Cancer: Precision medicine finds a new mantra – cure is inside the patient – India Today

He was a ruggedly handsome man in life: shirt unbuttoned, muscles rippling, cigarette dangling rakishly from his lips. He was unrecognisable in death: pinched, pale, almost skeletal. For those who knew him onscreen, there was shock and despair at the final terror of his illness. Vinod Khanna, one of the last screen titans of a generation, battled a lethal form of bladder cancer, resistant to chemotherapy, for six long years and finally succumbed on April 27. That very week, however, the world of science celebrated a "huge breakthrough": the discovery of a new drug based on malaria proteins that can dramatically reduce hard-to-treat bladder cancers.

Another breakthrough, another life. "It's finally here. A new ray of hope in the field of cancer. 'Nivolumab' for aggressive Hodgkin's lymphoma. Spread the word." Mamta Mohandas, 32, calls herself 'Actor. Singer. Survivor' on Twitter and posts messages of hope to her 495K followers. Her rising career graph in Malayalam and Telugu cinema, despite her seven-year-long fight against an aggressive lymph cancer, Diffuse Large B-Cell Lymphoma, is legend. Ever since she joined a clinical trial for an experimental drug in Los Angeles, USA, the southern beauty has been upbeat. "It's working for me," she informs her fans. "Brave girl", "love u", "jaldi aaja", they respond.

TIME OF BREAKTHROUGHS

It is the best of times, it is the worst of times, on the cancer front. Scientists continue to be baffled by the complexity and smartness of cancer cells: that they find ways to dodge even the most powerful therapies, that 'cancer' encompasses not one but hundreds of distinct diseases, that each individual cancer behaves differently, that two people with the same cancer, at the same stage, receiving the same treatment, can experience radically different outcomes. As US-based oncologist and Pulitzer-winning writer Dr Siddhartha Mukherjee says, "All cancers are alike, but they are alike in a unique way." With all that, cancer is catching up with heart disease as the leading cause of deaths globally, reports the World Health Organization. In India, the latest study based on the National Cancer Registry shows that there are 1.45 million new cases every year, a prevalence of over 3 million at any point of time, over 680,000 deaths a year. Although early detection saves lives, just 12.5 per cent Indians call on a doctor in the early stages.

But it's also a time of exceptional breakthroughs and innovations. No, there is no single death-defying magic bullet, but new generations of life-saving and life-extending 'smart drugs' are currently being developed and tested. At the root of all this is the idea that the cure for cancer is inside the patient. And the mantra in labs around the world is 'precision medicine'. That is, a line of treatment that is personalised to a patient's genetic make-up or molecular changes within one's tumour. Up until now, therapies have all been geared to treat cancer based on where it is located, say, in the breast, bladder or lung. Now, the shift is increasingly evident in finding precision medicine targeted at genetic glitches. On May 23, in a first, a cancer drug has won approval from the US Food and Drug Administration (USFDA) that can be given to anyone who harbours specific genetic abnormalities found in as many as 15 different types of cancers, all in patients for whom traditional treatment, like chemotherapy, has failed.

There has not been so much excitement as there is now since 2001, when one of the first cancer therapies to show the potential for targeted action, Imatinib, was approved. Thousands of clinical trials are humming with promising drug pipelines, many of which are being used by doctors to benefit patients. "It's an exciting time," says Dr Anil Suri, director of the National Institute of Immunology in Delhi and the man who discovered SPAG9, the cancer antigen to be used in India's first anti-cancer vaccine, now under phase II clinical trial in cervical cancer patients. "Cancer research is at the tipping point of major breakthroughs. Advances in molecular biology, next-generation gene sequencing, big data and innovative diagnostics are opening up a whole new world of possibilities."

