title: The clinical development of p53-reactivating drugs in sarcomas - charting future therapeutic approaches and understanding the clinical molecular toxicology of Nutlins.
abstract: BACKGROUND
  The majority of human sarcomas, particularly soft tissue sarcomas, are relatively resistant to traditional cytotoxic therapies. The proof-of-concept study by Ray-Coquard et al., using the Nutlin human double minute (HDM)2-binding antagonist RG7112, has recently opened a new chapter in the molecular targeting of human sarcomas.
  
  
  METHODS
  In this review, the authors discuss the challenges and prospective remedies for minimizing the significant haematological toxicities of the cis-imidazole Nutlin HDM2-binding antagonists. Furthermore, they also chart the future direction of the development of p53-reactivating (p53-RA) drugs in 12q13-15 amplicon sarcomas and as potential chemopreventative therapies against sarcomagenesis in germ line mutated TP53 carriers. Drawing lessons from the therapeutic use of Imatinib in gastrointestinal tumours, the authors predict the potential pitfalls, which may lie in ahead for the future clinical development of p53-RA agents, as well as discussing potential non-invasive methods to identify the development of drug resistance.
  
  
  CONCLUSIONS
  Medicinal chemistry strategies, based on structure-based drug design, are required to re-engineer cis-imidazoline Nutlin HDM2-binding antagonists into less haematologically toxic drugs. In silico modelling is also required to predict toxicities of other p53-RA drugs at a much earlier stage in drug development. Whether p53-RA drugs will be therapeutically effective as a monotherapy remains to be determined.
authors.affiliation: University Hospitals Southampton NHS Foundation Trust, Southampton General Hospital, Division of Medical Oncology, Sarcoma Unit , Floor D, East Wing, Southampton, Tremona Road, Southampton, SO16 6YD , UK swethajit.biswas@uhs.nhs.uk.
authors.forename: Swethajit
authors.initials: S
authors.lastname: Biswas
authors.forename: Emma
authors.initials: E
authors.lastname: Killick
authors.forename: Aart G
authors.initials: AG
authors.lastname: Jochemsen
authors.forename: John
authors.initials: J
authors.lastname: Lunec
mesh_terms: D000818:Animals; D032882:Comprehension; D055808:Drug Discovery / Q000639:trends*; D005544:Forecasting; D006801:Humans; D048288:Imidazolines / Q000494:pharmacology / Q000627:therapeutic use; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D048288:Imidazolines; C579783:RG7112; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2