are involved in proliferation and apoptosis of pancreatic cancer cells, we hypothesize that they are possibly associated with Hh pathway.
Materials and Methods:
We studied the relationship of Shh-Gli1 signaling pathway with proliferation and apoptosis of pancreatic cancer cells and the regulation of transcription factor Gli1 to insulin-like growth factor binding protein 6 (IGFBP6) and Bcl-2 genes at the level of transcription.
Sonic hedgehog (Shh), Smoothened (Smo), patched and Gli1 were expressed in pancreatic cancer cells. Cyclopamine inhibited cell proliferation at low concentration and induced apoptosis at high concentration. Effect of RNA interference (RNAi) for Gli1 to cell survival is mainly due to proliferation inhibition though involved in apoptosis. The transcription factor Gli1 bound to promoter regions of Bcl-2 and IGFBP6 genes and the levels of IGFBP6, proliferating cell nuclear antigen (PCNA) and Bcl-2 messenger RNA (mRNA) were decreased as well as Gli1 mRNA significantly by cyclopamine or RNAi in cultured pancreatic cancer cells (p < 0.01). Finally PCNA, IGFBP6 and Bcl-2 mRNA were upregulated as well as Shh or Gli1 in pancreatic cancer tissues (p < 0.01).
Our study reveals that Gli1 maintained cell survival by binding the promoter regions and facilitating transcription of IGFBP6 and Bcl-2 genes in a parallel manner in pancreatic cancer cells and suggests it may be one of the mechanisms of Shh-Gli1 signaling pathway in pancreatic cancer.
Journal of Carcinogenesis 09/2009; 8(1):13. DOI:10.4103/1477-3163.55429
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