THE PARADIGM SHIFTS

The war on cancer is now looking within, at the patient's own arsenal of weapons: genes, molecules and the immune system. The conventional regimen of surgery-radiotherapy-chemotherapy is slowly but surely giving way to targeted, personalised treatments and more intricate diagnostic tools. Combination therapies to keep cancers in check are being worked upon. The emerging field of cancer immunotherapy, or using the body's own immune system to help fight off the disease, is especially promising. Of the 30 new drugs for more than a dozen different types of cancers approved by the USFDA in the past one year, almost all are in immunotherapy. Indian scientists, too, are engaged in the battle to unlock the answers on how to prevent, detect and treat patients, in the best example of 'Make in India'.

A paradigm shift is taking place, with the approach moving toward a regimen where cancer may not have to be cured, but controlled, say, like diabetes or heart disease, explains Dr Mammen Chandy, director of Tata Medical Centre, Kolkata, and chair of the Human Genome Task Force of the department of biotechnology (DBT), Union ministry for science and technology. "With greater knowledge of the molecular genetics of cancer, we can study genetic mutations in a patient and target these with specific drugs," he says. A whole range of new drugs today can shrink and kill cancer cells without collateral damage. "We can precisely quantify the extent of the disease at diagnosis with better imaging techniques." The precision and accuracy of radiation technology make it possible to hit tumours with minimal damage to surrounding normal cells. "In several cancers, a patient can now pop a pill a day and live a normal life for many years. We are, thus, converting cancer into a chronic disease that one can live with."

LANGUAGE OF GENES

ATCG. ATCG. AGGCCTT. Oops, a typographical error. A tiny mistake can change the meaning of a sentence. What if there's a typo in your genes? Imagine a social network humming in each of your 37.2 trillion cells, with up to 100,000 genes talking to each other in a chemical code of four letters, A, T, C and G-to post, copy, tweak, repeat, adapt, modify messages and instructions constantly-for you to function. The proofreading tools inside cells correct some typos, junk many, but some get overlooked. And they fester. Like fake news on social media, they spread lies, sending wrong signals to other cells giving rise to a series of mistakes, sometimes profoundly altering the biology of cells. If 10 million cells repeat the same error, a tumour forms, as big as the head of a pin, and starts shedding bits of its genes into the bloodstream, like a trail of bread crumbs.

Francis S. Collins, geneticist and head of the National Institutes of Health, US, wrote in his book Language of God: A Scientist Presents Evidence for Belief: "Science reveals that the universe, our own planet and life itself are engaged in an evolutionary process. The consequences of that can include the unpredictability of the weather, the slippage of a tectonic plate, or the misspelling of a cancer gene in the normal process of cell division." With the Human Genome Project (HGP), a massive international effort to unlock the secrets of our genetic script, taking off in 1991, cancer research got a massive leg up. Genes could be isolated from cells in pure form, analysed in full detail, multiplied manifold in the lab, changed at will. They could also be used to discover defects in the blueprint of one's body and to take proactive measures to stem the consequences, most significantly, the processes that give rise to cancers. The 2015 Nobel Prize in Chemistry was awarded to three scientists for explaining precisely how cells make mistakes, repair those and predispose people to cancer when repair mechanisms fail.

THE NEW STRATEGY

Now cancer researchers from Johns Hopkins University and Harvard Medical School have published a new study on the biology of cancer cells (Science, March 2017) that has kicked up a new debate. Based on the mathematical modelling of 32 types of cancers from 69 countries, they argue that about 66 per cent of cancers occur due to random mistakes during cell division, with only 29 per cent due to environmental factors (say, smoking or sun exposure) and 5 per cent to inherited genetic traits. These percentages, however, vary from cancer to cancer. In some lung tumours, environmental factors account for 65 per cent, while in prostate, brain and bone cancers, more than 95 per cent are due to random errors in cells. The study, despite the fears that its conclusions would undercut prevention efforts, has evoked the need for a new strategy, one that would emphasise early detection and treatment, in addition to prevention.

