A Clue to Solve Chemotherapy Drug Resistance in Pancreatic Cancer

Today I am going to discuss about an innovative thinking to solve a biological mystery when it comes to treating Cancers. One of my colleague and fellow student at Jawaharlal Nehru University, New Delhi, Dr Pankaj Singh, has come up with a landmark hypothesis to explain the resistance in some patients against a chemotherapy drug called Gemcitabine.

Dr Singh is one of the 14 scientists from the USA, who has recently won a $200,000 grant from the Pancreatic Cancer Action Network to work on his hypothesis.

Dr Singh, an Associate Professor at the Eppley Institute for Research in Cancer and Allied Diseases at University of Nebraska Medical Center, proposed that the cancer cells may be naturally producing a chemical, which competes with the drug Gemcitabine and leaves it ineffective.

Gemcitabine is an analog of one of the building blocks of DNA, cytidine. When inside the cell, the drug replaces the natural molecule cytidine in DNA and stops the DNA synthesis. In this way the cancer cells stop dividing and finally die.

A report of American Cancer Society's annual statistical report in 2009 attributed Cancer as the number one killer in America, surpassing the deaths due to heart diseases.

Among various types of cancers, pancreatic cancer is on rise. It is currently at fourth place in cancer related deaths, but poised to become second leading cause of cancer related death very soon, behind only to lung cancer, the number one cancer killer.

Unlike other cancers, the survival rate of pancreatic cancer patient is only 6 percent in the next five years post-diagnosis. Three out of four newly diagnosed patients die within a year of diagnosis. There are many famous victims of this disease.

The mean life span of a diagnosed person is at most six months. The reason for poor prognosis of pancreatic cancer is that the prospective patient remains symptom free leading to late diagnosis, and by the time the disease is diagnosed; in most cases it is already metastasized.

The disease is treated based on stage and location of the tumor and patients age. The tumor can be surgically removed at early stage. The most effective drug at the later stages is a chemotherapy drug called Gemcitabine, which is also used for treating cancers of lung, bladder and breast.

Unfortunately, many pancreatic cancer patients develop resistance to this drug.

The reason for developing the resistance has been troubling scientists, until Dr Pankaj Singh came up with his hypothesis. He thinks that it has to do with the way the cancer cells metabolize their sugars.

As per Dr Singh’s theory, pancreatic cancer cells make a lot of natural cytidine molecule themselves which outcompete the Gemcitabine leaving it useless as a chemotherapeutic drug. Further, he thinks that cancer cells burn the glucose, the main energy source for cells, at a higher rate.

The process of glucose break down in cells called glycolysis, and excessive glycolysis combined with lack of oxygen, common in tumor microenvironment, produces a lot of lactate. If you have felt muscle pain after strenuous exercise, it is because of lactate accumulation in the muscle. Dr Singh is also working to find if the increased lactate production due to increased glucose utilization by cancer cells is linked with the resistance to Gemcitabine.

By working on his innovative theories, Dr Singh is aiming to find a metabolic diagnostic biomarker that will help in deciding whether a patient will benefit from chemotherapy using this drug.

Since most of the patients have very little time left after diagnosis, this will help patients with targeted treatment and save many others from highly toxic and expensive chemotherapy.

Dad's Liver Fibrosis May Protect Son’s Liver

The liver is a vital organ in our body which performs many important functions, but sometimes gets inflamed because of various reasons including virus infection, and alcohol and drug abuse. A chronic inflammation of the liver results in fibrosis wherein healthy liver cells are replaced by collagen loaded fibrotic cells which compromise the structure and function of the liver. This course of disease is known for many years now, and there is nothing new in this.

source: www.hivandhepatitis.com

What is new however is that scientists have now discovered that fibrosis in father’s liver somehow results in the protection from this disease in his sons. The chronic liver injury because of either viral infection or alcohol abuse induces an epigenetic change in the sperm’s DNA. When this changed DNA is transmitted to the next generation it would protect the male progeny from liver fibrosis.

Epigenetic changes are modifications in the DNA caused by non-genetic and mostly lifestyle related exposures in ones’ life time. Although these changes do not seems to last and have limited effects on long-term evolutionary changes, sometimes epigenetic changes in the germ cells such as sperm can be transmitted to the next generation. Epigenetic changes are now implicated in many present day diseases including cancer and diabetes.  

The scientists, Müjdat Zeybel and his colleagues, reported that a long history of liver damage in rodents was related with transfer of adaptive epigenetic changes that suppressed liver fibrosis in first and 2^nd generation male rats.

The scientists induced liver fibrosis in rats by two different methods using carbon tetra-chloride and bile duct ligation. They found that prolonged lung injury resulted in the changes in rat sperm DNA which were inherited by the progeny. The male rats born from those sperms when tested by giving similar insults showed increased protection from liver fibrosis.

The main reason for this protection is higher amounts of a factor that prevent liver fibrosis, called peroxisome proliferator-activated receptor-gamma (PPAR-γ) in scientific term, in the liver of male pups that inherited modified DNA. They also had lower amounts of fibrosis promoting growth factor called Transforming growth factor-beta1, compared to those that inherited normal DNA.

The study published in Nature thus suggests that a history of liver fibrosis in male can protect their male progeny from such disease in next generation. But this protective adaptation was limited to liver and was not found to protect other organs, for example kidney, from fibrosis.

Although it remains to be determined how applicable these findings are in humans, this report should not result in believing that paternal liver injury would protect against the alcohol abuse-related liver diseases. We must therefore resist temptation to run to the bar with the logic to give protection to our future sons because many other genetic and environmental components are involved in liver diseases.