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Re: Bispecific Small Molecule-Antibody Conjugate Targeting Prostate Cancer
Urological Survey Uro-Science Re: TALEN-Engineered AR Gene Rearrangements Reveal Endocrine Uncoupling of Androgen Receptor in Prostate Cancer M. D. Nyquist, Y. Li, T. H. Hwang, L. S. Manlove, R. L. Vessella, K. A. Silverstein, D. F. Voytas and S. M. Dehm Masonic Cancer Center, Graduate Program in Molecular, Cellular and Developmental Biology and Genetics, and Biostatistics and Bioinformatics Core, University of Minnesota, Minneapolis, Minnesota Proc Natl Acad Sci U S A 2013; 110: 17492e17497.
Abstract available at http://jurology.com/ Editorial Comment: The androgen receptor is a master regulator in cells of prostatic origin, including prostate cancer. How androgen receptor activity can persist in tumors that are resistant to second-generation androgen receptor targeted therapies remains unknown. The authors describe the discovery of androgen receptor gene rearrangements in clinical prostate cancer tissues and the use of genome engineering in prostate cancer cells with transcription activator-like effector nucleases to functionally classify these gene rearrangements as drivers of resistance. This knowledge is expected to lead to better treatment and allow the development of more effective therapies for advanced prostate cancer. Anthony Atala, MD
Suggested Reading Molina A and Belldegrun A: Novel therapeutic strategies for castration resistant prostate cancer: inhibition of persistent androgen production and androgen receptor mediated signaling. J Urol 2011; 185: 787. Qiao Y, Wang L, Cai LQ et al: Inhibition of aberrant androgen receptor induction of prostate specific antigen gene expression, cell proliferation and tumor growth by 17a-estradiol in prostate cancer. J Urol 2011; 185: 305. Jiang Q, Yeh S, Wang X et al: Targeting androgen receptor leads to suppression of prostate cancer via induction of autophagy. J Urol 2012; 188: 1361.
Re: Bispecific Small Molecule-Antibody Conjugate Targeting Prostate Cancer C. H. Kim, J. Y. Axup, B. R. Lawson, H. Yun, V. Tardif, S. H. Choi, Q. Zhou, A. Dubrovska, S. L. Biroc, R. Marsden, J. Pinstaff, V. V. Smider and P. G. Schultz Departments of Chemistry, Immunology and Microbial Science, and Molecular Biology, and Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California Proc Natl Acad Sci U S A 2013; 110: 17796e17801.
Abstract available at http://jurology.com/ Editorial Comment: The authors have developed a semisynthetic method for the production of bispecific antibody-like therapeutics consisting of a small molecule targeting moiety conjugated to an antibody. A highly selective prostate specific membrane antigen binding ligand was site specifically
0022-5347/14/1916-1927/0 THE JOURNAL OF UROLOGY® © 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
http://dx.doi.org/10.1016/j.juro.2014.03.010 Vol. 191, 1927-1929, June 2014 Printed in U.S.A.
www.jurology.com
j
1927
1928
URO-SCIENCE
conjugated to a mutant a cluster of differentiation 3 (aCD3) Fab containing an unnatural amino acid with orthogonal chemical reactivity. The optimized conjugate showed potent in vitro activity, good serum half-life and potent in vivo activity in prostate cancer xenograft mouse models. This simple (1-step conjugation and purification) and high yielding (greater than 90%) semisynthetic approach also is suitable for combinatorial synthesis of diverse bispecific antibodies to screen quickly for optimal combinations of the target and effector cell binding components. Anthony Atala, MD
Suggested Reading Hadaschik B, Su Y, Huter E et al: Antigen specific T-cell responses against tumor antigens are controlled by regulatory T cells in patients with prostate cancer. J Urol 2012; 187: 1458. Urba WJ, Nemunaitis J, Marshall F et al: Treatment of biochemical recurrence of prostate cancer with granulocyte-macrophage colony-stimulating factor secreting, allogeneic, cellular immunotherapy. J Urol 2008; 180: 2011.
Re: Leptin Signaling in GABA Neurons, but Not Glutamate Neurons, is Required for Reproductive Function W. A. Zuure, A. L. Roberts, J. H. Quennell and G. M. Anderson Centre for Neuroendocrinology and Department of Anatomy, University of Otago School of Medical Sciences, Dunedin, New Zealand J Neurosci 2013; 33: 17874e17883.
Abstract available at http://jurology.com/ Editorial Comment: Circulating leptin is an important metabolic signal regulating food intake and energy expenditure. Leptin also forms a permissive modulator of fertility. Reproduction is centrally regulated by the drivers of the hypothalamic-pituitary-gonadal axis, ie the gonadotropin-releasing hormone neurons. A significant body of research has been devoted to trying to understand how the effects of leptin are relayed to this reproductive axis. Leptin acts directly on the brain as transgenic removal of leptin receptors from forebrain neurons results in the same infertile and obese phenotype as does global mutation in the leptin gene itself. However, leptin affects gonadotropin-releasing hormone neurons indirectly, since they do not express leptin receptors. To elucidate the identity of the neuronal network that must exist between leptin responsive neurons and gonadotropin-releasing hormone neurons, the authors investigated leptin signaling in the major inhibitory and excitatory neuronal cell populations, ie GABA and glutamate neurons. The experiments show that there is a pivotal role for leptin receptors in GABA neurons, but surprisingly not in glutamate neurons, in metabolic regulation of male and female fertility. This finding serves to focus attention on GABA or a few known peptide cotransmitters as critical neurotransmitters for the control of reproduction. Future studies should determine which neurons are GABAergic, are leptin responsive and send inputs to gonadotropin-releasing hormone neurons to control fertility. Anthony Atala, MD
Suggested Reading Tincello DG, Taylor AH, Spurling SM et al: Receptor isoforms that mediate estrogen and progestagen action in the female lower urinary tract. J Urol 2009; 181: 1474. Banie L, Lin G, Ning H et al: Effects of estrogen, raloxifene and levormeloxifene on alpha1A-adrenergic receptor expression. J Urol 2008; 180: 2241.
