Abstract 4382: Inhibition of SDF-1 (CXCL12) using the Spiegelmer NOX-A12 markedly delays the recurrence of ENU-induced rat brain tumors following irradiation
Authors: Shie-chau Liu, Reem Alomran, Fang Quan, Milton Merchant, Steffan Zollner, Anna Kruschinski, Laurence Recht, Martin Brown
Journal: Cancer Research (2012)

Abstract We have previously shown that the post-irradiation recurrence of human glioblastomas implanted intracranially in the mouse brain can be delayed or prevented by inhibiting the interaction of the chemokine receptor CXCR4 with its ligand SDF-1 (CXCL12)1. This effect is due to inhibition of the post-irradiation recovery of the tumor vasculature from circulating cells, a process known as vasculogenesis. However, SDF-1 has a second receptor, CXCR7, which has been implicated in endothelial cell migration2, is present on tumor vasculature2, and is potentially also able to activate vasculogenesis. Therefore we investigated the efficacy of the SDF-1 inhibitor NOX-A12, an L-enantiomeric RNA oligonucleotide (Spiegelmer), on brain tumor recurrences after irradiation. NOX-A12 inhibits SDF-1 with subnanomolar affinity and should therefore inhibit SDF-1 mediated activation of both receptors, CXCR4 and CXCR7. In this study we used ENU-induced brain tumors in the Sprague-Dawley rat, a model that has proved extremely resistant to anticancer therapy in prior studies by a variety of investigators. Pregnant rats were injected with the carcinogen ethylnitrosourea (50mg/kg) on day 17 of gestation. In this model the pups appear normal at birth but begin 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 and began treatment with NOX-A12 immediately following irradiation and continued every 2 days with either 5 or 20 mg/kg injected subcutaneously for either 4 or 8 weeks. These doses and times were chosen as equivalent to human doses and times that based on existing data have been found to be safe and well tolerated in human volunteers and which are effective in inhibiting the action of SDF-1. We found that neither 20 Gy nor NOX-A12 alone prolonged the lifespan of the tumor-bearing rats. However, the addition of NOX-A12 to 20 Gy prolonged the lifespan of the rats particularly at the highest dose and for the longer treatment period of 8 weeks (median lifespans of 20 Gy alone and 20 Gy + 5 and 20 mg/kg of NOX-A12 were 196, 291 and 349 days respectively with p values for NOX-A12 treated rats &amp;lt;0.05 vs radiation or controls alone). We believe that these encouraging data justify a human trial in first line glioblastoma patients. 1. Kioi M, Vogel H, Schultz G, Hoffman RM, Harsh GR, Brown JM: Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Invest 120:694-705, 2010 2. Miao Z, Luker KE, Summers BC, Berahovich R, Bhojani MS, Rehemtulla A, et al: CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature. Proc Natl Acad Sci U S A 104:15735-15740, 2007 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4382. doi:1538-7445.AM2012-4382