Molecularly targeted therapies for malignant glioma: rationale for combinatorial strategies

Abstract

Median survival of patients with malignant glioma (MG) from time of diagnosis is approximately 1 year, despite surgery, irradiation and conventional chemotherapy. Improving patient outcome relies on our ability to develop more effective therapies that are directed against the unique molecular aberrations within a patient’s tumor. Such molecularly targeted therapies may provide novel treatments that are more effective than conventional chemotherapeutics. Recently developed therapeutic strategies have focused on targeting several core glioma signaling pathways, including pathways mediated by growth-factors, PI3K/Akt/PTEN/mTOR, Ras/Raf/MEK/MAPK and other vital pathways. However, given the molecular diversity, heterogeneity and diverging and converging signaling pathways associated with MG, it is unlikely that any single agent will have efficacy in more than a subset of tumors. Overcoming these therapeutic barriers will require multiple agents that can simultaneously inhibit these processes, providing a rationale for combination therapies. This review summarizes the currently implemented single-agent and combination molecularly targeted therapies for MG.

Keywords::

• angiogenesis
• combination therapy
• EGF receptor
• glioblastoma multiforme
• malignant glioma
• molecularly targeted therapeutics
• VEGF receptor

Financial & competing interests disclosure

This work was supported in part by National Institute of Health grant NSP0140923 and the Doris Duke Charitable Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Notes

EGFR: EGF receptor; HDAC: Histone deacetylase; HSP: Heat-shock protein; PDGFR: PDGF receptor; PKC: Protein kinase c; Topo I: Topoisomerase I; VEGFR: VEGF receptor.