Targeted Therapy for Pancreatic Cancer

Targeted Therapy for Pancreatic Cancer: Introduction

The increased understanding of the molecular and genetic changes associated with tumorigenesis has led to the development of agents that specifically target these alterations. Targets have included KRAS and downstream factors, such as mitogen-activated protein kinase, epidermal growth factor receptor, vascular endothelial growth factor A, and type I receptor for insulin-like growth factor.

Targeted Therapy for Pancreatic Cancer: EGFR

The epidermal growth factor receptor inhibitor EGFR erlotinib has been the only one of these reagents found to significantly prolong survival in phase III trials. In a double-blind, placebo-controlled study, 569 patients with metastatic or locally advanced cancer received either erlotinib with gemcitabine or gemcitabine with placebo. The erlotinib combination produced a modest but statistically significant benefit, prolonging survival by 2 weeks (6.2 vs 5.9 months for patients that received gemcitabine with placebo), which led to its approval by the Food and Drug Administration for treatment of metastatic pancreatic cancer. Integration into clinical practice has been slow, however, because of the cost and the mild but noteworthy side effects of erlotinib (primarily rash and diarrhea).
Additional studies of reagents that target epidermal growth factor receptor have failed to show benefits.

Targeted Therapy for Pancreatic Cancer: VEGF

Reagents that target vascular endothelial growth factor (VEGF) signaling, such as bevacizumab, axitinib, sorafenib, and aflibercept, in combination with gemcitabine, have not been shown to have statistically significant effects on survival compared with gemcitabine alone.

Targeted Therapy for Pancreatic Cancer: KRAS

Activating mutations in KRAS are frequently detected in pancreatic cancer (in 70%–90% of cases) and correlate with the degree of dysplasia in precursor lesions. However, the unique conformation of KRAS and its position in the cell membrane make it a challenge to inhibit. Attempts to manipulate its processing with the farnesyltransferase inhibitor tipifarnib showed no benefits in phase III trials, despite encouraging preclinical data. Efforts to target the Ras pathway have therefore focused on downstream effectors of KRAS activation, such as Raf and mitogen-activated protein kinase. The mitogen-activated protein kinase inhibitor selumetinib has shown results similar to capecitabine (a chemotherapy drug) in phase II studies, and is currently being tested in combination with erlotinib; blocking multiple pathways could have synergistic effects against tumors.

Targeted Therapy for Pancreatic Cancer: Reference

Paulson A S et al. Therapeutic advances in pancreatic cancer[J]. Gastroenterology, 2013, 144(6): 1316-1326.