title: 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.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada. ccollins@prostatecentre.com
authors.forename: Colin C
authors.initials: CC
authors.lastname: Collins
authors.forename: Stanislav V
authors.initials: SV
authors.lastname: Volik
authors.forename: Anna V
authors.initials: AV
authors.lastname: Lapuk
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Wang
authors.forename: Peter W
authors.initials: PW
authors.lastname: Gout
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Wu
authors.forename: Hui
authors.initials: H
authors.lastname: Xue
authors.forename: Hongwei
authors.initials: H
authors.lastname: Cheng
authors.forename: Anne
authors.initials: A
authors.lastname: Haegert
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bell
authors.forename: Sonal
authors.initials: S
authors.lastname: Brahmbhatt
authors.forename: Shawn
authors.initials: S
authors.lastname: Anderson
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.forename: Antonio
authors.initials: A
authors.lastname: Hurtado-Coll
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.forename: Francesca
authors.initials: F
authors.lastname: Demichelis
authors.forename: Himisha
authors.initials: H
authors.lastname: Beltran
authors.forename: Martin
authors.initials: M
authors.lastname: Hirst
authors.forename: Marco
authors.initials: M
authors.lastname: Marra
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Maher
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Bertino
authors.forename: Martin
authors.initials: M
authors.lastname: Lubin
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002872:Chromosome Deletion; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D003839:Deoxyadenosines / Q000008:administration & dosage; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018358:Neuroendocrine Tumors / Q000188:drug therapy / Q000235:genetics / Q000556:secondary; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D011683:Purine-Nucleoside Phosphorylase / Q000172:deficiency / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods*; D013866:Thioguanine / Q000008:administration & dosage; D013872:Thionucleosides / Q000008:administration & dosage; D016896:Treatment Outcome; D014523:Urethral Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000556:secondary; D023041:Xenograft Model Antitumor Assays
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D003839:Deoxyadenosines; D013872:Thionucleosides; C008500:5'-methylthioadenosine; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D013866:Thioguanine