Understanding cellular mechanisms opens up new therapeutic routes against colorectal cancer

Anjali Vaidya

Study reveals potential genetic target for future drug therapy.

Researchers at work in Bushra Ateeq's lab at IIT Kanpur
Researchers at work in Bushra Ateeq's lab at IIT Kanpur  (Photo: Bushra Ateeq)

We will never have a universal cure for cancer,” in part because there is no single type of cancer to cure. Cancer can result from many different kinds of breakdown in the body’s regulatory mechanisms, and in most cases we cannot pinpoint the cause closely enough to attack the problem at its root. However, research continues to improve our toolbox of cancer-specific therapies. Recent work by an Indo-US collaboration, involving researchers at the Indian Institute of Technology (IIT), Kanpur and the University of Michigan (UM) at Ann Arbor, has identified potential underlying cellular mechanisms for a sub-type of colorectal cancer, which may in turn give us new therapeutic routes to target the disease.

Colorectal cancer is one of the most common types of cancer diagnosed worldwide, and also one of the leading causes of cancer-related death. We already have targeted therapies approved for colorectal cancer patients, but these show poor response in over 40% of cases, correlating with two genetic mutations in KRAS and BRAF genes, frequently found in colorectal cancer. In their search for alternative therapies for these sub-types, the researchers at IIT Kanpur and UM Ann Arbor focused on one particular abnormality found in an overlapping subset of colorectal cancer cases. Many cases of colorectal (as well as pancreatic, lung, breast and prostate) cancer show over-expression of SPINK1, a gene that encodes a protein whose multiple functions include averting apoptosis, or cell death.

Correlation of SPINK1 over-expression with cancer is far easier to prove than causation, however, and when searching for treatments it is primarily causation that matters. Thus the researchers embarked on the arduous process of trying to find out how exactly SPINK1 might be linked with the underlying mechanisms of colorectal cancer. Searching for the gene’s functional effects within colorectal cancer cultures that showed SPINK1 over-expression, they found that blocking the gene’s expression reduced cancer proliferation while enhancing its expression had the opposite effect. They discovered, furthermore, that SPINK1 might act by suppressing the expression of Metallothioneins. These are proteins involved in balancing cellular zinc nutrition — or homeostasis — essential for normal function and can increase the responsiveness of cancerous cells to chemotherapy. Targeting the SPINK1 gene therefore has the dual effect of reducing SPINK1 protein levels while increasing the expression of Metallothioneins, making the cells far more sensitive to drug therapies.

Much still remains a mystery, however, says Bushra Ateeq, senior author on the study and Assistant Professor and Intermediate Fellow of the Wellcome Trust/​DBT India Alliance at IIT Kanpur. How precisely does SPINK1 over-expression exacerbate cancerous growth? And how do Metallothioneins have an ameliorative effect? Although we know their effects, the full story of these proteins and their interactions is not yet available to us. The mechanism behind this phenomenon is poorly understood and demands further attention,” says Ateeq. 

Developing a fuller understanding of the regulatory pathways involving SPINK1 and Metallothioneins could also have implications for many other types of cancer. We are exploring regulatory mechanisms that are involved in SPINK1 over-expression in prostate cancer,” says Ateeq. In collaboration with medicinal chemists, we are also planning to screen small molecule inhibitors against SPINK1.” The path from cell culture models to human clinical trials can be long, but the group is hopeful that targeted therapies that reduce SPINK1 expression may one day be able to help certain types of cancer patients where other treatments have failed.

Written By

Staff Writer, IndiaBioscience (March-August 2015)