MP49-15 DOES TUMOR MICROENVIRONMENT AFFECT THE RESPONSE OF CASTRATION RESISTANT PROSTATE CANCER TO THERAPY IN BONE VS VISCERAL METASTASES?

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research IV1 Apr 2014MP49-15 DOES TUMOR MICROENVIRONMENT AFFECT THE RESPONSE OF CASTRATION RESISTANT PROSTATE CANCER TO THERAPY IN BONE VS VISCERAL METASTASES? Maahum Haider, Ilsa Coleman, Xiaotun Zhang, Lisha Brown, Lori Kollath, Shahriar Koochekpour, Robert Montgomery, Paul Lange, Martine Roudier, Lawrence True, Celestia Higano, Peter Nelson, Robert Vessella, and Colm Morrissey Maahum HaiderMaahum Haider More articles by this author , Ilsa ColemanIlsa Coleman More articles by this author , Xiaotun ZhangXiaotun Zhang More articles by this author , Lisha BrownLisha Brown More articles by this author , Lori KollathLori Kollath More articles by this author , Shahriar KoochekpourShahriar Koochekpour More articles by this author , Robert MontgomeryRobert Montgomery More articles by this author , Paul LangePaul Lange More articles by this author , Martine RoudierMartine Roudier More articles by this author , Lawrence TrueLawrence True More articles by this author , Celestia HiganoCelestia Higano More articles by this author , Peter NelsonPeter Nelson More articles by this author , Robert VessellaRobert Vessella More articles by this author , and Colm MorrisseyColm Morrissey More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1116AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives Castration resistant prostate cancer (CRPC) often metastasizes to bone with evidence to suggest a differential response to treatment in bone versus visceral metastases. We identify molecular targets and pathways and their respective roles in bone metastatic CRPC. Methods We obtained tissue samples from 44 CRPC patients via rapid autopsy at the University of Washington. Each patient's clinical history, metastatic sites, pathology, and biomarker expression was evaluated. Laser capture microdissection was used to isolate mRNA from liver (n=19), lymph node (n=68) and bone metastases (n=20) and expression analyses were performed. Differential expression of proteins was validated with tissue microarrays (TMA) in bone (n=117) and visceral (n=65) metastases. Serial serum samples were assayed for prosaposin (PSAP) in patients who presented with localized disease and developed bone metastases. Results Specific genes were examined in 3 specific pathways that were altered in bone vs visceral metastases: 1) Epithelial mesenchymal transition; TWIST-associated proteins (ZEB1/2, SNAI1/2, TGFB1, VIM q<0.05), 2) Survival pathways (BAD, BAX q<0.05), and 3) Osteomimetic pathways (POSTN, SPP1, RUNX2, DKK1, DMP1, IBSP, THBS3 q<0.05). The TMAs showed that both nuclear and cytoplasmic Twist are significantly higher in bone than soft tissue metastases (p<0.01). It is mainly cytoplasmic in bone metastases, with nuclear expression seen in 24/117 bone sites and in only 1/65 soft tissue sites. This suggests that TWIST may only be transcriptionally active in a subset of epithelial cells. Gene set enrichment analysis identified mitochondrial proteins that are involved in survival pathways as being differentially expressed between bone and visceral metastases. We show overexpression of other survival proteins in addition to the previously shown BCL-2 and MCL-1. We continue to validate the expression of novel osteomimetic proteins in CRPC bone metastases and assess PSAP levels (a protein associated with disease progression and highly expressed in bone metastases). Conclusions The heterogeneity of CRPC within and between patients is a considerable obstacle in determining the appropriate treatment regimen for each patient. Our data show that differential response to therapy could be based on the site of metastases. We are also interrogating a marker that may predict future development of bone metastases and identifying molecular pathways in CRPC that could be specifically targeted in patients with predominantly bone metastatic disease. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e507-e508 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Maahum Haider More articles by this author Ilsa Coleman More articles by this author Xiaotun Zhang More articles by this author Lisha Brown More articles by this author Lori Kollath More articles by this author Shahriar Koochekpour More articles by this author Robert Montgomery More articles by this author Paul Lange More articles by this author Martine Roudier More articles by this author Lawrence True More articles by this author Celestia Higano More articles by this author Peter Nelson More articles by this author Robert Vessella More articles by this author Colm Morrissey More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...