title: Effects of HDM2 antagonism on sunitinib resistance, p53 activation, SDF-1 induction, and tumor infiltration by CD11b+/Gr-1+ myeloid derived suppressor cells.
abstract: BACKGROUND
  The studies reported herein were undertaken to determine if the angiostatic function of p53 could be exploited as an adjunct to VEGF-targeted therapy in the treatment of renal cell carcinoma (RCC).
  
  
  METHODS
  Nude/beige mice bearing human RCC xenografts were treated with various combinations of sunitinib and the HDM2 antagonist MI-319. Tumors were excised at various time points before and during treatment and analyzed by western blot and IHC for evidence of p53 activation and function.
  
  
  RESULTS
  Sunitinib treatment increased p53 levels in RCC xenografts and transiently induced the expression of p21(waf1), Noxa, and HDM2, the levels of which subsequently declined to baseline (or undetectable) with the emergence of sunitinib resistance. The development of resistance and the suppression of p53-dependent gene expression temporally correlated with the induction of the p53 antagonist HDMX. The concurrent administration of MI-319 markedly increased the antitumor and anti-angiogenic activities of sunitinib and led to sustained p53-dependent gene expression. It also suppressed the expression of the chemokine SDF-1 (CXCL12) and the influx of CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSC) otherwise induced by sunitinib. Although p53 knockdown markedly reduced the production of the angiostatic peptide endostatin, the production of endostatin was not augmented by MI-319 treatment.
  
  
  CONCLUSIONS
  The evasion of p53 function (possibly through the expression of HDMX) is an essential element in the development of resistance to VEGF-targeted therapy in RCC. The maintenance of p53 function through the concurrent administration of an HDM2 antagonist is an effective means of delaying or preventing the development of resistance.
authors.affiliation: Division of Hematology-Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. dpanka@bidmc.harvard.edu
authors.forename: David J
authors.initials: DJ
authors.lastname: Panka
authors.forename: Qingjun
authors.initials: Q
authors.lastname: Liu
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Geissler
authors.forename: James W
authors.initials: JW
authors.lastname: Mier
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D039481:CD11b Antigen / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D043169:Endostatins / Q000235:genetics / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology*; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D013141:Spiro Compounds / Q000008:administration & dosage / Q000494:pharmacology; D000077210:Sunitinib; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D039481:CD11b Antigen; D054377:Chemokine CXCL12; D043169:Endostatins; D007211:Indoles; C548961:MI 319; D011758:Pyrroles; D013141:Spiro Compounds; D016159:Tumor Suppressor Protein p53; D011393:Procollagen-Proline Dioxygenase; D051736:Proto-Oncogene Proteins c-mdm2; D000077210:Sunitinib