Pancreatic cancer patients have the lowest survival rates among cancer survivors. It is estimated that by the year 2020, the incidence of pancreatic cancer globally would have increased by 20%. A recent study by researchers from Rajiv Gandhi Centre for Biotechnology (RGCB) and Regional Cancer Centre (RCC), Thiruvananthapuram, in collaboration with researchers from National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, proposes that fingolimod (FTY720), a drug used for treating multiple sclerosis, can also be used for the treatment of pancreatic cancer.
“Most cancers get a lot of attention and fundraising by the survivors. Pancreatic cancer, however, fails to get attention as patients die within a short period after diagnosis,” says K.B. Harikumar, RGCB, corresponding author of the paper. “Finding a cure for pancreatic cancer was a major motivation behind this study since most patients end up with drug resistance,” he adds.
The researchers decided to target a receptor called Sphingosine-1-Phosphate receptor 1 (S1PR1) in pancreatic cancer cells. Signal Transducer and Activator of Transcription 3 (STAT3), a transcription factor, plays a major role in cell proliferation and differentiation. S1PR1 maintains a constitutively activated state of STAT3, which provides an advantage to tumour cells.
“We observed an abnormal upregulation of S1PR1 in pancreatic cancer patient samples,” says Harikumar, “Therefore, we targeted this using its antagonist fingolimod that is already in clinical use for multiple sclerosis. Since it is an FDA-approved drug, we know about its metabolism and toxicity and we can go through clinical trials faster.”
The researchers observed that when pancreatic cancer cell lines were exposed to fingolimod, the cells underwent apoptosis. This led to higher levels of Reactive Oxygen Species (ROS) and decreased cell migration. ROS, when they accumulate to a toxic level, cause oxidative stress in the cell, leading to cell death. Decreased cell migration translates to a reduced capacity of the tumour cells to invade the extracellular matrix and metastasize to other sites.
Gemcitabine has been a standard of chemotherapy for pancreatic cancer. However, increased instances of drug resistance have shifted the focus toward combination therapy. It was not a surprise, therefore, when the researchers observed maximum cell death when the cancer cell lines were treated with a combination of both gemcitabine and fingolimod.
In addition to pancreatic cancer cell lines, the researchers also used mouse models of pancreatic cancer for their studies. When these mice received combination therapy with gemcitabine and fingolimod, there was a marked decrease in tumour size compared to when they were treated with each drug alone.
Based on their experiments, Harikumar’s team concluded that fingolimod alters the tumour microenvironment, which causes gemcitabine to accumulate in the tumour cells and kill them. The study also found a second mechanism through which fingolimod exerts its anticancer effect: reactivation of a tumour suppressor gene, protein phosphatase 2 (PP2A), which is inactivated in most cancers.
“The challenge associated with all these studies is extending them to the clinic. While these are standard preclinical studies that all of us perform, the challenge is to determine whether these results will translate into clinical practice. This is true of most studies in cancer biology,” says Sorab Dalal, cancer researcher and principal investigator at Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Mumbai. “It has to be determined whether the drug will inhibit the growth and progression of all pancreatic cancers or only a subset where STAT3 signaling plays a role,” he says.
Harikumar has a similar course charted out for his team. “We will now aim to understand the involvement of signalling pathways other than STAT3 in reducing the tumour burden in combination therapy. We are also planning to check further use of chemotherapeutic drugs in combination with fingolimod,” he says.
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This is a companion discussion topic for the original entry at https://indiabioscience.org/news/2018/a-new-drug-for-pancreatic-cancer