Medical research

Interview: How genetic data of Indian lung cancer patients can now help them get better treatment

Amit Dutt, who won the Shanti Swarup Bhatnagar Prize this year, on how Indian lung cancer patients can now get less harmful therapy.

Lung cancer is one of the leading causes of disease and death in India. About 63,000 new lung cancer cases are detected and about 52,000 people die of lung cancer every year in the country. As oncologists say, every cancer is different. Though lung cancer is often brought on by smoking tobacco the chances of getting lung cancer are influenced by one’s genes. Genetic mechanisms also determine how the incidence and progression of lung cancer in a certain population may be different from that in another population. The difference in these genetic mechanisms can determine how different patients need to be treated.

This year, cancer researcher Amit Dutt won the Shanti Swarup Bhatnagar Award for medical sciences for identifying genetic mutations that occur specifically in Indian lung cancer patients. Dutt is a principal investigator at the Integrated Cancer Genomics Laboratory located at the Advanced Centre for Treatment, Research and Education in Cancer that is attached to Tata Memorial Centre in Mumbai. He has a PhD in Plant Genetics from Jamia Milia Islamia University for the work carried out at the International Centre for Genetic Engineering and Biotechnology in Delhi and a PhD in Developmental Biology from the University of Zurich, Switzerland. He completed his postdoctoral studies in cancer genomics at the Broad Institute of Harvard and MIT and the Dana Farber Cancer Institute in Boston, United States. In 2010, he joined ACTREC at Tata Memorial Center where he started his own independent research group.

Significant proportions of lung cancer patients among Caucasian and East Asian populations were known to have a mutation in the epidermal growth factor receptor or EGFR gene. There was no data for the incidence of this mutation among Indian lung cancer patients, until Dutt and his team conducted an analysis. They found a 23% incidence of the mutation.

The significance of this finding is that patients with this mutation can be given targeted therapies to identify and destroy cancer cells carrying these mutations, instead of more broad-based chemotherapy that kills tumour cells and healthy cells and so is much harsher on patients.

Dutt spoke to Scroll.in about his research and how cancer genetics has the potential to revolutionise the way cancer is treated. Here are excerpts from the interview.

Could you tell us about the research done by your laboratory and how it can change the way lung cancer patients are treated in India?
My laboratory began with addressing a germane and basic deficiency in the field of cancer research.

Our work involving a large cohort of 1,000 odd patients establishes that while Epidermal Growth Factor Receptor or EGFR mutation are present in over 30% of East Asian and 10% of Caucasian lung adenocarcinoma patients, they are only found in about 23-25% of Indian lung adenocarcinoma patients. Similarly, mutation in a protein called KRAS are present at 60% lower frequency in Indian lung adenocarcinoma patients than compared to the Caucasian population.

So far there was no data on the frequency of EGFR or KRAS mutation in the Indian lung cancer patients.

Equipped with this information, we are in much better capacity to manage the disease. Lung cancer patients who have the EGFR mutation can be offered a targeted therapy called EGFR tyrosine kinase inhibitors. But, if the same therapy is offered to a lung cancer patient who does not have the mutation, it could have detrimental effects. Thus, the next challenge was to offer an affordable test to detect the EGFR mutations in our patients. As you know, the majority of patients treated for cancer at Tata Memorial Centre are not from a background where they can afford expensive treatment. We worked along with the clinicians and developed a protocol to detect EGFR mutations, which remarkably reduces its cost from $200 to $12 per test. This test is now being offered at the Tata Memorial Hospital in a routine manner, enabling and transforming the way EGFR mutation profiling is been carried out at an affordable cost.

Amit Dutt, principal investigator at the Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research and Education in Cancer.
Amit Dutt, principal investigator at the Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment, Research and Education in Cancer.

Your laboratory has also identified inhibitors to stall the progression of lung cancer. Could you elaborate on the therapy?
Our discovery of the dependency of lung cancer cells on Fibroblast Growth Receptor 1 or FGFR1 amplification in lung cancer squamous subtypes has been one of the major contributions made by Advanced Centre for Treatment, Research and Education in Cancer, in collaboration with researchers from the USA, which has been widely acknowledged in the field. More recently, we presented the first comprehensive landscape of actionable mutations in Indian lung cancer genome and presented the first systematic evidence that mutations of another gene – Fibroblast Growth Receptor 3 or FGFR3 – are present in 20 of 363 (5.5%) lung adenocarcinoma patients of Indian origin.

