Small molecule kinase inhibitors in glioblastoma: a systematic review of clinical studies

Abstract

The efficacy of small-molecule kinase inhibitors has recently changed standard clinical practice for several solid cancers. Glioblastoma is a solid cancer that universally recurs and unrelentingly results in death despite maximal surgery and radiotherapy with concomitant and adjuvant temozolomide. Several clinical studies using kinase inhibitors in glioblastoma have been reported. The present study systematically reviews the efficacy, toxicity, and tissue analysis of small-molecule kinase inhibitors in adult patients with glioblastoma as reported in published clinical studies and determines which kinases have been targeted by the inhibitors used in these studies. Publications were retrieved using a MEDLINE search and by screening meeting abstracts. A total of 60 studies qualified for inclusion, of which 25 were original reports. A total of 2385 glioblastoma patients receiving kinase inhibitors could be evaluated. The study designs included 2 phase III studies and 37 phase II studies. Extracted data included radiological response, progression-free survival, overall survival, toxicity, and biomarker analysis. The main findings were that (i) efficacy of small-molecule kinase inhibitors in clinical studies with glioblastoma patients does not yet warrant a change in standard clinical practice and (ii) 6 main kinase targets for inhibitors have been evaluated in these studies: EGFR, mTOR, KDR, FLT1, PKCbeta, and PDGFR.

The role of the PI3K/AKT/mTOR pathway in brain tumor metastasis

“…[133,134] Unfortunately, the overall response rate of GBMs to kinase inhibitors in clinical trials has been poor so far. [135] One reason for these disappointing results may be inadequate trial design. Systematic flaws such as small sample sizes, absent control groups and unverified drug activity have been reported in the past.…”

“…Systematic flaws such as small sample sizes, absent control groups and unverified drug activity have been reported in the past. [135] Therefore, various changes in study design have been proposed to improve the reliability of the results. Clinical trials enriched for patients with an aberrant kinase target are likely to give a better picture of the overall performance of a particular inhibitor.…”

Selective inhibition of PDGFR by imatinib elicits the sustained activation of ERK and downstream receptor signaling in malignant glioma cells

“…Anti-RTK-based strategies using small molecule kinase inhibitors or antibodies have been tested in clinical trials for patients with malignant glioma. These were focused on the inhibition of excessive RTK activity and thus of the downstream cellular signaling cascades that are responsible for enhanced proliferation, angiogenesis and the survival of cancer cells (3,(5)(6)(7). Among others, two major intracellular signaling pathways that are activated by RTKs and are co-opted in tumor cells are the Ras/MAPK and PI3K/Akt/mTOR pathways.…”

“…Imatinib has shown remarkable effects not only in patients with chronic myeloid leukemia (CML) and Bcr-Abl activation, but has also been proven to inhibit c-Kit-and PDGFRAmediated signaling and to improve survival in patients with gastrointestinal stromal cell tumors (15) and hypereosinophilic syndrome (16). However, phase I/II clinical studies with single-agent imatinib have failed to demonstrate significant clinical effects in patients with malignant glioma (5,17). Although results from phase II studies on the agent in combination with hydroxyurea, have suggested beneficial effects and have supported the initiation of a randomized clinical trial (18), this trial was eventually halted due to proven lack of efficacy (7).…”

EGFR Expression Stratifies Oligodendroglioma Behavior

“…5,6 Testing for EGFR expression and/or amplification may also prove useful from a therapeutics perspective, assuming that an anti-EGFR drug can be developed that has significant therapeutic effects. 7,8 Several retrospective studies 9 -14 have tested the correlation between EGFR expression in WHO gradeadjusted gliomas and patient survival, with conflicting data. Herein, we describe the results of EGFR expression analysis from a prospective cohort of 750 infiltrative gliomas covering WHO grades II to IV, including its ability to predict EGFR amplification and its correlation with patient survival.…”