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Author Spotlight: Unveiling Transmembrane Protein Family-Related Markers in Gastric Cancer and Implications for Targeted Therapies
Published on: September 15, 2023
New therapeutic target molecules for gastric and gastroesophageal junction cancer
1Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-sayama, 589-8511, Japan. kawakami_h@med.kindai.ac.jp.
Abstract:
Molecularly targeted therapy for receptor tyrosine kinases (RTKs) has faced limitations in gastric and gastroesophageal junction (G/GEJ) cancer except for HER2-targeted agents, possibly due to inappropriate assay selection that has hindered identification of sensitive patients, in addition to coexisting genetic abnormalities as well as intratumoral heterogeneity. Immunohistochemistry of RTKs has, thus, proved largely unsuccessful for patient selection, and detection of RTK gene amplification as a true oncogenic driver is problematic given the small numbers of affected individuals. FGFR2 amplification is associated with poor prognosis in G/GEJ cancer, and immunohistochemistry of the FGFR2b protein isoform has proved effective for the detection of such FGFR2-dependent tumors. Phase III and Ib/III trials of the FGFR2-targeted antibody bemarituzumab for G/GEJ cancer overexpressing FGFR2b are ongoing based on the promising result in a phase II trial, especially in cases with an FGFR2b positivity of ≥ 10%. Challenges to EGFR- and MET-targeted therapies are being tackled with antibody-drug conjugates (ADCs) and bispecific antibodies. CLDN18.2 is expressed in some G/GEJ tumors but lacks oncogenic driver potential, and the CLDN18.2-targeted antibody zolbetuximab prolonged the survival of CLDN18.2-positive G/GEJ cancer patients in phase III trials. Antibody-drug conjugates and ADCs that target CLDN18.2 are also being pursued for treatment of such patients. Similarly, targeting of nondriver molecules such as DKK1, TROP2, and CEACAM5 is under investigation in early-stage clinical trials. This shift in focus from target molecules with driver potential to markers for precise drug delivery should increase the number of possible targets in G/GEJ cancer.
Insights
Targeted therapies for gastric cancer face challenges due to patient selection issues. New strategies focus on precise drug delivery markers, expanding treatment options beyond traditional oncogenic drivers.
Area of Science:
- Oncology
- Molecular Targeted Therapy
- Gastrointestinal Cancers
Background:
- Molecularly targeted therapies for receptor tyrosine kinases (RTKs) have shown limited success in gastric and gastroesophageal junction (G/GEJ) cancers.
- Challenges include inappropriate assay selection, genetic abnormalities, and intratumoral heterogeneity, hindering patient identification for RTK-targeted agents.
- Immunohistochemistry for RTKs has been largely unsuccessful for patient selection, and detecting RTK gene amplification is difficult in small patient cohorts.
Purpose of the Study:
- To review the limitations and advancements in molecularly targeted therapies for G/GEJ cancer.
- To highlight the evolving strategies in patient selection and drug development for G/GEJ cancer.
- To discuss the potential of targeting non-driver molecules for precise drug delivery.
Main Methods:
- Review of clinical trial data and scientific literature on targeted therapies in G/GEJ cancer.
- Analysis of the efficacy of specific targeted agents, including antibodies and antibody-drug conjugates (ADCs).
- Evaluation of diagnostic methods for identifying targetable biomarkers, such as FGFR2b and CLDN18.2.
Main Results:
- FGFR2 amplification is linked to poor prognosis, and FGFR2b immunohistochemistry effectively identifies FGFR2-dependent tumors, supporting bemarituzumab trials.
- Antibody-drug conjugates (ADCs) and bispecific antibodies are addressing challenges in EGFR and MET-targeted therapies.
- Zolbetuximab has shown survival benefits in CLDN18.2-positive G/GEJ cancer patients, with ADCs targeting CLDN18.2 also under investigation.
- Targeting non-driver molecules like DKK1, TROP2, and CEACAM5 is being explored in early-stage trials.
Conclusions:
- The focus is shifting from oncogenic driver targets to markers for precise drug delivery, potentially increasing therapeutic options in G/GEJ cancer.
- Advancements in antibody-based therapies and diagnostic assays are crucial for improving patient outcomes in G/GEJ cancer.
- Targeting CLDN18.2 and exploring novel markers represent promising avenues for future G/GEJ cancer treatment strategies.
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