The problem with early detection is that when tumours form, they do not shed enough of a "bread crumbs trail" that can be picked up by CT-MRI-PET scans or by needle biopsies for possible malignancy. But what if cancer can be detected at such an early stage? The idea of a simple blood test as an alternative has come up recently. In India, Bengaluru-based genetic diagnostics company, Strand Life Sciences, has started offering the first phase of liquid biopsies: a simple, non-invasive diagnostic test using circulating tumour genes in a patient's blood, the first such test in India. "In the case of cancer patients, such blood tests can provide early information about tumour presence, relapse after therapy and response to therapy," explains Dr Vijay Chandru, CEO of Strand, who launched the test in April in association with the Mazumdar Shaw Centre for Translational Research, also in Bengaluru.

But what about therapies? Ever since former US president Jimmy Carter announced in 2015 that he was free of a deadly form of skin cancer after receiving surgery, radiation and "a new kind of treatment", he became a poster boy for the exciting new field: immunotherapy. Dr Suri explains that normal cells of the body die when they are not needed, are damaged, or are infected with virus, bacteria, parasites or fungi. "The immune system, the body's first line of defence, keeps track and as soon as it detects anything abnormal or unknown, it attacks and kills it," he says. But cancer cells trick the immune system into not recognising them as a threat. "This allows the tumours to grow and spread," he says. In immunotherapy, the immune system is enlisted to attack and force cancer cells to kill themselves.

MAKE IN INDIA

Where does India stand in all this? Indian cancer patients have been the key partners in discovery of cancer antigen SPAG9, which is being used for personalised intervention by modulating the immune response, says Dr Suri. "Most new technologies are available in the country," says Dr Thangarajan Rajkumar, head of molecular oncology, Cancer Institute (WIA), Adyar, Chennai. "It is the cost of the newer therapies that is the major impediment. But that's true not only for India. Even some developed countries are finding it difficult to provide cancer care to people because of the prohibitive costs." The institute is conducting clinical trials of India's first therapeutic anti-cancer vaccine, SPAG9, in collaboration with Dr Suri and funded by the department of biotechnology and department of science and technology, Government of India. "Rather than directly attacking cancer cells, this therapy involves priming a patient's own immune cells to fight the cancer," he says. "Our immune system prevents most of us from developing cancer, but once cancer develops, the immune system becomes very subdued. The newer immunotherapies are addressing precisely this area, with great results."

With cervical cancer rising dramatically among Indian women-nearly 23 per cent of all cancers in women and over 100,000 deaths a year-it might just be a game-changer. One of the patients included in phase I of the clinical trials at the Cancer Institute, whose persistent cervical cancer had spread to the lungs even after radiotherapy, has been disease-free now for over nine years. The vaccine is being manufactured at a world-class industrial facility, owned by Biocon. Researchers at the institute have also developed a simple kit for cervical cancer screening, a biomarker panel for early diagnosis of ovarian cancer and a therapy to inhibit an aggressive bone cancer, Ewing's sarcoma-all awaiting further verification.

"There are major institutions across the country working on basic, translational and clinical research as applied to cancer," says Dr Rajkumar. New and potentially therapeutic molecules have been identified at the Indian Institute of Science, Bangalore, he points out. A multi-centre study under Professor Partha Majumdar of the National Institute of Biomedical Genomics at Kalyani, West Bengal, and Dr Rajiv Sarin of Tata Memorial Centre's ACTREC (Advanced Centre for Treatment, Research and Education in Cancer) in Mumbai, are doing promising work in cancer genomics. Truly cutting edge research may be taking place only at a few centres, but at hospitals and laboratories across the country, innovative molecular genetic tests, technology and techniques are being used. From next generation sequencing (NGS) technology to detecting genetic change driving a cancer, molecular diagnosis and monitoring, best-in-class radiotherapy equipment, new small molecules to specifically target the tumour cells, stem cell transplantation, hormone therapy to cellular therapy, it's all happening.

RUSH FOR DRUGS

In December 2015, when Jimmy Carter called a press conference to announce that he had been cured of his cancer, the 'breakthrough' immunotherapy drug, Pembrolizumab, sold by pharma giant Merck as Keytruda, got a new moniker, "the president's drug". Keytruda, along with Bristol-Myers Squibb's Opdivo (Nivolumab), is one of a growing number of 'immuno-onco' drugs that unleash the body's immune system to fight malignant cells. Keytruda and Opdivo, effective against some forms of lung, skin, kidney and other cancers, are set to launch in the Indian market soon. Prohibitively expensive, above Rs 1 crore for an entire treatment, the drugs may not be for the general public. But they are shaping up to be the biggest blockbusters for the global pharma industry.

