Scientists at the Indian Institute of Science (IISc) have discovered a new molecule that, they say, could potentially lead to an anti-cancer drug, which may help reduce the dosage of current treatment methods like chemotherapy or radiotherapy. The molecule, aimed at killing cancer cells by blocking their DNA repair mechanism, was successful in removing tumours in mice during laboratory experiments, say the researchers.

The team is now evaluating offers to collaborate, including one from a US-based pharma company, for further research and clinical trials. Typically, the road to market for a new molecule can take at least a decade.

The molecule named SCR7, developed chemically using bioinformatics tools, was found to be effective in the case of carcinoma, the most common form of cancer in humans, but did not have any impact on leukemia or lymphoma, says Sathees Raghavan, associate professor at IISc?s department of Biochemistry, who led the research published in the journal Cell in December. The paper?s first author Mrinal Srivastava is a PhD student at Raghavan?s laboratory and researchers from institutions, such as the KLE University College of Pharmacy and Institute of Bioinformatics and Applied Biotechnology (IBAB) in Bangalore and the Mumbai-based Advanced Centre for Treatment, Research and Education in Cancer (Actrec), also contributed to the study.

Cell damage in mammals such as a break in the double stranded DNA evokes two types of natural repair processes called homologous recombination and non-homologous end joining (NHEJ). The latter is a more widespread method of repairing double strand breaks in which the DNA uses a protein called Ligase IV to bind the strand. A break in the DNA double strand can be a lethal form of damage and could lead to a tumour if it is not properly repaired.

?We have designed an inhibitor that can bind to the protein that is responsible for NHEJ repair. The idea here is if you can block the DNA repair specifically in cancer cells, that will result in the accumulation of DNA damage in these cells and kill that cell,? said Raghavan. ?We are targetting this inhibitor on to Ligase IV so that the protein cannot bind to the DNA for repair.?

Following the tests on cancer cells, the team studied four different tumour models in mice. ?What we found was that out of the four cases, three showed very good effect. It resulted in the regression of the tumour in a time dependent manner and about 3-4 fold increase in the lifespan of the mice,? said Raghavan.

Without treatment, the mice would have died in 45-55 days, but treating the tumours with the inhibitor molecule helped at least 50% of them live more than 350 days without side-effects, the study said. ?The best part of our finding is, if it is successful in trials, it can improve radio and chemotherapy, which is generally used all over the world. Who knows, maybe our molecule can bring down the dose of radiation and that will have a lot of advantages with respect to patients,? added Raghavan. Typically, ionizing radiation and several chemotherapeutic agents induce DNA breaks to cause cell death and Raghavan?s lab found that SCR7, when co-administered with the radiation or chemotherapeutic agents, potentiated their effects many fold.

In India, an estimated 5,55,000 people died of cancer in 2010, according to a study by the Centre for Global Health Research in Toronto along with the International Agency for Research on Cancer (IARC), an arm of the World Health Organisation. Globally, cancer accounted for 7.6 million deaths in 2008, or around 13% of all deaths that year. An August 2012 factsheet of the IARC projected that the burden of cancer will likely increase to 22 million new cases each year by 2030, going by the recent trends in major cancers.

While cancer research globally looks at different approaches to killing cancer cells, the IISc study is among the few to demonstrate the role of a DNA repair inhibitor, says experts.

?It looks very promising and it will be quite exciting if it can go to clinical trials. But they still have to do a lot of biological studies to understand what is happening in the animal models,? says Rita Mulherkar, scientist at Actrec. A key area of the global research into cancer cure is kinase inhibitors, which target the enzyme involved in the cell proliferation pathway, she added. ?It is the first approach which actually validates this concept in non-homologous end joining. The beauty of this paper is that they have shown that shutting down an enzyme can actually become a handle in the fight against cancer,? says Sagar Sengupta, a scientist at the Delhi-based National Institute of Immunology.

Raghavan says that the discovery of the molecule opens up several lines of study and can perhaps even lead to a better molecule. ?Obviously, we are going to look in different directions to see how we can take this to the next level,? he says.

Statfacts

Crucial breakthrough

* The new molecule, discovered by IISc scientists, is aimed at killing cancer cells by blocking their DNA repair mechanism

* It could potentially help reduce dosage of current chemotherapy and radiotherapy methods

* In India, an estimated 5,55 000 people died of cancer in 2010, according to a study

* Globally, cancer accounted for an estimated 7.6 million deaths in 2008