Identification of targeted therapy options for gastric adenocarcinoma by comprehensive analysis of genomic data
Daniel A Hescheler1,2, Patrick S Plum1,2, Thomas Zander2,3
1Department of General, Visceral and Cancer Surgery, University Hospital of Cologne Germany, Cologne, Germany.
Background:
So far only trastuzumab, pembrolizumab and ramucirumab have been approved by the FDA for targeted therapy in gastric cancer (GC). Here we report on potential targeted therapy options for gastric adenocarcinoma based on a novel analysis of "The Cancer Genome Atlas (TCGA)" database.
Methods:
One hundred two FDA-approved targeted cancer drugs were compiled and molecular targets defined. Drugs were considered as potentially effective if targeted genes showed (1) an increase in copy number, (2) gain of function with oncogene activation, (3) specific alterations responsive to approved drugs. Additionally, genetic changes that confer drug resistance and/or sensitivity were evaluated.
Results:
Fifty percentage of patients with GC may be treatable with non-GC but FDA-approved targeted cancer therapies. The major drug identified in our in silico study for GC is copanlisib, a PI3K inhibitor. In the TCGA patient database, our genetically based drug response prediction identified more patients with alterations sensitive to copanlisib compared to the already-GC-approved drug trastuzumab (20%, 78 out of 393 patients, vs. trastuzumab: 13%, 52 of 393 patients), which is mainly due to the high incidence of PIK3CA gain of function mutations within mutation hot spots.
Conclusion:
Our results demonstrate that various currently FDA-approved drugs might be candidates for targeted therapy of GC. For clinical trials, cancer patients should be selected based on the genomic profile of their tumor.
Insights
New analysis of The Cancer Genome Atlas reveals that copanlisib, a PI3K inhibitor, shows promise for gastric cancer (GC) targeted therapy. Many FDA-approved drugs may offer new treatment options for GC patients based on tumor genomic profiles.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Gastric cancer (GC) currently has limited FDA-approved targeted therapies, including trastuzumab, pembrolizumab, and ramucirumab.
- Novel targeted therapy options for gastric adenocarcinoma are explored using The Cancer Genome Atlas (TCGA) database.
Purpose of the Study:
- To identify potential FDA-approved targeted therapies for gastric adenocarcinoma beyond existing treatments.
- To analyze the TCGA database for genetic alterations that could predict response to targeted drugs.
Main Methods:
- Compiled a list of 102 FDA-approved targeted cancer drugs and their molecular targets.
- Identified potentially effective drugs based on gene copy number increase, oncogene activation, or specific alterations.
- Evaluated genetic changes related to drug resistance and sensitivity.
Main Results:
- Approximately 50% of GC patients may benefit from non-GC FDA-approved targeted therapies.
- Copanlisib, a PI3K inhibitor, emerged as a major candidate, with 20% of patients showing sensitivity due to PIK3CA mutations.
- This sensitivity rate for copanlisib exceeded that of trastuzumab (13%) in the TCGA cohort.
Conclusions:
- Several FDA-approved drugs show potential for targeted therapy in gastric cancer.
- Patient selection for clinical trials should be guided by the genomic profile of their tumors.
