PMID- 18821591
OWN - NLM
STAT- MEDLINE
DCOM- 20081027
LR  - 20231105
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 48
IP  - 4
DP  - 2008 Oct
TI  - Molecular targeted therapies in hepatocellular carcinoma.
PG  - 1312-27
LID - 10.1002/hep.22506 [doi]
AB  - Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with several 
      genomic alterations. There is evidence of aberrant activation of several 
      signaling cascades such as epidermal growth factor receptor (EGFR), 
      Ras/extracellular signal-regulated kinase, phosphoinositol 3-kinase/mammalian 
      target of rapamycin (mTOR), hepatocyte growth factor/mesenchymal-epithelial 
      transition factor, Wnt, Hedgehog, and apoptotic signaling. Recently a multikinase 
      inhibitor, sorafenib, has shown survival benefits in patients with advanced HCC. 
      This advancement represents a breakthrough in the treatment of this complex 
      disease and proves that molecular therapies can be effective in HCC. It is 
      becoming apparent, however, that to overcome the complexity of genomic 
      aberrations in HCC, combination therapies will be critical. Phase II studies have 
      tested drugs blocking EGFR, vascular endothelial growth factor/platelet-derived 
      growth factor receptor, and mTOR signaling. No relevant data has been produced so 
      far in combination therapies. Future research is expected to identify new 
      compounds to block important undruggable pathways, such as Wnt signaling, and to 
      identify new oncogenes as targets for therapies through novel high-throughput 
      technologies. Recent guidelines have established a new frame for the design of 
      clinical trials in HCC. Randomized phase II trials with a time-to-progression 
      endpoint are proposed as pivotal for capturing benefits from novel drugs. 
      Survival remains the main endpoint to measure effectiveness in phase III studies. 
      Patients assigned to the control arm should receive standard-of-care therapy, 
      that is, chemoembolization for patients with intermediate-stage disease and 
      sorafenib for patients with advanced-stage disease. Biomarkers and molecular 
      imaging should be part of the trials, in order to optimize the enrichment of 
      study populations and identify drug responders. Ultimately, a molecular 
      classification of HCC based on genome-wide investigations and identification of 
      patient subclasses according to drug responsiveness will lead to a more 
      personalized medicine.
FAU - Llovet, Josep M
AU  - Llovet JM
AD  - Mount Sinai Liver Cancer Program, Division of Liver Diseases, Mount Sinai School 
      of Medicine, New York, NY, USA. jmllovet@clinic.ub.es
FAU - Bruix, Jordi
AU  - Bruix J
LA  - eng
GR  - R01 DK076986/DK/NIDDK NIH HHS/United States
GR  - R01 DK076986-01/DK/NIDDK NIH HHS/United States
GR  - 1R01DK076986-01/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzenesulfonates)
RN  - 0 (Phenylurea Compounds)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyridines)
RN  - 25X51I8RD4 (Niacinamide)
RN  - 9ZOQ3TZI87 (Sorafenib)
SB  - IM
MH  - Antineoplastic Agents/*therapeutic use
MH  - Benzenesulfonates/therapeutic use
MH  - Carcinoma, Hepatocellular/*drug therapy/physiopathology
MH  - Drug Design
MH  - Humans
MH  - Liver Neoplasms/*drug therapy/physiopathology
MH  - Niacinamide/analogs & derivatives
MH  - Phenylurea Compounds
MH  - Protein Kinase Inhibitors/therapeutic use
MH  - Pyridines/therapeutic use
MH  - Signal Transduction/physiology
MH  - Sorafenib
PMC - PMC2597642
MID - NIHMS65495
EDAT- 2008/09/30 09:00
MHDA- 2008/10/28 09:00
PMCR- 2009/10/01
CRDT- 2008/09/30 09:00
PHST- 2008/09/30 09:00 [pubmed]
PHST- 2008/10/28 09:00 [medline]
PHST- 2008/09/30 09:00 [entrez]
PHST- 2009/10/01 00:00 [pmc-release]
AID - 10.1002/hep.22506 [doi]
PST - ppublish
SO  - Hepatology. 2008 Oct;48(4):1312-27. doi: 10.1002/hep.22506.