BioCentury
ARTICLE | Distillery Therapeutics

Therapeutics: Mdm4 p53 binding protein homolog (MDM4; MDMX)

December 17, 2015 8:00 AM UTC

In vitro, patient sample and mouse studies suggest antisense oligonucleotides targeting MDM4 exon 6 could help treat cancer. Human melanoma, ovarian, breast, and other cancer cell lines and melanoma tumor samples from patients expressed high levels of full-length MDM4 and low levels of an MDM4 isoform lacking exon 6, whereas normal mouse tissues expressed low levels of full-length MDM4 and high levels of the MDM4 isoform. In human melanoma, neuroblastoma, breast and ovarian cancer cell lines expressing wild-type p53, a splice-switching antisense oligonucleotide designed to skip exon 6 of the MDM4 gene decreased expression of full-length MDM4 protein, decreased growth and increased p53 activity compared with a scrambled control. In patient-derived xenograft mouse models of melanoma and diffuse large B cell lymphoma (DLBCL), intratumoral or IV injection of the antisense oligo decreased tumor growth and increased survival compared with control. Next steps could include testing oligos in specific cancer models. ...