PCSD1, a new patient-derived model of bone metastatic prostate cancer, is castrate-resistant in the bone-niche.

Abstract

INTRODUCTION:

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: Elana Godebu, Michelle Muldong, Amy Strasner, Christina N Wu, Seung Chol Park, Jason R Woo, Wenxue Ma, Michael A Liss, Takeshi Hirata, Omer Raheem, Nicholas A Cacalano, Anna A Kulidjian, Christina A M Jamieson
• Journal: Journal of translational medicine (J Transl Med) Vol. 12 Pg. 275 (Oct 03 2014) ISSN: 1479-5876 [Electronic] England
• PMID: 25278011 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Androgen Antagonists
• Anilides
• Nitriles
• Tosyl Compounds
• bicalutamide

Topics

• Androgen Antagonists (therapeutic use)
• Anilides (therapeutic use)
• Animals
• Bone Neoplasms (drug therapy, pathology, secondary)
• Disease Models, Animal
• Heterografts
• Humans
• Male
• Mice
• Nitriles (therapeutic use)
• Orchiectomy
• Prostatic Neoplasms (drug therapy, pathology)
• Tosyl Compounds (therapeutic use)