Next generation sequencing of prostate cancer from a patient identifies a deficiency of methylthioadenosine phosphorylase, an exploitable tumor target.

Abstract

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 tumor sequencing program, a patient tumor was analyzed using Illumina genome sequencing and a matched renal capsule tumor xenograft was generated. Both tumor 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 tumors, yet approximately 10% express decreased levels of methylthioadenosine phosphorylase (MTAP) mRNA. Decreased MTAP expression is a prognosticator for poor outcome. Moreover, it seems 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 as deletion or hypermethylation of the MTAP gene occurs in a broad spectrum of tumors at high frequency. The combination of genome sequencing and patient-derived xenografts can identify candidate therapeutic agents and evaluate them for personalized oncology.

• Authors: Colin C Collins, Stanislav V Volik, Anna V Lapuk, Yuwei Wang, Peter W Gout, Chunxiao Wu, Hui Xue, Hongwei Cheng, Anne Haegert, Robert H Bell, Sonal Brahmbhatt, Shawn Anderson, Ladan Fazli, Antonio Hurtado-Coll, Mark A Rubin, Francesca Demichelis, Himisha Beltran, Martin Hirst, Marco Marra, Christopher A Maher, Arul M Chinnaiyan, Martin Gleave, Joseph R Bertino, Martin Lubin, Yuzhuo Wang
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 11 Issue 3 Pg. 775-83 (Mar 2012) ISSN: 1538-8514 [Electronic] United States
• PMID: 22252602 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclin-Dependent Kinase Inhibitor p16
• Deoxyadenosines
• Thionucleosides
• 5'-methylthioadenosine
• Purine-Nucleoside Phosphorylase
• 5'-methylthioadenosine phosphorylase
• Thioguanine

Topics

• Aged
• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Chromosome Deletion
• Chromosomes, Human, Pair 9 (genetics)
• Cyclin-Dependent Kinase Inhibitor p16 (genetics)
• Deoxyadenosines (administration & dosage)
• Humans
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neuroendocrine Tumors (drug therapy, genetics, secondary)
• Prostatic Neoplasms (genetics, pathology, therapy)
• Purine-Nucleoside Phosphorylase (deficiency, genetics)
• Sequence Analysis, DNA (methods)
• Thioguanine (administration & dosage)
• Thionucleosides (administration & dosage)
• Treatment Outcome
• Urethral Neoplasms (drug therapy, genetics, secondary)
• Xenograft Model Antitumor Assays