Health

Identifying viable targets and potential immunotherapeutic strategies to treat gallbladder cancer

MedGenome Inc, Bioinformatics Scientist, Dr. Kushal Suryamohan

Gallbladder cancer (GBC) is a progressive gastrointestinal malignancies with a poor prognosis. It is the 20th most common type of cancer in the world, with prevalence especially high in certain parts of the world such as Bolivia, Chile, Ecuador, Peru, South Korea, Japan and India, and is currently increasing in the Western population. (Https: // bit. Ly / 3kSLDMw) (Fig. 1). In the United States, it is a more common malignancies in Southwestern Native Americans and Mexican-Americans. There is also a gender gap with GBC, which is more common in women than in men. Median survival for GBC patients is usually less than 1 year. This is mainly due to the fact that early diagnosis is difficult and most patients are asymptomatic until the disease reaches the advanced or metastatic stage. In addition, the anatomical location of the gallbladder below the liver makes it easier for GBC to grow undetected. Radical surgery, chemotherapy and radiation therapy continue to be the current mainstays of treating GBC. However, only about 10-15% of patients are susceptible to surgery, with a 5-year overall survival rate of less than 5%. Currently, the cause of gallbladder cancer is unknown. Possible causative factors include gallstones, the female hormone estrogen, lifestyle, diet and eating habits.

Figure 1. Global prevalence of GBC.

Most cancer genomic sequencing studies to date have focused on highly prevalent cancers, but few large-scale studies have been done on rare forms of cancer such as GBC. Therefore, we decided to focus on GBC and established a global consortium with researchers from India, the United States, South Korea and Chile. Through this collaboration, we were able to obtain 167 GBC primary samples, 39 non-GBC samples, and the corresponding matching normal tissue. This unprecedented dataset allowed us to map the genomic changes frequently observed in GBC to determine if there are differences between tumors in different geographic regions. In our study, published in Nature Communications, we performed GBC exome, whole-genome, transcriptome sequences from these ethnically diverse populations, and some that were not previously linked to GBC. We have identified a significantly mutated gene. It contained ELF3, a gene that frequently mutates in GBC with genomic alterations in 21% of sequenced tumors. We integrated somatic mutations, copy number polymorphisms, and gene fusion data to identify GBC-affected pathways. The TP53 / RB1 route has been most commonly modified in GBC. In addition, activation of the WNT pathway and KEAP1 / NFE2L2 pathway was observed in GBC. Activation of the WNT pathway was promoted primarily by mutational activation in the fusion of CTNNB1 and RSPO3. Frequent inactivated mutations were found in SWI / SNF pathway genes such as SMARCA4, ARID1A, and ARID2. We also found some therapeutically viable mutations in the RAS / PI3K pathway with frequent changes in ERBB2. ERBB3, BRAF and PIK3CA.

The advent of immunotherapy has revolutionized cancer treatment with the significant survival benefits observed in a variety of cancers, including melanoma and lung cancer. To determine the potential opportunities for immunotherapy in GBC, we evaluated new antigens resulting from somatic mutations. High-affinity MHC class I-binding neoantigen peptides were predicted for each tumor. This identified about 15 new antigens per tumor. Most predicted new antigens were derived from frequently mutated genes in GBC, including TP53, ELF3, CTNNB1, ERBB2, ARID1A, and CDKN2A. Peripheral blood mononuclear cells (PBMCs) from healthy HLA-matched donors could be used to determine the ability of mutant peptides to activate T cells. Three mutant ELF3 peptides, two mutant ERBB2 peptides and one mutant TP53 peptide have been found to actually activate T cells and can be used as potential cancer vaccines. We also identified several viable targets at GBC based on a comprehensive characterization of genomic alterations. We found that up to 20% of all tumors in our study have viable targets based on the approved targeted therapies available (OncoKB). We also identified new antigens that could be pursued to develop immunotherapy strategies for the treatment of gallbladder cancer (Figure 2).


Figure 2. Viable targets and potential immunotherapeutic strategies for treating GBC.

By studying diverse sets of GBC samples across geographically diverse populations, our study identified new and potential cancer vaccine candidate genes for the treatment of GBC. This is an important milestone in our ongoing global efforts to find biomarkers of translational importance. By selecting ethnically (and genetically) diverse population groups, this study emphasizes the importance and need to incorporate genomic data analysis to identify candidate marker genes for diagnostic and therapeutic applications. I emphasize it further. This improves patient outcomes in the clinic by using approved targeted therapies.

References

Kushal Surya Mohan1, Pramod Kumar Tiwari2, Harsha Gouda3, Eric Stawhiskey1 And Soma Sekar SeshagiriFour

  1. 1 MedGenome Inc., Foster City, CA, USA
  2. 2 University of Jiwaji, Gwariel, Madhya Pradesh, India
  3. 3 QIMR Berghofer Medical Research Institute, Brisbane, Australia
  4. Four SciGenom Research Foundation, Chennai, Tamil Nadu, India

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