Getting more out of radiation therapy in glioblastoma.

While radiation therapy has been standard of care for newly diagnosed glioblastoma for several decades, it only delays but does not prevent recurrence of these aggressive tumors. Therefore, the identification and targeting of factors allowing glioblastoma cells to escape the deleterious effects of radiation is essential to allow this therapeutic modality to fulfill its potential. In an elegant study published in 2010, the Brown lab reported that irradiation induces recruitment of bone marrow-derived cells (BMDCs) into glioblastoma to form blood vessels de novo, a process defined as vasculogenesis, in contrast to angiogenesis which involves the remodeling of existing vessels in the tumor bed In that study, pharmacologic inhibition of HIF-1 or of the interaction between the chemokine stromalderivedfactor-1(SDF-1, CXCL12)and its receptor CXCR4prevented the influxofBMDCs, primarily CD11b+myelomonocytes, and the development of functional tumor vasculature after radiation, resulting in abrogation of tumor regrowth. Now, in a follow-up study entitled “Blockade of SDF-1 after irradiation inhibits tumor recurrences of autochthonous brain tumors in rats” published in this issue of Neuro-Oncology, Liu and colleagues from that same group sought to improve upon limitations previously reported when they and others targeted the SDF-1/CXCR4 interaction using the small molecule CXCR4 inhibitor plerixafor (AMD3100). Specifically, the authors noted that endothelial cells in tumors like glioblastoma express high levels of CXCR7, the more recently discovered second receptor for SDF-1. Of note, besides its blockade of CXCR4, plerixafor is actually an allosteric agonist of CXCR7, which can signal through b-arrestin and may activate the endothelium leading to increased invasiveness of cancer cells. The authors therefore investigated combining radiation therapy with NOX-A12, 45 L-enantiomeric RNA nucleotides which form a structural scaffold that recognizes SDF-1 with high affinity and thus efficiently blocks the chemokine’s interaction with CXCR4 and CXCR7 (Figure 1). Theyshowed that NOX-A12 inhibits SDF-1 dependent chemotaxis of CXCR4 myelomonocytes and SDF-1 dependent CXCR7 internalization in endothelial cells. NOX-A12 also inhibits SDF-1 dependent migration of endothelial cells. Rats treated in utero with the carcinogen ethylnitrosourea (ENU) begin to die of brain tumors from approximately 120 days of age. The authors delivered a single dose of whole brain irradiation (20 Gy) on day 115 of age and began treatment with NOX-A12 immediately following irradiation and continued with either 5 or 20 mg/kg for 4 or 8 weeks, doses and times equivalent to well tolerated human exposures. The authors found a marked prolongation of rat lifespan that was dependent both on drug dose and duration of treatment. When treating tumors only when they were visible by MRI, the authors demonstrated complete regression of the tumors with combined treatment that was not achieved by radiation alone or with the addition of temozolomide to radiation.