Novel therapies in glioblastoma

Abstract

Conventional treatment of glioblastoma has advanced only incrementally in the last 30 years and still yields poor outcomes. The current strategy of surgery, radiation, and chemotherapy has increased median survival to approximately 15 months. With the advent of molecular biology and consequent improved understanding of basic tumor biology, targeted therapies have become cornerstones for cancer treatment. Many pathways (RTKs, PI3K/AKT/mTOR, angiogenesis, etc.) have been identified in GBM as playing major roles in tumorigenesis, treatment resistance, or natural history of disease. Despite the growing understanding of the complex networks regulating GBM tumors, many targeted therapies have fallen short of expectations. In this paper, we will discuss novel therapies and the successes and failures that have occurred. One clear message is that monotherapies yield minor results, likely due to functionally redundant pathways. A better understanding of underlying tumor biology may yield insights into optimal targeting strategies which could improve the overall therapeutic ratio of conventional treatments.

Figure 1

Novel therapies in GBM. RTKs and survival signaling pathways are major drug targets in GBM. Receptors have been targeted extracellularly by monoclonal antibodies or intracellularly at the tyrosine kinase domain. Major nodes in survival signaling pathways (P13K, AKT, mTOR) have been the focus of intense study and drug development. More recent approaches include stem-cell targeting (GSIs), inhibition of DNA rapair (PARP inhibitors), and targeting a host of cellular pathways through microRNA manipulation. Novel tumor cell killing approaches are also being studied. Oncolytic virus therapy, either alone or in combination with targeted agent delivery and immunotherapy, are being employed to efficiently kill tumor cells while sparing normal tissue. RTK, receptor tyrosine kinase; EGFR, epidermal growth factor receptor; VEGFR, vascular endothelial growth factor receptor; IGFR, insulin-like growth factor receptor 1; PDGFR, platelet-derived growth factor receptor; mTor, mammalian target of rapamycin; GSI, gamma-secretase inhibitor; APC, antigen-presenting cell; CTL, cytotoxic T lymphocyte, MHC class I, major histocompatibility complex I; PARP, poly(ADP-ribose) polymerase; HDAC, histone deacetylase inhibitor.