Targeted Molecular Therapies in the Treatment of Esophageal Adenocarcinoma, Are We There Yet?

Abstract

Esophageal adenocarcinoma is one of the leading causes of cancer-related deaths worldwide. The incidence of esophageal adenocarcinoma has increased at an alarming rate in the Western world and long-term survival remains poor. Current treatment approaches involve a combination of surgery, chemotherapy, and radiotherapy. Unfortunately, standard first-line approaches are met with high rates of recurrence and metastasis. More recent investigations into the distinct molecular composition of these tumors have uncovered key genetic and epigenetic alterations involved in tumorigenesis and progression. These discoveries have driven the development of targeted therapeutic agents in esophageal adenocarcinoma. While many agents have been studied, therapeutics targeting the human epidermal growth factor receptor (HER2) and vascular endothelial growth factor (VEGF) pathways have demonstrated improved survival. More recent advances in immunotherapies have also demonstrated survival advantages with monoclonal antibodies targeting the programmed death ligand 1 (PD-L1). In this review we highlight recent advances of targeted therapies, specifically agents targeting receptor tyrosine kinases, small molecule kinase inhibitors, and immune checkpoint inhibitors. While targeted therapeutics and immunotherapies have significantly improved survival, the benefits are limited to patients whose tumors express biomarkers such as PD-L1 and HER2. Survival remains poor for the remainder of patients with esophageal adenocarcinoma, underscoring the critical need for development of novel treatment strategies.

Keywords: esophageal adenocarcinoma; immunotherapy; targeted therapy.

Figure 1

Schematic overview of select receptor tyrosine kinases involved in esophageal adenocarcinoma tumorigenesis. The intracellular signaling of the depicted receptor tyrosine kinases (RTKs) is primarily mediated by the RAS/RAF and PI3K/AKT pathways. Aberrant activation of these pathways ultimately favors tumor growth and survival. mTOR is a major downstream effector that is modulated by AKT signaling. Molecular therapies targeting RTKs either disrupt ligand binding or function to prevent intracellular activation of the tyrosine kinase domain.

Figure 2

Schematic representation of aurora kinase A (AURKA) signaling networks involved in cancer. AURKA overexpression inhibits the DNA damage response and attenuates DNA-damage induced cell cycle arrest and apoptosis through inhibition of p53 family member proteins [129]. AURKA induces inflammatory signaling mediated by NF-κB [133], as well as pro-survival signaling mediated by beta-catenin [132] and p70S6K [135].

Figure 3

Schematic drawing of the major molecular mechanisms involved in checkpoint blockade for cancer immunotherapy. (A) Interaction of the programmed death 1 (PD-1) receptor on T-cells with the programmed death ligand 1 (PD-L1) on tumor cells results in T-cell suppression [148]. A similar suppressive interaction occurs between B7 on tumor cells and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) on T-cells [149]; (B) Monoclonal antibodies targeting PD-1 and PD-L1 disrupt T-cell checkpoint suppression and facilitate antitumor T-cell effector functions. Anti-CTLA-4 therapy allows binding of B7 with CD28 on T-cells which stimulates further T-cell activation.