ATPS-72: A NOVEL CXCR4 ANTAGONIST COMBINES SYNERGISTICALLY WITH BEVACIZUMAB AND SUNITINIB TO INHIBIT PROGRESSION OF GLIOBLASTOMA

BACKGROUND: SDF1 and its receptor CXCR4 are strongly implicated in the maintenance of the highly aggressive cancer Glioblastoma multiforme (GBM). SDF1 and CXCR4 are also involved in the recruitment of vasculogenic precursors from the bone marrow, so we hypothesized that combining the anti-vasculogenic activity of CXCR4 inhibition with anti-angiogenic therapy would have profound anti-tumor activity. CXCR4 inhibition was achieved through the use of Compound B, a high affinity (Ki <10nM), highly selective, small molecule, brain penetrant CXCR4 antagonist which inhibits xenograft progression in nude mice after irradiation and/or temozolomide. METHODS: The expression of CXCR4 and release of CXCL12 in three human glioma cell lines (U87, U251 and T98G) was measured in vitro. Xenograft tumours (s.c.) were induced using 2 x10⁶ cells in groups of 8 SCID mice, and after the tumours had grown to 100mm³ the mice were randomized to receive vehicle, bevacizumab (4 mg/kg iv every 4 days), sunitinib (40mg/kg po qd) or Compound B (50mg/kg po qd), bevacizumab plus Compound B or sunitinib plus Compound B. The same dosing schedules (but without sunitinib) were used in intracranial experiments using tumours induced by 10⁵ luciferase labelled U87 cells. Time to progression (doubling of tumour size) was assessed. RESULTS: The GBM cell lines expressed CXCR4 and released CXCL12 in vitro. In vivo Compound B inhibited the progression of U87, U251 and T98G xenografts (s.c.), to approximately the same extent as bevacizumab and sunitinib, while the combination of Compound B with either anti-angiogenic agent showed a synergistic inhibition of tumour progression (p < 0.0001 with all three cell lines). Subsequently the effect of the combination of Compound B with bevacizumab on U87 intracranial tumours was investigated. CONCLUSION: Compound B may be used in combination with anti-angiogenic treatments to inhibit the progression of GBM.