title: Ganetespib, a novel Hsp90 inhibitor in patients with KRAS mutated and wild type, refractory metastatic colorectal cancer.
abstract: BACKGROUND
  Heat shock protein 90 (Hsp90) is a cellular chaperone that is required for the maturation and stability of a variety of proteins that play key roles in colon cancer initiation and progression. The primary objective of the current study was to define the safety and efficacy of ganetespib, a novel, selective small-molecule Hsp90 inhibitor, in patients with refractory metastatic colorectal cancer.
  
  
  METHODS
  The study was a single-arm, Simon 2-stage, phase II trial for patients with chemotherapy-refractory, metastatic colorectal cancer. Patients received ganetespib 200 mg/m(2) intravenously. Tumor tissue was collected before treatment and 48 hours after treatment for changes in expression of Hsp90 client proteins and other potential pharmacodynamics markers. V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), v-Raf murine sarcoma viral oncogene homolog B, and phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutational status was also determined.
  
  
  RESULTS
  Seventeen patients were treated (median age, 58; range, 44-79 years). No patients demonstrated objective regression of disease. Two patients had stable disease of 6.8 and 5.1 months duration. Serious adverse events that were potentially attributable to ganetespib included diarrhea (12%, n = 2), fatigue (17%, n = 3), and increased aspartate aminotransferase/alanine aminotransferase (12%, n = 2) and alkaline phosphatase (6%, n = 1) levels. Of the 17 evaluable patients, 9 (53%) including patients with stable disease as best response, had KRAS-mutant tumors.
  
  
  CONCLUSIONS
  In this first phase II investigation of an Hsp90 inhibitor in colorectal cancer, ganetespib as a single agent did not demonstrate activity in chemotherapy-refractory metastatic colorectal cancer. However, on the basis of the drug's promising preclinical combination data and the relatively mild toxicity profile, further clinical investigation of this agent in combination with standard cytotoxic agents is planned.
authors.affiliation: Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY. Electronic address: cerceka@mskcc.org.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cercek
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Jinru
authors.initials: J
authors.lastname: Shia
authors.affiliation: Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Marc
authors.initials: M
authors.lastname: Gollub
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Joanne F
authors.initials: JF
authors.lastname: Chou
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Marinela
authors.initials: M
authors.lastname: Capanu
authors.affiliation: Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Pamela
authors.initials: P
authors.lastname: Raasch
authors.affiliation: Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Diane
authors.initials: D
authors.lastname: Reidy-Lagunes
authors.affiliation: Synta Pharmaceuticals Corp, Lexington, MA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX.
authors.forename: David A
authors.initials: DA
authors.lastname: Proia
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Efsevia
authors.initials: E
authors.lastname: Vakiani
authors.affiliation: Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.affiliation: Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Saltz
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D016879:Salvage Therapy; D015996:Survival Rate; D014230:Triazoles / Q000627:therapeutic use*; D018631:ras Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D018841:HSP90 Heat-Shock Proteins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C533237:STA 9090; D014230:Triazoles; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: Ganetespib; HSP 90; KRAS; Metastatic colorectal cancer; Single agent