Nature reviews. Clinical oncology
-
Esophagogastric cancer represents a significant global health problem, with most patients presenting with advanced-stage disease and consequently with a poor prognosis. Chemotherapy improves survival compared with supportive care alone, and combination chemotherapy regimens are more effective than monotherapy. Overexpression of EGFR and possibly HER2 confer a poor prognosis, providing potentially important therapeutic targets for selected patients. ⋯ In patients with advanced-stage gastric or esophagogastric-junction adenocarcinomas, the addition of trastuzumab to a cisplatin plus fluoropyrimidine doublet was reported to improve response rate, progression-free survival and overall survival, with the greatest benefit reported in the subgroup of patients with the highest expression of HER2. Cetuximab and panitumumab, two monoclonal antibodies against EGFR, and the dual EGFR and HER2 tyrosine kinase inhibitor lapatinib are currently undergoing phase III evaluation in esophagogastric cancer. We discuss the preclinical rationale for targeting human EGFRs and recent clinical reports of these targeted agents in esophagogastric cancer.
-
After decades of stagnation, recent therapeutic advances in melanoma seem on the horizon. The discovery of the genetic underpinnings of this historically refractory disease has exposed potential targets for therapy, BRAF mutations being principal among them. In the 8 years following the discovery of BRAF mutations in 50-60% of advanced melanomas, only recently have potent and selective inhibitors of this intracellular signaling molecule shown efficacy from early clinical testing. Vemurafenib (PLX4032) and GSK2118436, two orally available and well tolerated agents are on the verge of transforming the landscape of melanoma therapy based on the promising results of their respective phase I, II, and III trials.
-
Tumor relapse and metastasis remain major obstacles for improving overall cancer survival, which may be due at least in part to the existence of cancer stem cells (CSCs). CSCs are characterized by tumorigenic properties and the ability to self-renew, form differentiated progeny, and develop resistance to therapy. CSCs use many of the same signaling pathways that are found in normal stem cells, such as Wnt, Notch, and Hedgehog (Hh). ⋯ Therapeutic targeting of both CSCs and bulk tumor populations may provide a strategy to suppress tumor regrowth. Development of agents that target critical steps in the Wnt, Notch, and Hh pathways will be complicated by signaling cross-talk. The role that embryonic signaling pathways play in the function of CSCs, the development of new anti-CSC therapeutic agents, and the complexity of potential CSC signaling cross-talk are described in this Review.