Gallbladder cancer is one of the most common cancers in the Gangetic belt. The Cancer is often diagnosed late and has poor survival rate. The current 5-year survival rate is 10-20%. Researchers at Banaras Hindu University have been working on Gallbladder cancer for the past 25 years to find out the probable causes which continue to remain elusive. However, while one looks at possible causes it’s also important to identify newer treatments to increase survival of those who are inflicted with this cancer.

Achieving a major breakthrough in this regard, a research team led by Prof. Manoj Pandey from the Department of Surgical Oncology in the Institute of Medical Sciences, BHU, has identified the somatic mutations responsible for developing gallbladder cancer. Scientists at the department of Surgical Oncology had started looking for newer therapeutic targets in the year 2016. As part of the research, the team carried out next generation sequencing of tumor DNA from gallbladder cancer in 33 patients. This was further subjected to bioinformatics analysis. The research team comprising Dr. Satyavjiay Chigurupati, Dr. Roli Purwar, Ms. Monika Rajput and Dr. Mridula Shukla identified 27 somatic mutations that involved 14 critical genes. Of these, two genes namely p53 and KRAS were the most commonly mutated and appeared to be driver mutations behind these cancers.

The bioinformatics analysis identified MAP kinase, PI3K-AKT, EGF/EGFR, and Focal Adhesion PI3K-AKT-mTOR signaling pathways and cross-talk between these pathways. The study suggested that the complex crosstalk between the mTOR, MAPK, and multiple interacting cells signaling cascades promotes gallbladder Cancer progression, and hence, Mtor targeted treatment is an attractive option in the cure of gallbladder cancer. These targeting molecules are available and approved for different indications, however, they have never been used in gallbladder cancer. The findings of the study have been published in the prestigious scientific journal Molecular biology reports.

According to Prof. Manoj Pandey, the driver mutations for gall bladder cancers have been identified for the first time, solving an unresolved mystery to some extent. However, it is still unclear why the mutations are occurring mainly in these two genes in this geographical area. It is possible that they may be the result of environmental exposure to carcinogenic substances, whatever they may be. Heavy metal toxicity and typhoid carrier state have earlier been implicated in gallbladder carcinogenesis.

Prof. Pandey says this pathway and the cross talk have been identified for the first time in the world, and this opens the gate for use of new therapeutic drugs like evrolimus and temsirolimus in gallbladder cancer. Both of these drugs are mTOR inhibitors and interfere with the synthesis of proteins that regulate proliferation, growth, and survival of tumor cells. They also reduce tumor growth by reducing angiogenesis (new blood vessel formation in tumor) by inhibiting VEGF (gene) and hence cut its food supply, thereby killing the cells. So far these drugs are approved for treatment of breast cancer, neuroendocrine tumors and renal carcinoma.

The research team of Dr. Pandey has submitted a proposal for a clinical trial of mTOR inhibitors in gallbladder cancer, which if successful will open a new doorway for treatment of gallbladder cancer which is considered incurable till now. This brings new hope for gallbladder cancer prevalent in Gangetic belt.