Next Generation Sequencing of Prostate Cancer from a Patient Identifies a Deficiency of Methylthioadenine Phosphorylase (MTAP), an Exploitable Tumor Target
Menée sur un échantillon tumoral prélevé sur un patient atteint d'un cancer de la prostate, cette étude de séquençage identifie la présence d'une mutation du gène d'une enzyme, la méthylthioadénine phosphorylase, et, à l'aide d'une xénogreffe, suggère l'efficacité d'un traitement à l'aide de méthylthioadénosine
Castrate resistant prostate cancer (CRPC) and neuroendocrine carcinoma of the prostate are invariably fatal diseases for which only palliative therapies exist. As part of a prostate tumour sequencing program, a patient tumour was analyzed using Illumina genome sequencing and a matched renal capsule tumour xenograft was generated. Both tumour and xenograft had a homozygous 9p21 deletion spanning the MTAP, CDKN2 and ARF genes. It is rare for this deletion to occur in primary prostate tumours yet approximately 10% express decreased levels of MTAP mRNA. Decreased MTAP expression is a prognosticator for poor outcome. Moreover, it appears that this deletion is more common in CRPC than in primary prostate cancer. We show for the first time that treatment with methylthioadenosine and high dose 6-thioguanine causes marked inhibition of a patient derived neuroendocrine xenograft growth while protecting the host from 6- thioguanine toxicity. This therapeutic approach can be applied to other MTAP-deficient human cancers since deletion or hypermethylation of the MTAP gene occurs in a broad spectrum of tumours at high frequency. The combination of genome sequencing and patient-derived xenografts can identify candidate therapeutic agents and evaluate them for personalized oncology.
http://mct.aacrjournals.org/content/early/2012/01/17/1535-7163.MCT-11-0826.abstract