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Targeting malignant glioma survival signalling to improve clinical outcomes
Michael L H Wong1, Andrew H Kaye, Christopher M Hovens
1Department of Surgery, University of Melbourne, Royal Melbourne Hospital, Parkville, 3050, Melbourne, Victoria, Australia. pazu@ozemail.com.au
Abstract:
Malignant gliomas are common and aggressive brain tumours in adults. Current treatments for glioblastoma multiforme result in a poor median survival of less than 12 months. The blood-brain barrier restricts the delivery of many chemotherapies to the central nervous system, contributing to the failure of treatment. PI3K/Akt and Ras/MAPK pathways have been identified as important oncogenic pathways in these tumours. The PI3K/Akt pathway mediates cell survival and growth, whereas the Ras/MAPK pathway signals cell differentiation, proliferation and anti-apoptosis. Modern targeted therapies include antibodies to circulating growth factors and cell surface receptors, as well as inhibitors of receptor tyrosine kinases and specific intracellular signalling proteins. Monotherapy with most targeted therapies produces only modest efficacy. Better results are achieved in combination with cytotoxic chemotherapies. Future therapeutics should focus on combination therapy with small lipophilic molecules.
Insights
Malignant gliomas like glioblastoma have poor survival rates due to treatment challenges. Combination therapy with small lipophilic molecules shows promise for improving outcomes in brain tumor treatment.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Pharmacology
Background:
- Malignant gliomas, including glioblastoma multiforme, are aggressive adult brain tumors with poor median survival.
- The blood-brain barrier limits chemotherapy efficacy in the central nervous system.
- Key oncogenic pathways, PI3K/Akt (cell survival/growth) and Ras/MAPK (differentiation/proliferation/anti-apoptosis), are implicated in glioma progression.
Purpose of the Study:
- To review current treatment strategies for malignant gliomas.
- To evaluate the efficacy of targeted therapies and combination approaches.
- To identify promising future therapeutic directions for glioblastoma.
Main Methods:
- Literature review of current and emerging treatments for malignant gliomas.
- Analysis of the role of PI3K/Akt and Ras/MAPK signaling pathways in glioma.
- Evaluation of targeted therapies, including antibodies and kinase inhibitors.
- Assessment of combination therapy strategies with cytotoxic agents.
Main Results:
- Current glioblastoma treatments yield a median survival of less than 12 months.
- Monotherapy with targeted agents shows modest efficacy.
- Combination therapy, particularly with cytotoxic chemotherapies, demonstrates improved results.
- Small lipophilic molecules are identified as potential components of future combination therapies.
Conclusions:
- Targeted therapies are crucial but often require combination with other agents for improved glioblastoma outcomes.
- Overcoming the blood-brain barrier remains a significant challenge in CNS cancer treatment.
- Future research should prioritize combination therapies, especially utilizing small lipophilic molecules, to enhance treatment efficacy for malignant gliomas.
