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Exploring multi-targeting strategies for the treatment of gliomas
1Memorial Sloan-Kettering Cancer Center, Department of Neurology, 1275 York Avenue, New York, NY 10065, USA. omuroa@mskcc.org
Abstract:
Molecularly targeted therapies hold the promise of providing new anticancer treatments that are more effective and less toxic than traditional cytotoxic chemotherapy. Unfortunately, results of first generation targeted therapy trials for malignant gliomas (glioblastomas and anaplastic forms of astrocytomas, oligodendrogliomas and oligoastrocytomas) have been disappointing. While combination strategies targeting angiogenesis through inhibition of the VEGFR pathway (eg, bevacizumab combined with irinotecan) have demonstrated promising activity, single-agent drugs have been largely unsuccessful when tested in recurrent disease clinical trials. These single agents include EGF receptor tyrosine kinase inhibitors (gefitinib and erlotinib), PDGF receptor inhibitors (imatinib), mTOR inhibitors (temsirolimus and everolimus), and VEGFR, protein kinase C-beta and other angiogenesis pathway inhibitors (vatalanib and enzastaurin). A new generation of trials is seeking to define whether inhibiting multiple targets simultaneously through utilization of less specific, multi-targeting drugs, or through combination of two or more single-targeted drugs, can overcome tumor resistance. In this review, the rationale and challenges of developing such multi-targeted strategies in gliomas are presented.
Insights
First-generation molecularly targeted therapies have shown limited success in malignant gliomas. Future strategies focus on multi-targeted drugs or combinations to overcome tumor resistance and improve efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Molecularly targeted therapies offer potential for more effective and less toxic cancer treatments compared to traditional chemotherapy.
- First-generation targeted therapies have yielded disappointing results in clinical trials for malignant gliomas.
- While combination therapies targeting angiogenesis (e.g., bevacizumab with irinotecan) show promise, single-agent drugs have largely failed in recurrent disease settings.
Purpose of the Study:
- To review the rationale and challenges of developing multi-targeted therapeutic strategies for malignant gliomas.
- To explore the potential of overcoming tumor resistance through simultaneous inhibition of multiple targets.
Main Methods:
- Review of existing literature on targeted therapies for malignant gliomas.
- Analysis of clinical trial outcomes for single-agent and combination therapies.
- Discussion of novel approaches involving multi-targeting drugs or drug combinations.
Main Results:
- Single-agent targeted therapies (e.g., EGFR, PDGF, mTOR, VEGFR inhibitors) have been largely unsuccessful in recurrent malignant gliomas.
- Combination strategies, particularly those inhibiting angiogenesis via the VEGFR pathway, have shown some promising activity.
- Tumor resistance remains a significant challenge for current targeted therapy approaches.
Conclusions:
- Developing effective molecularly targeted therapies for malignant gliomas requires overcoming significant challenges, including tumor resistance.
- Next-generation trials are investigating simultaneous inhibition of multiple targets using less specific drugs or drug combinations.
- Multi-targeted strategies represent a promising avenue for improving treatment outcomes in malignant gliomas.
