Pioneering cutting edge cancer research from Bangladesh

A recent article published on the famed Nature magazine titled "The RNA and protein landscape that could bring precision medicine to more people" spoke about the prevalence of genomics in cancer research. While genomics is useful in trying to find an effective solution to cancer, it is riddled with multiplicities of complex problems such as the development of gene therapy and finding out the mutations that enable the spread of cancer.

The article quoted Dr Sajib Chakraborty, a computational biologist at the University of Dhaka has been working with his colleagues at the University of Freiburg to find out new horizons in the treatment of cancer, which in reality remains one of humanity's gravest illnesses.

Toggle sat down with Dr Sajib this week to talk about his research and more.

T: What is the current stage of cancer research in Bangladesh?

Dr Sajib: The survival rate of cancer patients, especially for childhood cancer, is much lower in the low/middle-income countries such as Bangladesh, compared to developed countries. The reason is multifaceted--lack of molecular diagnosis, limited access to effective cancer drugs, affordability, to name among few.

We are lacking far behind in identifying the molecular causes of cancer in Bangladesh, where the developed countries have achieved tremendous success and generated a wealth of molecular data from cancer patients which are proving to be crucial not only in untangling the complexities of cancer but also in determining the effective drugs for cancer patients.   

T: How effective is gene therapy in the fight against cancer?

Dr Sajib: Gene therapy typically refers to replacing a faulty gene with a functional copy of the same gene. It has been proved to have benefits when applied to a genetic disease caused by a faulty copy of one particular gene. For example, we can consider the disease - Cystic Fibrosis (CF) caused by the faulty copy of a single (CFTR) gene. By principle gene therapy showed much promise to cure genetic diseases such as CF.

In contrast, cancer is entirely different in many respects. For instance, multiple genes are responsible for cancer. Moreover many symptoms of cancer cannot simply be explained by genes alone.

Genes, RNAs, and proteins are like three pillars of any cellular functions. Cancer initiation depends on the multiple genetic mutations but the effects of these mutations are far-reaching and can modify a great number of RNAs and proteins without causing a direct mutation in their respective genes.

Therefore, by analysing genes we can only understand what genetic mutations caused the cancer initiation in the first place but if we want to understand how cancer evolves over time and becomes metastatic we need to focus on RNAs and proteins as well. Proteins are particularly important in the fight against cancer because they can directly serve as biomarkers and targets for anti-cancer drugs.      

T: How successful have cancer drugs been so far in mitigating the spread of cancer in general?

Dr Sajib: One of the major factors that decrease the success of anti-cancer drugs is the resistance developed by cancer patients. Some patients just become unresponsive to certain anti-cancer drugs as time progresses. In other cases, the anti-cancer drugs may be successful to restrict the cancer spread and may shrink the tumour size, but more often than not after an initial phase of success, cancer may reappear

The success of anti-cancer drugs broadly depends on the clinical stages of cancer. If we can detect cancer in the early stage, a combination of surgery or radiotherapy with anti-cancer drugs can have a powerful effect to combat and destroy the cancer cells.

However, the same drug can become less effective when administered in the advanced or late stage of cancer. Physicians rely on a trial and error basis when it comes to administering anti-cancer drugs. All these factors boil down to the major challenge in cancer treatment.

However, we are now beginning to understand why this might happen and what changes from early to late stages of cancer. We now know that as the cancer progresses, it acquires a variety of different genetic mutations that contributes to the alteration of a large number of RNAs and proteins making it immune to the body's natural defence system as well as certain anti-cancer drugs.

These acquisitions of mutations over time modify a number of molecular pathways in the cancer cells so that it becomes resistant to anti-cancer drugs. Molecular pathways are like a network of proteins that act in concert to achieve a certain biological function.

So far we have generated evidence suggesting that different molecular pathways are switched on and off depending on the stage of cancer. Therefore we need to administer specific drugs that can inhibit those pathways at a particular stage of cancer.

In essence, we are proposing stage-dependent anti-cancer therapy. For instance, 5-fluorouracil (5FU) is an anti-cancer drug that is normally administered to colon cancer patients.

We now have preliminary data that supports the theory that molecular pathways that confer resistance to 5FU are switched on in the late stages of cancer.  

T: What are the other exciting findings from the world of cancer research?

Dr Sajib: We are lucky to witness the post-genomic era (after the completion of the human genome in 2003). We have witnessed tremendous growth in techniques to analyze DNA, RNA, and proteins. Equipped with these cutting edge techniques, cancer research is moving rapidly. 

Experimental scientists and clinicians worldwide are generating a massive amount of molecular (DNA, RNA, and protein) data from a huge number of cancer patients with the aim to better understand the intricate mechanisms of cancer.

In this endeavour, the computational biologists are playing a pivotal role in analyzing the huge amount of data in a biologically meaningful manner. For instance, by developing a mathematical algorithm, Dr Andrea Califano at Columbia University, USA and his team identified the molecular pathway that is responsible for developing resistance against the drug trastuzumab (Herceptin) in breast cancer patients.

The algorithm also predicted that blocking the pathway with another drug ruxolitinib may overcome the resistance. The combination therapy consisting of these two drugs (trastuzumab + ruxolitinib) is now under phase II clinical trial.

Another exciting area of cancer research is immunotherapy which acts by augmenting the body's immune response against cancer cells.

However, the challenge of immunotherapy is that all the patients receiving immunotherapy do not respond in the same way. Nearly half of the patients remain unresponsive to immunotherapy. Recently, Prof. Matthias Mann at Max Planck Institute of Biochemistry, Germany and his team identified a pathway that is associated with higher immunotherapy response in skin cancer patients.

My team in collaboration with the University of Freiburg, Germany is also working on identifying such molecular pathways that can alter the response to a particular anti-cancer drug.

So far, what we saw was that these molecular pathways are not static rather show dynamic behaviour over time. The pathways become switched on and off with the different cancer stages. Therefore drug targeting a particular pathway may become ineffective over time when the pathway is switched off.

Overall, aided by computational and mathematical models, cancer research is heading in the right direction, and in near future, we may see the fruitful outcome which may lead to early diagnosis and effective therapy development for cancer.     

T: What are its technological barriers?

Dr Sajib: One major challenge is the restricted availability and high cost of the molecular diagnosis of cancer. In Bangladesh, molecular testing is not widely available and it costs a significant amount which raises the question of affordability.

However, I believe with the advancement of technology, these testing will become pervasive at the same time cheaper.

The second challenge is the skilled manpower that is required to perform widespread molecular testing. This certainly is achievable as we have seen for Covid-19 molecular testing in Bangladesh.

Graduate students with a background in Biochemistry, Molecular Biology, Microbiology and Biotechnology can certainly meet the requirement of skilled manpower to perform widespread molecular testing for cancer.

Finally, the clinicians should work closely with scientists to facilitate the molecular diagnosis of cancer patients.