title: Inhibition of the Ras/Raf/MEK/ERK and RET kinase pathways with the combination of the multikinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib in medullary and differentiated thyroid malignancies.
abstract: OBJECTIVE
  Ras/Raf/MAPK kinase/ERK and rearranged in transformation (RET) kinase pathways are important in thyroid cancer. We tested sorafenib, a B-Raf, RET, and vascular endothelial growth factor receptor kinase inhibitor, combined with tipifarnib, a farnesyltransferase inhibitor that inactivates Ras and other farnesylated proteins.
  
  
  METHODS
  We treated 35 patients with differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC) in a phase I trial. Sorafenib and tipifarnib were given for 21 d with 7 d rest in each 28-d cycle.
  
  
  RESULTS
  We enrolled 22 patients with metastatic DTC (16 papillary, five follicular, and one poorly differentiated) and 13 patients with MTC, of whom 15 with DTC and 10 with MTC reached first restaging. When tissue was available, eight of 15 DTC patients (53%) had B-Raf mutations; eight of 13 MTC (61.5%) patients had RET mutations. MTC partial response rate was 38% (five of 13) (duration = 9+, 12, 13, 16+, and 34+ months), stable disease of at least 6 months was 31% (four of 13). The DTC partial response rate was 4.5% (one of 22), and stable disease of at least 6 months was 36% (eight of 22). Median progression-free survival for all 35 patients was 18 months (95% confidence interval, 14.6 to not reached months). Median overall survival has not been reached, with a median follow-up of 24 months with 80% overall survival. Grade 1-2 toxicities were mainly rash, fatigue, and diarrhea. The most common grade 3-4 toxicities were rash, rise in amylase/lipase, and fatigue.
  
  
  CONCLUSIONS
  Inhibiting the Ras/Raf/MAPK kinase/ERK and RET kinase pathways with sorafenib and tipifarnib is well tolerated and active against thyroid cancer.
authors.affiliation: Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. dshong@mdanderson.org
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.forename: Maria E
authors.initials: ME
authors.lastname: Cabanillas
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wheler
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.forename: Apostolia M
authors.initials: AM
authors.lastname: Tsimberidou
authors.forename: Lei
authors.initials: L
authors.lastname: Ye
authors.forename: Naifa L
authors.initials: NL
authors.lastname: Busaidy
authors.forename: Steven G
authors.initials: SG
authors.lastname: Waguespack
authors.forename: Mike
authors.initials: M
authors.lastname: Hernandez
authors.forename: Adel K
authors.initials: AK
authors.lastname: El Naggar
authors.forename: Alder K
authors.initials: AK
authors.lastname: El Naggar
authors.forename: Savita
authors.initials: S
authors.lastname: Bidyasar
authors.forename: John
authors.initials: J
authors.lastname: Wright
authors.forename: Steven I
authors.initials: SI
authors.lastname: Sherman
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D018263:Adenocarcinoma, Follicular; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D018278:Carcinoma, Neuroendocrine; D002454:Cell Differentiation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D015689:Oncogene Protein p21(ras) / Q000037:antagonists & inhibitors; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D015363:Quinolones / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D000077157:Sorafenib; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000473:pathology; D048490:raf Kinases / Q000037:antagonists & inhibitors
chemical_list: D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D015363:Quinolones; D009536:Niacinamide; D000077157:Sorafenib; D051231:Farnesyltranstransferase; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D015689:Oncogene Protein p21(ras); C402769:tipifarnib