Androgen Receptor Signaling in Castration-Resistant Prostate Cancer Alters Hyperpolarized Pyruvate to Lactate Conversion and Lactate Levels In Vivo

• Published in: Molecular imaging and biology 2019-02, Vol.21 (1), p.86-94
• Main Authors: Zacharias, Niki, Lee, Jaehyuk, Ramachandran, Sumankalai, Shanmugavelandy, Sriram, McHenry, James, Dutta, Prasanta, Millward, Steven, Gammon, Seth, Efstathiou, Eleni, Troncoso, Patricia, Frigo, Daniel E., Piwnica-Worms, David, Logothetis, Christopher J, Maity, Sankar N, Titus, Mark A, Bhattacharya, Pratip
• Format: Article
• Language: English
• Subjects: Alternative splicing; Androgen receptors; Androgens; Animal models; Animals; Cancer; Carbon 13; Castration; Chemotherapy; Conversion; Deprivation; Disease Models, Animal; Disease Progression; Heterografts; Humans; Image Enhancement - methods; Imaging; In vivo methods and tests; Lactic acid; Lactic Acid - analysis; Lactic Acid - metabolism; Magnetic Resonance Imaging - methods; Magnetic Resonance Spectroscopy - methods; Male; Mass spectrometry; Mass spectroscopy; Medicine; Medicine & Public Health; Metabolism; Mice; Mice, SCID; Mutation; Neoplasm Invasiveness; NMR; Nuclear magnetic resonance; p53 Protein; Phenotyping; Prostate - chemistry; Prostate - diagnostic imaging; Prostate - metabolism; Prostate - pathology; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - diagnosis; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; PTEN protein; Pyruvic acid; Pyruvic Acid - analysis; Pyruvic Acid - metabolism; Radiology; Receptors, Androgen - metabolism; Research Article; Signal Transduction - physiology; Signaling; Suppressors; Tumor Cells, Cultured; Tumors; Xenografts; Xenotransplantation
• ISSN: 1536-1632; 1860-2002
• DOI: 10.1007/s11307-018-1199-6

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.