Molecular targeted therapies in hepatocellular carcinoma

Abstract

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.

Figure 1. Schematic representation of the molecular pathogenesis of HCC

Two molecular types of alterations are delineated. Self-sufficiency in cell signals are the main responsible of initiation and proliferation of liver cancer. These alterations result from activation of pathways that might be activated only in specific subgroups of tumors: Wnt signaling, EGF-Ras-MAPK signaling, IGF signaling, mTOR signaling and others. Alterations present in almost all tumors involve limitless replicative potential resulting from activation of TERT, neoangiogenesis (per activation of VEGF,PDGF, angiopoetin and others), and insensitivity to anti-growth signals and checkpoint disruption (due to disturbances in TP53, p21,retinoblastoma,cyclin D1) -,.

Figure 2. Molecular targeted therapies in HCC

Representation of monoclonal antibodies against ligands (VEGFR-bevacizumab, EGFR-cetuximab) tyrosine kinase inhibitors (VEGFR:sorafenib, sunitinib, PDFGR: sorafenib, sunitinib; EGFR: erlotinib, lapatinib, AEE788, Her2/nu: lapatinib, AEE788), ST kinase inhibitors (Raf: sorafenib; mTOR: rapamycin,everolimus, PI3K: XL-765) in preclinical studies or clinical trials in HCC. (Modified from Villanueva A et al. Clinical Opinion in Oncology, 2008)

Figure 3. Natural history of patients with HCC according to the BCLC staging system

Natural history of 746 patients included in the seocalcitol vs placebo randomized controlled trial for hepatocellular carcinoma. The study was negative, and drug was considered not effective, but not toxic. (A). Natural history of the 370 patients belonging to the BCLC B staging group. Median survival ranged from 15. 8 months and 15.1 months, in the placebo group and seocalcitol group, respectively. Thus, it can be estimated that the expected survival for this subgroup is around 16 months. (B) Natural history of the 376 patients belonging to the BCLC C staging group. Median survival ranged from 5.7 months and 5.6 months, in the placebo group and seocalcitol group, respectively. Thus, the median survival for trial design of the target population of BCLC C patients is around 6 months.

Figure 4. Survival curves of patients randomized to sorafenib or placebo (SHARP trial)

The median overall survival of patients randomized to sorafenib (299 patients) was 10.7 months compared with 7.9 months for placebo (303 patients). (Hazard ratio for death, 0.69; 95% CI, 0.55–0.87). (Reproduced with permission from Llovet JM et al, New England Journal of Medicine 2008) .

Figure 5. Barcelona-Clinic Liver Cancer (BCLC) staging classification and treatment schedule

Patients with very early HCC (stage 0) are optimal candidates for resection. Patients with early HCC (stage A) are candidates for radical therapy (resection, liver transplantation [LT], or local ablation [via percutaneous ethanol injection {PEI} or radiofrequency ablation{RF}]). Patients with intermediate HCC (stage B) benefit from chemoembolization (TACE). Patients with advanced HCC, defined as presence of macroscopic vascular invasion, extrahepatic spread and/or cancer-related symptoms-ECOG 1-2 (stage C), benefit from sorafenib. Patients with end-stage disease (stage D) receive symptomatic treatment. Treatment strategy will transition from one stage to another upon treatment failure or contraindications for the procedures. (Reproduced with permission from Llovet JM et al, J Natl Cancer Inst 200853).