Farmington, Conn. – A Jackson Laboratory-led research team has identified two druggable targets for gastric cancer through a genomic molecular profiling technique, and validated the findings in mouse models capable of hosting human tumors.
The findings, published online on Sept. 21 in the Proceedings of the National Academy of Sciences, provide proof-of-concept for a new drug discovery platform, notes Charles Lee, Ph.D., professor and director of The Jackson Laboratory for Genomic Medicine and senior author of the study. Lee is also a Distinguished Professor at Ewha Womans University in Seoul, South Korea.
“Gastric cancer is the third leading cause of cancer-related deaths worldwide,” Lee says, “but therapy based on genetic profiling is limited for the disease. Our study has revealed two potential novel molecular mechanisms for the treatment of subsets of gastric cancers. Moreover, our approach of integrating genomic molecular profiling and PDX mouse models provides a valuable platform for novel drug-target discovery and validation.”
The researchers examined the DNA of 103 Asian gastric cancer patients for sequence variations—aberrations in the number of copies or the sequence of certain genes. Using array comparative genomic hybridization (aCGH) to find copy number alterations and whole exome sequencing to find sequence mutations, they identified 342 genes they deemed “significantly altered.” Upon further analysis, they focused on two genes—BCL2L1 and DLC1—as possible drug targets.
BCL2L1 is part of the p53 signaling and apoptosis pathway. In healthy individuals this pathway is involved in the normal death of cells; in cancers mutations causing the failure of this system lead to unchecked cell proliferation. Some gastric cancers show overexpression of BCL2L1 due to copy number amplification.
The researchers tested therapeutic drugs for BCL2L1 in gastric cancer cells in vitro, targeting it in combination with chemotherapeutic drugs, and found enhanced sensitivity to one (afatinib) that is now in phase 2 clinical trials. Then, working with mice that can host human cancers (known as PDX - for patient-derived xenograft), the researchers developed a colony of models for gastric cancer. They observed inhibition of BCL2L1 in combination with irinotecan, a conventional chemo drug.
DLC1 is a tumor suppressor gene, and the researchers found sequence mutations in DLC1 in about 11 percent of the gastric cancer cases sequenced. The mutation appears to confer a growth advantage for the gastric cancer cells via activation of the Rho-ROCK signaling pathway. Suppressing the ROCK pathway thus offers a potential drug target, the researchers conclude.
“This study represents a successful international collaboration between Seoul National University Hospital (SNUH) – a leading hospital for gastric cancer research - and The Jackson Laboratory – a leading genomics research institute, and provides two new exciting targets for gastric cancer therapy,” says Han-Kwang Yang, M.D., Ph.D., chief of gastrointestinal surgery at Seoul National University Hospital and co-senior author on the study.
The Jackson Laboratory is an independent, nonprofit biomedical research institution and National Cancer Institute-designated Cancer Center based in Bar Harbor, Maine, with a facility in Sacramento, Calif., and The Jackson Laboratory for Genomic Medicine in Farmington, Conn. It employs 1,700 staff, and its mission is to discover precise genomic solutions for disease and empower the global biomedical community in the shared quest to improve human health.
The Division of Gastrointestinal Surgery at Seoul National University Hospital performs over 1,000 gastric cancer operations and over 30 clinical trials and 20 translational studies per year. Dr. Yang has been elected as an honorary fellow of the American Surgical Association. He is involved in several large scale randomized controlled trials for gastric cancer treatment. His translational research interests include gastric carcinogenesis, DDS, familial gastric cancer and biomarkers.
Park et al.: Genomic alterations in BCL2L1 and DLC1 contribute to drug sensitivity in gastric cancer. Proceedings of the National Academy of Sciences, early online edition, Sept. 21, 2015, www.pnas.org/cgi/doi/10.1073/pnas.1507491112.