Blockade of SDF-1 after irradiation inhibits tumor recurrences of autochthonous brain tumors in rats

Abstract

BackgroundTumor irradiation blocks local angiogenesis, forcing any recurrent tumor to form new vessels from circulating cells. We have previously demonstrated that the post-irradiation recurrence of human glioblastomas in the brains of nude mice can be delayed or prevented by inhibiting circulating blood vessel–forming cells by blocking the interaction of CXCR4 with its ligand stromal cell-derived factor (SDF)–1 (CXCL12). In the present study we test this strategy by directly neutralizing SDF-1 in a clinically relevant model using autochthonous brain tumors in immune competent hosts.MethodsWe used NOX-A12, an l-enantiomeric RNA oligonucleotide that binds and inhibits SDF-1 with high affinity. We tested the effect of this inhibitor on the response to irradiation of brain tumors in rat induced by n-ethyl-N-nitrosourea.ResultsRats treated in utero with N-ethyl-N-nitrosourea began to die of brain tumors from approximately 120 days of age. We delivered a single dose of whole brain irradiation (20 Gy) on day 115 of age, 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. We found a marked prolongation of rat life span that was dependent on both drug dose and duration of treatment. In addition we treated tumors only when they were visible by MRI and demonstrated complete regression of the tumors that was not achieved by irradiation alone or with the addition of temozolomide.ConclusionsInhibition of SDF-1 following tumor irradiation is a powerful way of improving tumor response of glioblastoma multiforme.

Increasing Tumor-Infiltrating T Cells through Inhibition of CXCL12 with NOX-A12 Synergizes with PD-1 Blockade

“…NOX-A12 was previously shown to not only directly bind and inhibit, but also detach the cell-surface bound CXCL12, leading to abrogation of the CXCL12 gradient (10). Of note, NOX-A12 inhibits the interaction of CXCL12 with both its receptors, CXCR4 and CXCR7 (9,11). Clinically, NOX-A12 has been shown to be efficacious on top of standard therapy in relapsed or refractory multiple myeloma and chronic lymphatic leukemia (12,13).…”

Effect of Irradiation on Tumor Microenvironment and Bone Marrow Cell Migration in a Preclinical Tumor Model

“…In support of this idea, the SRT group exhibited increased tumor hypoxia and ablation of tumor vasculature, with a concomitant increase in intra-tumoral VEGF levels. These data suggest that SRT irradiated tumors activate angiogenic signals, which may promote tumor regrowth mechanisms (2,7,10,(17)(18)(19). Since these hypoxia-mediated responses were less evident after PRT than SRT, we speculate that a diminished activation of these angiogenic signals may occur after PRT.…”

Distinct Luminal-Type Mammary Carcinomas Arise from Orthotopic Trp53-Null Mammary Transplantation of Juvenile versus Adult Mice

“…Breast cancers positive for ER have a distinct methylome profile compared to the more aggressive ER-negative cancers (47). Methylation is a key component of differentiation-associated patterns of transcription in normal development of the mammary gland (48). Both hypo- and hyper-methylation changes are associated with disease.…”