A Potential Role for the Inhibition of PI3K Signaling in Glioblastoma Therapy

Abstract

Glioblastoma multiforme (GBM) is the most common primary brain tumor and among the most difficult to treat malignancies per se. In almost 90% of all GBM alterations in the PI3K/Akt/mTOR have been found, making this survival cascade a promising therapeutic target, particular for combination therapy that combines an apoptosis sensitizer, such as a pharmacological inhibitor of PI3K, with an apoptosis inducer, such as radio- or chemotherapy. However, while in vitro data focusing mainly on established cell lines has appeared rather promising, this has not translated well to a clinical setting. In this study, we analyze the effects of the dual kinase inhibitor PI-103, which blocks PI3K and mTOR activity, on three matched pairs of GBM stem cells/differentiated cells. While blocking PI3K-mediated signaling has a profound effect on cellular proliferation, in contrast to data presented on two GBM cell lines (A172 and U87) PI-103 actually counteracts the effect of chemotherapy. While we found no indications for a potential role of the PI3K signaling cascade in differentiation, we saw a clear and strong contribution to cellular motility and, by extension, invasion. While blocking PI3K-mediated signaling concurrently with application of chemotherapy does not appear to be a valid treatment option, pharmacological inhibitors, such as PI-103, nevertheless have an important place in future therapeutic approaches.

Combination of a STAT3 Inhibitor and an mTOR Inhibitor Against a Temozolomide-resistant Glioblastoma Cell Line

“…Additionally, we made the novel observation of an association between mTOR and STAT3 signaling that is mediated by the YKL-40 protein ( Figure 4E). Considering that novel dual or triple inhibitor development against PI3K/Akt/mTOR signal activation has been in progress since the development of rapalogs, everolimus and temsirolimus (33)(34)(35)(36)(37)(38), the novel effective combination of an mTOR inhibitor and a STAT3 inhibitor shown in the present study deserves attention as a novel therapeutic approach against relapsed TMZ-resistant glioblastomas.…”

Bcl‐2/Bcl‐xL inhibition predominantly synergistically enhances the anti‐neoplastic activity of a low‐dose CUSP9 repurposed drug regime against glioblastoma

“…ULM‐GBM‐PC35, ULM‐GBM‐PC38, and ULM‐GBM‐PC40 are primary cultured human glioblastoma cells derived from tumour resections performed at our institution and were generated and characterized as previously described (Karpel‐Massler et al, ; Opel et al, ; Schneider et al, ; Ströbele et al, ). ULM‐GBM‐SC35, ULM‐GBM‐SC38, and ULM‐GBM‐SC40 are stem‐like glioma cells which were also derived and characterized at our institution (Karpel‐Massler et al, ; Opel et al, ; Schneider et al, ; Ströbele et al, ). All cells were cultured as previously described (Karpel‐Massler, Horst, et al, ; Karpel‐Massler, Ishida, Bianchetti, Zhang, et al, ).…”

“…For human tumour samples, consent was obtained from the patient or next of kin and procedures were carried out with the approval of the internal review board. ULM-GBM-PC35, ULM-GBM-PC38, and ULM-GBM-PC40 are primary cultured human glioblastoma cells derived from tumour resections performed at our institution and were generated and characterized as previously described (Karpel-Massler et al, 2013;Opel et al, 2008;Schneider et al, 2016;Ströbele et al, 2015). ULM-GBM-SC35, ULM-GBM-SC38, and ULM-GBM-SC40 are stem-like glioma cells which were also derived and characterized at our institution (Karpel-Massler et al, 2013;Opel et al, 2008;Schneider et al, 2016;Ströbele et al, 2015).…”

Extracellular Hyaluronic Acid Influences the Efficacy of EGFR Tyrosine Kinase Inhibitors in a Biomaterial Model of Glioblastoma

“…However, data report that inhibition of Akt is not as efficient as inhibition of PI3K. [28,29] Immunoblotting assays in our PDX laden constructs show the important influence of matrix-bound hyaluronan in defining the effect of erlotinib exposure. Quantification of PI3K signaling via densitometry (Figure 5) suggests EGFR GBM10 (PTEN − ) are more susceptible to EGFR inhibition if CD44 is also blocked in HA-containing matrices.…”

“…[28] The use of tyrosine kinase inhibitors (TKIs) such as erlotinib have the potential to inhibit PI3K signaling in GBM, and therefore reduce tumor invasion and growth. [29] Potential explanations for the reduced efficacy of TKIs as single therapy agents in GBM include that PI3K signaling may be uncoupled from upstream control by inactivation of PTEN or that interactions between EGFR and HA-mediated signaling paths may lead to unexpected biological outcomes that are difficult to monitor in vivo. As a result, biomaterial models of the tumor microenvironment provide a platform to explore the functional importance of microenvironmental ligands such as HA (Figure 1) in the intrinsic resistance of GBM cells to TKI, such as erlotinib.…”