Genetic study flags gallbladder cancer therapy, vaccine candidates

October 5, 2020 0 By FM

A team of US- and India-based scientists from leading genetic research-and-data-based diagnostic company MedGenome, along with an international team of researchers from institutions in the US, India, South Korea, Chile and Australia, reported sequencing and analysis of over 150 gallbladder cancer (GBC) samples. 

This landmark study, which identified several genomic alterations by analysing these samples, could pave the way for new targeted therapies, including vaccines for treating this cancer, highly prevalent among the American and Asian populations. Currently, there are no targeted therapies for treating gallbladder cancer. 

The new study, published in Nature Communications, says the researchers analyzed exomes (n = 160), transcriptomes (n = 115), and low pass whole genomes (n = 146) from 167 gallbladder cancers from patients in Korea, India and Chile. The team also sequenced samples from 39 GBC high-risk patients and detected evidence of early cancer-related genomic lesions. 

According to the paper— https://www.nature.com/articles/s41467-020-17880-4, the study found that several significantly mutated genes not linked to GBC are the ETS domain genes— ELF3 and EHF, CTNNB1, APC, NSD1, KAT8, STK11 and NFE2L2. But a majority of ELF3 alterations were frame-shift mutations that result in several cancer-specific neoantigens. These neoantigens activate T-cells, indicating that they are potential cancer vaccine candidates. In addition, the scientists also identified recurrent alterations in KEAP1/NFE2L2 and WNT pathway in GBC. Taken together, these define multiple targetable therapeutic intervention opportunities for GBC treatment and management, the paper suggested.

No approved therapies 

Gallbladder cancer, an aggressive gastrointestinal malignancy mainly prevalent among Southwestern Native Americans and Mexican Americans, is also prevalent in South American countries, including Chile, Bolivia, and Ecuador, and in Asian countries such as Korea, India, Pakistan and Japan, and has no approved targeted therapies as of now.

However, the study identified several targetable genomic alterations through a comprehensive genomic analysis. In particular, frequent alterations of the ELF3 gene. The genomic analysis showed that the mutated peptides derived from ELF3 have the potential for use as a cancer vaccine to treat GBC patients carrying alteration in this gene. It has also reported a new class of hypermutated mismatch deficient GBCs that will likely respond to check-point inhibitors.

“This work has deepened the understanding of the underlying genomics of GBC, including the identification of new pathways, immune microenvironment and actionable mutations,” says Eric Stawiski, the co-communicating author of the new paper and vice president (Bioinformatics) at MedGenome, US.

ELF3-derived mutant peptides

The Nature Communication paper noted that the researchers performed a comprehensive integrative genomic analysis of 167 gallbladder primary tumours, and 7 GBC cell lines. Also, they analysed premalignant gallbladder tissue from 23 cholecystitis cases, 14 gallstones, and 2 gallbladder polyps, and found somatic mutations in cholecystitis that were indicative of a premalignant stage. 

The study uncovered a class of hypermutated GBC that carried mutations in mismatch repair genes. It reported 25 significantly mutated GBC genes that include several targetable driver genes such as ERBB2, ERBB3, KRAS, PIK3CA, and BRAF. Importantly, several of the ERBB2 mutations observed are known to be oncogenic and targetable and patients with such mutations are candidates for targeted HER2 therapy. Analysis of exome and RNA-seq data identified recurrent alterations in KEAP1/NFE2L2 and WNT pathways. Cancer vaccines or checkpoint inhibitors have not been approved for treating gallbladder cancers. The study identified neoantigens from several mutated GBC genes including ELF3, ERBB2, and TP53 and found that they were capable of T-cell activation indicating that they are potential cancer vaccine candidates. Further, the study identified GBC samples with MSI, and they likely are candidates for checkpoint inhibitor therapy. Together these findings provide an opportunity for testing immunotherapy in gallbladder cancer.

This new study also significantly expanded on previous genomic studies providing a comprehensive genomics view of GBCs. Specifically, it identified actionable alterations in over 20% of cases. 

“Applying our proprietary OncoPept platform, our scientists were able to show the potential for use of ELF3-derived mutant peptides as a cancer vaccine for treating GBC and shows the value of the platform for the identification of cancer vaccine candidates,” said Rayman Mathoda, CEO, MedGenome US.

This landmark study offers new insight and opportunities for combating GBC, she added.