93IN - Targeting HDM2 (Human MDM2) in Sarcomas

Abstract

ABSTRACT Liposarcomas represent three families of genetically distinct cancers. The most common of these is well-differentiated / dedifferentiated liposarcoma (WD-DD LS), which represents half of the liposarcomas with an incidence of 4–5 per million people. The well differentiated version of the tumor appears somewhat like fat, while dedifferentiated liposarcomas have typically lost most or all ability to store lipids. WD-DD LS is a unique entity with high copy number amplification of chromosome 12q, followed by loss of portions of other chromosomes, such as 19q13, in more aggressive tumors, which notably is the locus for CEBPA, a key main adipocytic differentation gene. On chromosome 12q are located important genes in maintaining cell survival, such as CDK4 and HDM2 (the human version of MDM2) and YEATS4. Recent data also show epigentic effects to turn off adiopocytic differentiation genes. The presence of the amplified genes such as those above as well as AURKA nearby suggests inhibitors of these proteins may be useful to trigger dysregulation and cell death of these tumors cells with highl abnormal genomes. CDK4 inhibitors and HDM2 inhibitors are now being examined in phase I-II clinical trials in WD DD LS patients. In this talk, the biological background for examining HDM2 inhibitors in WD DD LS patients is discussed, as well as the potential role for these inhibitors both in cancers with wild type p53 as well as those with genetically altered p53. There may not be the need to limit the examination of HDM2 inhibitors to WD DD LS, although issues remain regarding the toxicity observed with these compounds to date. Disclosure R.G. Maki: Consulting fees: GlaxoSmithKline, Bayer, Sanofi, Lilly, Morphotek, Eisai, Pfizer Research Support: Eisai, Ziopharm, Roche Honoraria: Ziopharm, Novartis Unpaid consulting: n-of-one, 23 & Me