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A Circulating Tumor Cell-RNA Assay for Assessment of Androgen Receptor Signaling Inhibitor Sensitivity in Metastatic Castration-Resistant Prostate Cancer.
Jan, Yu Jen; Yoon, Junhee; Chen, Jie-Fu; Teng, Pai-Chi; Yao, Nu; Cheng, Shirley; Lozano, Amber; Chu, Gina C Y; Chung, Howard; Lu, Yi-Tsung; Chen, Pin-Jung; Wang, Jasmine J; Lee, Yi-Te; Kim, Minhyung; Zhu, Yazhen; Knudsen, Beatrice S; Feng, Felix Y; Garraway, Isla P; Gao, Allen C; Chung, Leland W K; Freeman, Michael R; You, Sungyong; Tseng, Hsian-Rong; Posadas, Edwin M.
Afiliação
  • Jan YJ; Urologic Oncology Program and Uro-Oncology Research Laboratories, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Yoon J; Division of Cancer Biology and Therapeutics, Departments of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Chen JF; Urologic Oncology Program and Uro-Oncology Research Laboratories, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Teng PC; Urologic Oncology Program and Uro-Oncology Research Laboratories, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Yao N; Urologic Oncology Program and Uro-Oncology Research Laboratories, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Cheng S; Urologic Oncology Program and Uro-Oncology Research Laboratories, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Lozano A; Urologic Oncology Program and Uro-Oncology Research Laboratories, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Chu GCY; Urologic Oncology Program and Uro-Oncology Research Laboratories, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Chung H; Department of Molecular and Medical Pharmacology, California NanoSystems Institute, Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, California, USA.
  • Lu YT; Urologic Oncology Program and Uro-Oncology Research Laboratories, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Chen PJ; Department of Molecular and Medical Pharmacology, California NanoSystems Institute, Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, California, USA.
  • Wang JJ; Department of Molecular and Medical Pharmacology, California NanoSystems Institute, Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, California, USA.
  • Lee YT; Department of Molecular and Medical Pharmacology, California NanoSystems Institute, Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, California, USA.
  • Kim M; Division of Cancer Biology and Therapeutics, Departments of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Zhu Y; Department of Molecular and Medical Pharmacology, California NanoSystems Institute, Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, California, USA.
  • Knudsen BS; Translational Oncology Program, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Feng FY; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Garraway IP; Departments of Radiation Oncology, Urology, and Medicine, University of California, San Francisco, San Francisco, California, USA.
  • Gao AC; Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
  • Chung LWK; Department of Urology, University of California Davis, Davis, CA, USA.
  • Freeman MR; Urologic Oncology Program and Uro-Oncology Research Laboratories, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • You S; Division of Cancer Biology and Therapeutics, Departments of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Tseng HR; Cancer Biology Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Posadas EM; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Theranostics ; 9(10): 2812-2826, 2019.
Article em En | MEDLINE | ID: mdl-31244925
ABSTRACT
Rationale Our objective was to develop a circulating tumor cell (CTC)-RNA assay for characterizing clinically relevant RNA signatures for the assessment of androgen receptor signaling inhibitor (ARSI) sensitivity in metastatic castration-resistant prostate cancer (mCRPC) patients.

Methods:

We developed the NanoVelcro CTC-RNA assay by combining the Thermoresponsive (TR)-NanoVelcro CTC purification system with the NanoString nCounter platform for cellular purification and RNA analysis. Based on the well-validated, tissue-based Prostate Cancer Classification System (PCS), we focus on the most aggressive and ARSI-resistant PCS subtype, i.e., PCS1, for CTC analysis. We applied a rigorous bioinformatic process to develop the CTC-PCS1 panel that consists of prostate cancer (PCa) CTC-specific RNA signature with minimal expression in background white blood cells (WBCs). We validated the NanoVelcro CTC-RNA assay and the CTC-PCS1 panel with well-characterized PCa cell lines to demonstrate the sensitivity and dynamic range of the assay, as well as the specificity of the PCS1 Z score (the likelihood estimate of the PCS1 subtype) for identifying PCS1 subtype and ARSI resistance. We then selected 31 blood samples from 23 PCa patients receiving ARSIs to test in our assay. The PCS1 Z scores of each sample were computed and compared with ARSI treatment sensitivity.

Results:

The validation studies using PCa cell line samples showed that the NanoVelcro CTC-RNA assay can detect the RNA transcripts in the CTC-PCS1 panel with high sensitivity and linearity in the dynamic range of 5-100 cells. We also showed that the genes in CTC-PCS1 panel are highly expressed in PCa cell lines and lowly expressed in background WBCs. Using the artificial CTC samples simulating the blood sample conditions, we further demonstrated that the CTC-PCS1 panel is highly specific in identifying PCS1-like samples, and the high PCS1 Z score is associated with ARSI resistance samples. In patient bloods, ARSI-resistant samples (ARSI-R, n=14) had significantly higher PCS1 Z scores as compared with ARSI-sensitive samples (ARSI-S, n=17) (Rank-sum test, P=0.003). In the analysis of 8 patients who were initially sensitive to ARSI (ARSI-S) and later developed resistance (ARSI-R), we found that the PCS1 Z score increased from the time of ARSI-S to the time of ARSI-R (Pairwise T-test, P=0.016).

Conclusions:

Using our new methodology, we developed a first-in-class CTC-RNA assay and demonstrated the feasibility of transforming clinically-relevant tissue-based RNA profiling such as PCS into CTC tests. This approach allows for detecting RNA expression relevant to clinical drug resistance in a non-invasive fashion, which can facilitate patient-specific treatment selection and early detection of drug resistance, a goal in precision oncology.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: RNA / Transdução de Sinais / Antagonistas de Receptores de Andrógenos / Transcriptoma / Neoplasias de Próstata Resistentes à Castração / Células Neoplásicas Circulantes / Antineoplásicos Tipo de estudo: Diagnostic_studies / Prognostic_studies / Screening_studies Limite: Humans / Male Idioma: En Revista: Theranostics Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: RNA / Transdução de Sinais / Antagonistas de Receptores de Andrógenos / Transcriptoma / Neoplasias de Próstata Resistentes à Castração / Células Neoplásicas Circulantes / Antineoplásicos Tipo de estudo: Diagnostic_studies / Prognostic_studies / Screening_studies Limite: Humans / Male Idioma: En Revista: Theranostics Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos