Emerging targets in gastroesophageal adenocarcinoma: what the future looks like

Abstract

Gastroesophageal adenocarcinoma (GEA) is a heterogeneous disease with a poor prognosis. Chemotherapy has been the cornerstone in treating metastatic diseases. Recently, the introduction of immunotherapy demonstrated improved survival outcomes in localized and metastatic diseases. Beyond immunotherapy, several attempts were made to improve patient survival by understanding the molecular mechanisms of GEA and several molecular classifications were published. In this narrative review, we will discuss emerging targets in GEA, including fibroblast growth factor receptor and Claudin 18.2, as well as the accompanying drugs. In addition, novel agents directed against well-known targets, such as HER2 and angiogenesis, will be discussed, as well as cellular therapies like CAR-T and SPEAR-T cells.

Cancer/testis antigen expression and co-expression patterns in Gastroesophageal Adenocarcinoma

“…GEAC is often diagnosed in the locally advanced stage or after metastasis [2]. Only 5.5% of patients diagnosed with metastatic GEA are alive after ve years [3]. Furthermore, individuals with locally advanced disease face a signi cant risk of relapse after curative surgery, leading to an unfavorable prognosis [4].…”

Clinical Updates for Gastrointestinal Malignancies

“…Moreover, trastuzumab deruxtecan (T-Dxd) was approved for HER2-positive GC in several countries. In more recent years, immune checkpoint inhibitors (ICIs) also gained a foothold both in the perioperative and advanced setting and in combination with other therapeutic targets including HER2-positive GC [ 47 ]. However, several other immune-based therapies including anti-T cell immunoreceptor with immunoglobulin, chimeric antigen receptor T-cell (CAR-T) therapy and immunoreceptor tyrosine-based inhibitory motif domain (anti-TIGIT) therapy have been evaluated [ 46 , 47 ].…”

“…In more recent years, immune checkpoint inhibitors (ICIs) also gained a foothold both in the perioperative and advanced setting and in combination with other therapeutic targets including HER2-positive GC [ 47 ]. However, several other immune-based therapies including anti-T cell immunoreceptor with immunoglobulin, chimeric antigen receptor T-cell (CAR-T) therapy and immunoreceptor tyrosine-based inhibitory motif domain (anti-TIGIT) therapy have been evaluated [ 46 , 47 ]. Furthermore, alternative therapeutic targets are currently under investigation as predictive biomarkers including claudin 18.2 (25% of GC) and fibroblast growth factor receptor 2b (FGFR2b) (30% of GC) [ 46 ].…”