title: Everolimus combined with gefitinib in patients with metastatic castration-resistant prostate cancer: Phase 1/2 results and signaling pathway implications.
abstract: BACKGROUND
  The effects of mammalian target of rapamycin (mTOR) inhibition are limited by feedback reactivation of receptor tyrosine kinase signaling in phosphatase and tensin homolog-null tumors. Thus, this study tested the combination of mTOR inhibition (everolimus) and epidermal growth factor receptor inhibition (gefitinib) in castration-resistant prostate cancer (CRPC).
  
  
  METHODS
  In phase 1, 12 patients (10 with CRPC and 2 with glioblastoma) received daily gefitinib (250 mg) with weekly everolimus (30, 50, or 70 mg). In phase 2, 27 CRPC patients received gefitinib with everolimus (70 mg).
  
  
  RESULTS
  Phase 1 revealed no pharmacokinetic interactions and no dose-limiting toxicities. In phase 2, 18 of 27 patients (67%) discontinued treatment before the 12-week evaluation because of progression as evidenced by prostate-specific antigen (PSA) levels (n = 6) or imaging (n = 5) or because of a grade 2 or higher toxicity (n = 7). Thirteen of the 37 CRPC patients (35%) exhibited a rapidly rising PSA level after they had begun treatment, and this declined upon discontinuation. Fluorodeoxyglucose positron emission tomography 24 to 72 hours after the initiation of treatment showed a decrease in the standardized uptake value consistent with mTOR inhibition in 27 of the 33 evaluable patients (82%); there was a corresponding rise in PSA in 20 of these 27 patients (74%).
  
  
  CONCLUSIONS
  The combination of gefitinib and everolimus did not result in significant antitumor activity. The induction of PSA in tumors treated with mTOR inhibitors was consistent with preclinical data showing that phosphoinositide 3-kinase (PI3K) pathway signaling feedback inhibits the androgen receptor (AR). This clinical evidence of relief of feedback inhibition promoting enhanced AR activity supports future studies combining PI3K pathway inhibitors and second-generation AR inhibitors in CRPC.
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.|Weill Cornell Medical College, New York, New York.
authors.forename: Dana E
authors.initials: DE
authors.lastname: Rathkopf
authors.affiliation: Weill Cornell Medical College, New York, New York.|Division of Nuclear Medicine, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Larson
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.|Division of Urological Cancers, Lund University, Lund, Sweden.
authors.forename: Aseem
authors.initials: A
authors.lastname: Anand
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.|Weill Cornell Medical College, New York, New York.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Morris
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.|Weill Cornell Medical College, New York, New York.
authors.forename: Susan F
authors.initials: SF
authors.lastname: Slovin
authors.affiliation: New York Oncology Hematology, Albany, New York.
authors.forename: David R
authors.initials: DR
authors.lastname: Shaffer
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Glenn
authors.initials: G
authors.lastname: Heller
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.|Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Brett
authors.initials: B
authors.lastname: Carver
authors.affiliation: Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.|Weill Cornell Medical College, New York, New York.
authors.forename: Howard I
authors.initials: HI
authors.lastname: Scher
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000068338:Everolimus / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000077156:Gefitinib; D006801:Humans; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology*; D011799:Quinazolines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011944:Receptors, Androgen / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D011944:Receptors, Androgen; D000068338:Everolimus; C546842:MTOR protein, human; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases; D017430:Prostate-Specific Antigen; D000077156:Gefitinib
keywords: mammalian target of rapamycin (mTOR); pharmacokinetics; prostatic neoplasms; quinazolines (gefitinib); sirolimus derivatives (everolimus); target of rapamycin (TOR) serine-threonine kinases