title: The addition of Sunitinib to radiation delays tumor growth in a murine model of glioblastoma.
abstract: OBJECTIVE
  Recent preclinical studies suggest that treating glioblastoma (GBM) with a combination of targeted chemotherapy and radiotherapy may enhance the anti-tumor effects of both therapies. However, the effects of these treatments on glioma growth and  progression are poorly understood.
  
  
  METHODS
  In this study, we have tested the effects of combination therapy in a mouse glioma model that utilizes a PDGF-IRES-Cre-expressing retrovirus to infect adult glial progenitors in mice carrying conditional deletions of Pten and p53. This  model produces tumors with the histological features of GBM with 100% penetrance, making it a powerful system to test novel treatments. Sunitinib is an orally active, small molecule inhibitor of multiple receptor tyrosine kinases critical for tumor growth and angiogenesis, including PDGF receptors.  We investigate the addition of Sunitinib to radiotherapy, and use bioluminescence imaging to characterize the effects of treatment on glioma growth and progression.
  
  
  RESULTS
  Treating our PDGF-driven mouse model with either Sunitinib or high-dose radiation alone delayed tumor growth  and had a modest but significant effect on survival, while treating with low-dose radiation alone failed to control glioma growth and progression. The addition of Sunitinib to low-dose radiation caused a modest, but significant delay in tumor growth. However, no significant survival benefit  was seen as tumors progressed in 100% of animals. Histological analysis revealed a reduction in vascular proliferation and a marked increase in brain invasion. An additional study combining Sunitinib with high-dose radiation revealed a fatal toxicity despite individual monotherapies being  well tolerated.
  
  
  CONCLUSIONS
  These results show that the addition of Sunitinib to radiotherapy fails to significantly alter survival in GBM despite enhancement of the effects of radiation. Furthermore, an enhanced risk of toxicity associated with combined therapy must be considered  in the design of future clinical studies.
authors.affiliation: Department of Biophysics, Columbia University Medical Center, New York, USA. damicors@umdnj.edu
authors.forename: Randy
authors.initials: R
authors.lastname: D'Amico
authors.forename: Liang
authors.initials: L
authors.lastname: Lei
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Kennedy
authors.forename: Julia
authors.initials: J
authors.lastname: Sisti
authors.forename: Victoria
authors.initials: V
authors.lastname: Ebiana
authors.forename: Celina
authors.initials: C
authors.lastname: Crisman
authors.forename: James G
authors.initials: JG
authors.lastname: Christensen
authors.forename: Orlando
authors.initials: O
authors.lastname: Gil
authors.forename: Steven S
authors.initials: SS
authors.lastname: Rosenfeld
authors.forename: Peter
authors.initials: P
authors.lastname: Canoll
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bruce
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D018450:Disease Progression; D005909:Glioblastoma / Q000473:pathology / Q000628:therapy*; D007211:Indoles / Q000008:administration & dosage*; D051379:Mice; D008822:Mice, Transgenic; D011758:Pyrroles / Q000008:administration & dosage*; D011829:Radiation Dosage; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib