TY - JOUR
T1 - Androgen Receptor Signaling in Castration-Resistant Prostate Cancer Alters Hyperpolarized Pyruvate to Lactate Conversion and Lactate Levels In Vivo
AU - Zacharias, Niki
AU - Lee, Jaehyuk
AU - Ramachandran, Sumankalai
AU - Shanmugavelandy, Sriram
AU - McHenry, James
AU - Dutta, Prasanta
AU - Millward, Steven
AU - Gammon, Seth
AU - Efstathiou, Eleni
AU - Troncoso, Patricia
AU - Frigo, Daniel E.
AU - Piwnica-Worms, David
AU - Logothetis, Christopher J.
AU - Maity, Sankar N.
AU - Titus, Mark A.
AU - Bhattacharya, Pratip
PY - 2019/2/15
Y1 - 2019/2/15
N2 - Purpose: Androgen receptor (AR) signaling affects prostate cancer (PCa) growth, metabolism, and progression. Often, PCa progresses from androgen-sensitive to castration-resistant prostate cancer (CRPC) following androgen-deprivation therapy. Clinicopathologic and genomic characterizations of CRPC tumors lead to subdividing CRPC into two subtypes: (1) AR-dependent CRPC containing dysregulation of AR signaling alterations in AR such as amplification, point mutations, and/or generation of splice variants in the AR gene; and (2) an aggressive variant PCa (AVPC) subtype that is phenotypically similar to small cell prostate cancer and is defined by chemotherapy sensitivity, gain of neuroendocrine or pro-neural marker expression, loss of AR expression, and combined alterations of PTEN, TP53, and RB1 tumor suppressors. Previously, we reported patient-derived xenograft (PDX) animal models that contain characteristics of these CRPC subtypes. In this study, we have employed the PDX models to test metabolic alterations in the CRPC subtypes. Procedures: Mass spectrometry and nuclear magnetic resonance analysis along with in vivo hyperpolarized 1-[ 13 C]pyruvate spectroscopy experiments were performed on prostate PDX animal models. Results: Using hyperpolarized 1-[ 13 C]pyruvate conversion to 1-[ 13 C]lactate in vivo as well as lactate measurements ex vivo, we have found increased lactate production in AR-dependent CRPC PDX models even under low-hormone levels (castrated mouse) compared to AR-negative AVPC PDX models. Conclusions: Our analysis underscores the potential of hyperpolarized metabolic imaging in determining the underlying biology and in vivo phenotyping of CRPC.
AB - Purpose: Androgen receptor (AR) signaling affects prostate cancer (PCa) growth, metabolism, and progression. Often, PCa progresses from androgen-sensitive to castration-resistant prostate cancer (CRPC) following androgen-deprivation therapy. Clinicopathologic and genomic characterizations of CRPC tumors lead to subdividing CRPC into two subtypes: (1) AR-dependent CRPC containing dysregulation of AR signaling alterations in AR such as amplification, point mutations, and/or generation of splice variants in the AR gene; and (2) an aggressive variant PCa (AVPC) subtype that is phenotypically similar to small cell prostate cancer and is defined by chemotherapy sensitivity, gain of neuroendocrine or pro-neural marker expression, loss of AR expression, and combined alterations of PTEN, TP53, and RB1 tumor suppressors. Previously, we reported patient-derived xenograft (PDX) animal models that contain characteristics of these CRPC subtypes. In this study, we have employed the PDX models to test metabolic alterations in the CRPC subtypes. Procedures: Mass spectrometry and nuclear magnetic resonance analysis along with in vivo hyperpolarized 1-[ 13 C]pyruvate spectroscopy experiments were performed on prostate PDX animal models. Results: Using hyperpolarized 1-[ 13 C]pyruvate conversion to 1-[ 13 C]lactate in vivo as well as lactate measurements ex vivo, we have found increased lactate production in AR-dependent CRPC PDX models even under low-hormone levels (castrated mouse) compared to AR-negative AVPC PDX models. Conclusions: Our analysis underscores the potential of hyperpolarized metabolic imaging in determining the underlying biology and in vivo phenotyping of CRPC.
KW - 13C MR
KW - Hyperpolarized pyruvate
KW - NMR spectroscopy
UR - http://www.scopus.com/inward/record.url?scp=85046829787&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85046829787&partnerID=8YFLogxK
U2 - 10.1007/s11307-018-1199-6
DO - 10.1007/s11307-018-1199-6
M3 - Article
C2 - 29748904
AN - SCOPUS:85046829787
VL - 21
SP - 86
EP - 94
JO - Molecular Imaging and Biology
JF - Molecular Imaging and Biology
SN - 1536-1632
IS - 1
ER -