Opportunities and Challenges of Small Molecule Inhibitors in Glioblastoma Treatment: Lessons Learned from Clinical
Linde Hoosemans1, Marc Vooijs1, Ann Hoeben2
1Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Reproduction, Maastricht University Medical Center+, 6229 HX Maastricht, The Netherlands.
Abstract:
Glioblastoma (GBM) is the most prevalent central nervous system tumour (CNS). Patients with GBM have a dismal prognosis of 15 months, despite an intensive treatment schedule consisting of surgery, chemoradiation and concurrent chemotherapy. In the last decades, many trials have been performed investigating small molecule inhibitors, which target specific genes involved in tumorigenesis. So far, these trials have been unsuccessful, and standard of care for GBM patients has remained the same since 2005. This review gives an overview of trials investigating small molecule inhibitors on their own, combined with chemotherapy or other small molecule inhibitors. We discuss possible resistance mechanisms in GBM, focussing on intra- and intertumoral heterogeneity, bypass mechanisms and the influence of the tumour microenvironment. Moreover, we emphasise how combining inhibitors can help overcome these resistance mechanisms. We also address strategies for improving trial outcomes through modifications to their design. In summary, this review aims to elucidate different resistance mechanisms against small molecule inhibitors, highlighting their significance in the search for novel therapeutic combinations to improve the overall survival of GBM patients.
Insights
Glioblastoma (GBM) treatment faces challenges due to drug resistance. This review explores resistance mechanisms and combination therapies to improve survival for patients with this aggressive brain cancer.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Clinical Trials
Background:
- Glioblastoma (GBM) is the most common and aggressive primary brain tumor.
- Current standard treatments yield a poor prognosis of approximately 15 months.
- Small molecule inhibitor trials have largely failed to improve outcomes since 2005.
Purpose of the Study:
- To review clinical trials of small molecule inhibitors for GBM.
- To discuss resistance mechanisms including tumor heterogeneity and the microenvironment.
- To highlight therapeutic combinations and trial design modifications for improved outcomes.
Main Methods:
- Literature review of clinical trials investigating small molecule inhibitors in GBM.
- Analysis of resistance mechanisms reported in scientific literature.
- Discussion of novel therapeutic strategies and trial design improvements.
Main Results:
- Despite numerous trials, small molecule inhibitors alone or with chemotherapy have not improved GBM patient survival.
- Intra- and intertumoral heterogeneity, bypass pathways, and the tumor microenvironment contribute to treatment resistance.
- Combining inhibitors and modifying trial designs are promising strategies.
Conclusions:
- Understanding GBM resistance mechanisms is crucial for developing effective therapies.
- Combination therapies targeting multiple pathways show potential for overcoming resistance.
- Optimizing clinical trial designs is essential for advancing GBM treatment.
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