Abstract available at http://jurology.com/ Editorial Comment: The androgen receptor is a master regulator in cells of prostatic origin, including prostate cancer. How androgen receptor activity can persist in tumors that are resistant to second-generation androgen receptor targeted therapies remains unknown. The authors describe the discovery of androgen receptor gene rearrangements in clinical prostate cancer tissues and the use of genome engineering in prostate cancer cells with transcription activator-like effector nucleases to functionally classify these gene rearrangements as drivers of resistance. This knowledge is expected to lead to better treatment and allow the development of more effective therapies for advanced prostate cancer. Anthony Atala, MD
Suggested Reading Molina A and Belldegrun A: Novel therapeutic strategies for castration resistant prostate cancer: inhibition of persistent androgen production and androgen receptor mediated signaling. J Urol 2011; 185: 787. Qiao Y, Wang L, Cai LQ et al: Inhibition of aberrant androgen receptor induction of prostate specific antigen gene expression, cell proliferation and tumor growth by 17a-estradiol in prostate cancer. J Urol 2011; 185: 305. Jiang Q, Yeh S, Wang X et al: Targeting androgen receptor leads to suppression of prostate cancer via induction of autophagy. J Urol 2012; 188: 1361.
Re: Bispecific Small Molecule-Antibody Conjugate Targeting Prostate Cancer C. H. Kim, J. Y. Axup, B. R. Lawson, H. Yun, V. Tardif, S. H. Choi, Q. Zhou, A. Dubrovska, S. L. Biroc, R. Marsden, J. Pinstaff, V. V. Smider and P. G. Schultz Departments of Chemistry, Immunology and Microbial Science, and Molecular Biology, and Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, California Proc Natl Acad Sci U S A 2013; 110: 17796e17801.
Abstract available at http://jurology.com/ Editorial Comment: The authors have developed a semisynthetic method for the production of bispecific antibody-like therapeutics consisting of a small molecule targeting moiety conjugated to an antibody. A highly selective prostate specific membrane antigen binding ligand was site specifically
0022-5347/14/1916-1927/0 THE JOURNAL OF UROLOGY® © 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
http://dx.doi.org/10.1016/j.juro.2014.03.010 Vol. 191, 1927-1929, June 2014 Printed in U.S.A.
www.jurology.com
j
1927
1928
URO-SCIENCE
conjugated to a mutant a cluster of differentiation 3 (aCD3) Fab containing an unnatural amino acid with orthogonal chemical reactivity. The optimized conjugate showed potent in vitro activity, good serum half-life and potent in vivo activity in prostate cancer xenograft mouse models. This simple (1-step conjugation and purification) and high yielding (greater than 90%) semisynthetic approach also is suitable for combinatorial synthesis of diverse bispecific antibodies to screen quickly for optimal combinations of the target and effector cell binding components. Anthony Atala, MD
Suggested Reading Hadaschik B, Su Y, Huter E et al: Antigen specific T-cell responses against tumor antigens are controlled by regulatory T cells in patients with prostate cancer. J Urol 2012; 187: 1458. Urba WJ, Nemunaitis J, Marshall F et al: Treatment of biochemical recurrence of prostate cancer with granulocyte-macrophage colony-stimulating factor secreting, allogeneic, cellular immunotherapy. J Urol 2008; 180: 2011.
Re: Leptin Signaling in GABA Neurons, but Not Glutamate Neurons, is Required for Reproductive Function W. A. Zuure, A. L. Roberts, J. H. Quennell and G. M. Anderson Centre for Neuroendocrinology and Department of Anatomy, University of Otago School of Medical Sciences, Dunedin, New Zealand J Neurosci 2013; 33: 17874e17883.
Abstract available at http://jurology.com/ Editorial Comment: Circulating leptin is an important metabolic signal regulating food intake and energy expenditure. Leptin also forms a permissive modulator of fertility. Reproduction is centrally regulated by the drivers of the hypothalamic-pituitary-gonadal axis, ie the gonadotropin-releasing hormone neurons. A significant body of research has been devoted to trying to understand how the effects of leptin are relayed to this reproductive axis. Leptin acts directly on the brain as transgenic removal of leptin receptors from forebrain neurons results in the same infertile and obese phenotype as does global mutation in the leptin gene itself. However, leptin affects gonadotropin-releasing hormone neurons indirectly, since they do not express leptin receptors. To elucidate the identity of the neuronal network that must exist between leptin responsive neurons and gonadotropin-releasing hormone neurons, the authors investigated leptin signaling in the major inhibitory and excitatory neuronal cell populations, ie GABA and glutamate neurons. The experiments show that there is a pivotal role for leptin receptors in GABA neurons, but surprisingly not in glutamate neurons, in metabolic regulation of male and female fertility. This finding serves to focus attention on GABA or a few known peptide cotransmitters as critical neurotransmitters for the control of reproduction. Future studies should determine which neurons are GABAergic, are leptin responsive and send inputs to gonadotropin-releasing hormone neurons to control fertility. Anthony Atala, MD
Suggested Reading Tincello DG, Taylor AH, Spurling SM et al: Receptor isoforms that mediate estrogen and progestagen action in the female lower urinary tract. J Urol 2009; 181: 1474. Banie L, Lin G, Ning H et al: Effects of estrogen, raloxifene and levormeloxifene on alpha1A-adrenergic receptor expression. J Urol 2008; 180: 2241.