Improving the prognosis for patients with glioblastoma: the rationale for targeting Src.
Glioblastoma is the most common and aggressive form of primary brain tumor. The prognosis for patients diagnosed with glioblastoma is poor, with a median survival of 12-14 months and a 5-year survival rate of <5%. The upfront standard treatment for patients with newly diagnosed glioblastoma, consisting of surgery followed by chemotherapy combined with radiotherapy, provides only short-term survival benefits. Recurrent glioblastoma is an extremely challenging therapeutic setting because of the aggressive and resistant nature of the tumor. A set of key molecular targets in oncology is the Src family of non-receptor protein kinases. Dysregulated signaling via the Src kinases has been shown to underlie glioma-related proliferation, angiogenesis, migration, and survival. Here we review the biologic role of Src in malignant glioma and discuss key preclinical studies demonstrating the potential utility of inhibiting Src in glioma. Proof of clinical benefit is forthcoming from the first clinical studies involving the newest generation of small molecule Src inhibitors currently in clinical trials for recurrent glioblastoma. Blocking Src alone will likely not translate into a significant clinical benefit; thus, strategies for combining Src inhibitors with potential synergistic therapeutic modalities will be discussed. This review will focus on dasatinib, the most advanced Src inhibitor being tested in glioblastoma, which is currently in phase I/II trials in this setting.
The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 431, Houston, TX, 77030-4009, USA. jdegroot@mdanderson.org.
John
J
de Groot
Department of Biological Sciences, The University of Notre Dame, 107 Galvin Life Science Center, Notre Dame, IN, 46556-5645, USA.
Vanessa
V
Milano
D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000069439:Dasatinib; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D013844:Thiazoles / Q000627:therapeutic use*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D019061:src-Family Kinases; D000069439:Dasatinib