title: Synergistic co-targeting of prostate-specific membrane antigen and androgen receptor in prostate cancer.
abstract: BACKGROUND
  Antibody-drug conjugates (ADCs) are an emerging class of cancer therapies that have demonstrated favorable activity both as single agents and as components of combination regimens. Phase 2 testing of an ADC targeting prostate-specific membrane antigen (PSMA) in advanced prostate cancer has shown antitumor activity. The present study examined PSMA ADC used in combination with potent antiandrogens (enzalutamide and abiraterone) and other compounds.
  
  
  METHODS
  Antiproliferative activity and expression of PSMA, prostate-specific antigen and androgen receptor were evaluated in the prostate cancer cell lines LNCaP and C4-2. Cells were tested for susceptibility to antiandrogens or other inhibitors, used alone and in combination with PSMA ADC. Potential drug synergy or antagonism was evaluated using the Bliss independence method.
  
  
  RESULTS
  Enzalutamide and abiraterone demonstrated robust, statistically significant synergy when combined with PSMA ADC. Largely additive activity was observed between the antiandrogens and the individual components of the ADC (free drug and unmodified antibody). Rapamycin also synergized with PSMA ADC in certain settings. Synergy was linked in part to upregulation of PSMA expression. In androgen-dependent LNCaP cells, enzalutamide and abiraterone each inhibited proliferation, upregulated PSMA expression, and synergized with PSMA ADC. In androgen-independent C4-2 cells, enzalutamide and abiraterone showed no measurable antiproliferative activity on their own but increased PSMA expression and synergized with PSMA ADC nonetheless. PSMA expression increased progressively over 3 weeks with enzalutamide and returned to baseline levels 1 week after enzalutamide removal.
  
  
  CONCLUSIONS
  The findings support exploration of clinical treatment regimens that combine potent antiandrogens and PSMA-targeted therapies for prostate cancer.
authors.affiliation: Progenics Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Jose D
authors.initials: JD
authors.lastname: Murga
authors.forename: Sameer M
authors.initials: SM
authors.lastname: Moorji
authors.forename: Amy Q
authors.initials: AQ
authors.lastname: Han
authors.forename: Wells W
authors.initials: WW
authors.lastname: Magargal
authors.forename: Vincent A
authors.initials: VA
authors.lastname: DiPippo
authors.forename: William C
authors.initials: WC
authors.lastname: Olson
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use*; D000736:Androstenes / Q000627:therapeutic use*; D000906:Antibodies; D000954:Antigens, Surface / Q000276:immunology*; D001549:Benzamides; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D043425:Glutamate Carboxypeptidase II / Q000276:immunology*; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D008297:Male; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D011944:Receptors, Androgen / Q000276:immunology*
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000736:Androstenes; D000906:Antibodies; D000954:Antigens, Surface; D001549:Benzamides; D018796:Immunoconjugates; D009570:Nitriles; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; C089740:abiraterone
keywords: PSMA ADC; androgen receptor; enzalutamide; prostate; rapamycin