title: PCSD1, a new patient-derived model of bone metastatic prostate cancer, is castrate-resistant in the bone-niche.
abstract: BACKGROUND
  Prostate cancer bone metastasis occurs in 50-90% of men with advanced disease for which there is no cure. Bone metastasis leads to debilitating fractures and severe bone pain. It is associated with therapy resistance and rapid decline. Androgen deprivation therapy (ADT) is standard of care for advanced prostate cancer, however, bone metastatic prostate cancer (PCa) often becomes resistant to ADT. There are few pre-clinical models to understand the interaction between the bone microenvironment and prostate cancer. Here we report the castrate resistant growth in the bone niche of PCSD1, a patient-derived intra-femoral xenograft model of prostate bone metastatic cancer treated with the anti-androgen, bicalutamide.
  
  
  METHODS
  PCSD1 bone-niche model was derived from a human prostate cancer femoral metastasis resected during hemiarthroplasty and serially transplanted into Rag2(-/-); γ c(-/-) mice intra-femorally (IF) or sub-cutaneously (SC). At 5 weeks post-transplantation mice received bicalutamide or vehicle control for 18 days. Tumor growth of PCSD1 was measured with calipers. PSA expression in PCSD1 xenograft tumors was determined using quantitative RT-PCR and immunohistochemistry. Expression of AR and PSMA, were also determined with qPCR.
  
  
  RESULTS
  PCSD1 xenograft tumor growth capacity was 24 fold greater in the bone (intra-femoral, IF) than in the soft tissue (sub-cutaneous, SC) microenvironment. Treatment with the anti-androgen, bicalutamide, inhibited tumor growth in the sub-cutaneous transplantation site. However, bicalutamide was ineffective in suppressing PCSD1 tumor growth in the bone-niche. Nevertheless, bicalutamide treatment of intra-femoral tumors significantly reduced PSA expression (p < = 0.008) and increased AR (p < = 0.032) relative to control.
  
  
  CONCLUSIONS
  PCSD1 tumors were castrate resistant when growing in the bone-niche compared to soft tissue. Bicalutamide had little effect on reducing tumor burden in the bone yet still decreased tumor PSA expression and increased AR expression, thus, this model closely recapitulated castrate-resistant, human prostate cancer bone metastatic disease. PCSD1 is a new primary prostate cancer bone metastasis-derived xenograft model to study bone metastatic disease and for pre-clinical drug development of novel therapies for inhibiting therapy resistant prostate cancer growth in the bone-niche.
authors.forename: Elana
authors.initials: E
authors.lastname: Godebu
authors.forename: Michelle
authors.initials: M
authors.lastname: Muldong
authors.forename: Amy
authors.initials: A
authors.lastname: Strasner
authors.forename: Christina N
authors.initials: CN
authors.lastname: Wu
authors.forename: Seung Chol
authors.initials: SC
authors.lastname: Park
authors.forename: Jason R
authors.initials: JR
authors.lastname: Woo
authors.forename: Wenxue
authors.initials: W
authors.lastname: Ma
authors.forename: Michael A
authors.initials: MA
authors.lastname: Liss
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hirata
authors.forename: Omer
authors.initials: O
authors.lastname: Raheem
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Cacalano
authors.forename: Anna A
authors.initials: AA
authors.lastname: Kulidjian
authors.forename: Christina A M
authors.initials: CA
authors.lastname: Jamieson
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use; D000813:Anilides / Q000627:therapeutic use; D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000556:secondary*; D004195:Disease Models, Animal; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D009570:Nitriles / Q000627:therapeutic use; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D014105:Tosyl Compounds / Q000627:therapeutic use
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; D009570:Nitriles; D014105:Tosyl Compounds; C053541:bicalutamide