In true sense this finding could be a game changer in treating a subgroup of lung cancer patients as our study has also identified certain commercially available small molecule inhibitors, which can stop the mutated FGFR3 activity. Our test tube and animal model experiments have already established that.

Why is it vital to identify genetic mutations in cancer? Is targeted therapy better than chemotherapy and radiotherapy?
A major limitation of the current chemotherapy is its non-specificity to discern between a cancer cell and a normal cell. In a non-specific manner it destroys all dividing cells in the human body. A compromise dosage is thus used that could kill the maximum possible cancerous cells with minimal possible harm inflicted to the normal cells. However, the damage done to the normal cells very often has serious implications.

Targeted therapies, on the other hand, are designed to inhibit the function of specific molecular pathways exclusive to the tumor cells by interfering with their growth or spreading of the tumor cells with minimal or no effect on the functioning of the normal cells. Thus, identifying cancer-causing genetic alterations unique to the tumour cells is essential for the success of targeted therapies. Several unbiased genome based approaches are now possible, with the advent of next generation sequencing technology, that allows us to compare the genome of a tumour cell to the normal cells from the same individual to the highest possible of resolution of a single DNA base-pair.

Targeted therapy, or precision medicine, has several advantages over conventional treatment especially in improving the quality of life of the cancer patients, with the potential of reducing cancer as a chronic disease that can be managed by taking oral pills for an extended period of time with minimal side effects. However, as the field is in a state of flux, there are several impediments to overcome such as understanding the mechanism of how cancer cells learn to utilize alternative pathways to evade response to the therapy. In summary, I would say, targeted therapy may not replace traditional chemotherapy and radiation treatment but it certainly forms an essential part of the overall plan of attack to win over cancer.

Lung cancer cell during cell division. (Image: National Institutes of Health/Wikimedia Commons)
Lung cancer cell during cell division. (Image: National Institutes of Health/Wikimedia Commons)

You came to India after completing your second doctorate in cancer genomics in 2010. How easy or difficult it is to conduct research on cancer in India compared to the west?
With more than 10 years abroad in Europe and the US, leaving a prolific career behind in the west, I headed back to India to pursue my curiosity to study Indian specific cancer types that otherwise wasn’t possible if I would have stayed by in the west.

While the financial dent at personal end is huge, the funding to pursue one’s scientific experiments does not lag much behind in India at this point of time. If I compare the competitive funds I have generated for my laboratory in terms of scientific grants over the last six years, it is comparable to that of most of my colleagues in the west (not including their seed or startup funds, which are the most lucrative ones in the west). The funding agencies in India have become generous with initiatives such as Wellcome Trust/ DBT India Alliance as the game changer. Also, initiatives by the Department of Biotechnology and the Department of Science and Technology through their Ramalingaswami and Ramanujam fellowship programs have had a great influence.

What do you think needs to change in Indian academia to boost cancer research here?
The foremost need to boost cancer research in India is to create an ecosystem of collaborative interface between the clinicians and basic researchers. The success of Tata Memorial Centre model need to be replicated and expanded at much larger scale to bring clinicians and basic researchers together under the same administrative ambit, with defined intent to translate the findings from a basic research lab to the clinics. While India has no dearth of world-class clinicians, the number of established senior basic cancer biologists or clinician- scientist is comparatively much less. To fill this

adequate incentives for an individual’s career path with provisions for establishing state-of-the art infrastructure need to be carefully drafted to generate a pool of talented basic and translational cancer biologists with proven track record of international excellence.

Secondly, to ensure an effective amalgamation and generate a collective wisdom, we need an overall administrative overhaul. Most of the government institutes in India are director-centric. However, most director positions are awarded in honor of people’s life-time achievements, which essentially are administrative positions and requires less scientific acumen. In my humble opinion, this trend needs to be radically changed as it retards progress and makes research institutes “bureaucratic daftars”, which is detrimental to scientific progress. While every active effort should be made to retain and tap the wisdom of the senior scientists, enthusiastic younger minds in late 40s or early 50s with disruptive ideas should be encouraged for such administrative positions. These scientists would have more than 10 years to contribute at a stretch. A bunch of strong and visionary young administrative heads from the fraternity of scientists, with proven international standing and enterprising mindset, can transform the research face of India in no time.

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