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         headline:Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients
         description:The androgen receptor (AR) is a pivotal drug target for the treatment of prostate cancer, including its lethal castration-resistant (CRPC) form. All current non-steroidal AR antagonists, such as hydroxyflutamide, bicalutamide, and enzalutamide, target the androgen binding site of the receptor, competing with endogenous androgenic steroids. Several AR mutations in this binding site have been associated with poor prognosis and resistance to conventional prostate cancer drugs. In order to develop an effective CRPC therapy, it is crucial to understand the effects of these mutations on the functionality of the AR and its ability to interact with endogenous steroids and conventional AR inhibitors. We previously utilized circulating cell-free DNA (cfDNA) sequencing technology to examine the AR gene for the presence of mutations in CRPC patients. By modifying our sequencing and data analysis approaches, we identify four additional single AR mutations and five mutation combinations associated with CRPC. Importantly, we conduct experimental functionalization of all the AR mutations identified by the current and previous cfDNA sequencing to reveal novel gain-of-function scenarios. Finally, we evaluate the effect of a novel class of AR inhibitors targeting the binding function 3 (BF3) site on the activity of CRPC-associated AR mutants. This work demonstrates the feasibility of a prognostic and/or diagnostic platform combining the direct identification of AR mutants from patients’ serum, and the functional characterization of these mutants in order to provide personalized recommendations regarding the best future therapy.
         datePublished:2016-01-26T00:00:00Z
         dateModified:2016-01-26T00:00:00Z
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            Androgen receptor
            Castration-resistant prostate cancer
            Cell-free circulating DNA
            Mutations
            Drug resistance
            Anti-androgens and steroids
            Animal Genetics and Genomics
            Human Genetics
            Plant Genetics and Genomics
            Microbial Genetics and Genomics
            Bioinformatics
            Evolutionary Biology
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      headline:Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients
      description:The androgen receptor (AR) is a pivotal drug target for the treatment of prostate cancer, including its lethal castration-resistant (CRPC) form. All current non-steroidal AR antagonists, such as hydroxyflutamide, bicalutamide, and enzalutamide, target the androgen binding site of the receptor, competing with endogenous androgenic steroids. Several AR mutations in this binding site have been associated with poor prognosis and resistance to conventional prostate cancer drugs. In order to develop an effective CRPC therapy, it is crucial to understand the effects of these mutations on the functionality of the AR and its ability to interact with endogenous steroids and conventional AR inhibitors. We previously utilized circulating cell-free DNA (cfDNA) sequencing technology to examine the AR gene for the presence of mutations in CRPC patients. By modifying our sequencing and data analysis approaches, we identify four additional single AR mutations and five mutation combinations associated with CRPC. Importantly, we conduct experimental functionalization of all the AR mutations identified by the current and previous cfDNA sequencing to reveal novel gain-of-function scenarios. Finally, we evaluate the effect of a novel class of AR inhibitors targeting the binding function 3 (BF3) site on the activity of CRPC-associated AR mutants. This work demonstrates the feasibility of a prognostic and/or diagnostic platform combining the direct identification of AR mutants from patients’ serum, and the functional characterization of these mutants in order to provide personalized recommendations regarding the best future therapy.
      datePublished:2016-01-26T00:00:00Z
      dateModified:2016-01-26T00:00:00Z
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      pageEnd:15
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         Androgen receptor
         Castration-resistant prostate cancer
         Cell-free circulating DNA
         Mutations
         Drug resistance
         Anti-androgens and steroids
         Animal Genetics and Genomics
         Human Genetics
         Plant Genetics and Genomics
         Microbial Genetics and Genomics
         Bioinformatics
         Evolutionary Biology
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            name:University of British Columbia
            address:
               name:Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada
      name:Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada
      name:Laboratory for Advanced Genome Analysis (LAGA), Vancouver, Canada
      name:Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada
      name:Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada
      name:Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada
      name:Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada
      name:Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada
      name:Department of Medical Oncology, BC Cancer Agency, Vancouver, Canada
      name:Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada
      name:Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada
      name:Laboratory for Advanced Genome Analysis (LAGA), Vancouver, Canada
      name:Department of Medical Oncology, BC Cancer Agency, Vancouver, Canada
      name:Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada
      name:Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada
      name:Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada
      name:Laboratory for Advanced Genome Analysis (LAGA), Vancouver, Canada
      name:Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada

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