Most patented medicines are unaffordable to the average patient in India, even if priced lower than their western counterparts. But Indian companies, with their track record in generic drugs, are emerging as strong global players in the biosimilar (or exact copies of biological medicines that are already approved) segment of molecularly targeted cancer drugs. From Biocon, Cipla, Aurobindo Pharma, Dr Reddy's Laboratories, Intas Pharmaceuticals to Hetero Drugs, they are all expanding their biosimilar portfolios. Roche has teamed up with Emcure Pharmaceuticals to manufacture and sell its breast cancer drug, Herceptin, at a reduced price in India. "Biosimilars have made cancer treatment affordable to the middle class, and most companies have compassionate usage programmes," says Dr Chandy.

Immunotherapy is emerging as a 'sweet spot' among smaller research companies as well as investors. Biotech company Aurigene Discovery Technologies of Bengaluru has got into off-licence deals with global pharma companies like Curis, Orion and Pierre Fabre for its novel immunotherapy molecules. Delhi-based Curadev, a drug discovery company, has entered into collaboration with Roche. Ratan Tata, chairman emeritus of Tata Sons, has invested an undisclosed amount in biopharmaceutical firm Invictus Oncology, Delhi, to develop a cancer technology platform.

THE NEW NEW

Jugnu Jain, molecular geneticist, cell biologist and inventor with three patents, returned to India from the US in 2011 and realised, surprisingly, that India did not have a human biobank. Globally, there are over 350. "Leftover tissues from surgery or diagnostic procedures, say, cancer tissue, blood or urine, are precious," she says, "highly sought after worldwide by researchers, diagnostics, biotech and pharma companies" to validate their drug candidates in target patient population samples, prior to launching clinical trials. They spur research into diseases: from identifying risk factors to diagnosing early, screening family members at risk to customising a patient's treatment to improve outcomes. Results from such studies can boost, sometimes even replace, the need to test new drugs. Ultimately, the war against cancer depends on cancer research.

Jain co-founded a health science firm, Saarum Innovations, and finally set up India's first commercial biobank and personalised medicine company, Sapien Biosciences, a joint venture with Apollo Hospitals, in Hyderabad in 2013. The work is in full flow. Imagine live cancer cells growing in the lab. Study those to understand the complexity of a tumour, screen new drug candidates, use cultured cancer cells as models to investigate the changes that may have caused cancer, or its spread, or its resistance to a therapy. There are many other applications of fresh samples in a biobank, she says. "Several companies in China have built thousands of cancer models in biobanks, which are being used by pharma companies to screen drug molecules. We can too."

With excitement building around the innovative research in the cancer space, it's hard not to think of a cure. "But to conquer a complicated, costly and devastating disease such as cancer, many more major scientific breakthroughs are needed," says Mukherjee. Medicine still needs to catch up. The battle still relies largely on three brute-force weapons: surgery, radiation and chemotherapy. Cancer cells are subtle and smart. So the treatment needs to be more sophisticated. And bringing in the latest and the best are gene therapies. He points to an important development that took place in 2013: a unique technology, the CRISPR-Cas9 system, currently the most versatile method of genetic manipulation. It's somewhat like conducting a molecular surgery on genes: remove abnormal sequences, replace them with normal ones, pull out genes that give an advantage to cancer cells. The idea comes from some types of bacteria that have a built-in gene editing system against invaders, say, a virus. "Your genome has three billion letters, ATCGs. If it were to be written down, it would be 66 full sets of Encyclopaedia Britannica," he explains. "What if you can take out a letter, one that predisposes you to cancer, erase or tweak it to your advantage?"

Can that be the future of cancer? Or, perhaps, our future without cancer?

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Cancer: Precision medicine finds a new mantra - cure is inside the patient - India Today