Cancer is responsible for one in every six deaths worldwide. A conservative estimation from the American Association of Cancer Research (AACR) suggests that by 2030 the number of cancer patients worldwide will increase to 22.2 million, of which 13.2 million will die. What makes this disease worse is the emotional and economical toil it brings forth, crippling families and livelihoods. Paradoxically, the healthcare system has never been in a better position to take the lifesaving cancer science forward with the advent of cutting edge pharmacology, novel detection systems and various private public partnerships.
To understand the effectiveness and breadth of cancer treatment, its successes and failures, one needs to break down cancer into four steps: a) the disease initiation, when some cells go rogue and keep on multiplying; b) disease progression, when further genetic defects build up on these rogue cells expediting their growth; c) spreading of the rogue cells from one part of the body to another, a phenomenon called metastasis; and d) the ability or on this case the inability of the body’s defence system to detect and kill these rogue cells. Historically all previous treatments were either chemotherapy or radiotherapy that would kill all growing cells, the good or bad, thus being toxic and mostly not effective over a period of time. Then came targeted therapy that addressed the genetic defects driving cancer growth (step b), followed by immunotherapy that gave a boost to the body’s immune system (step d) enabling it to detect and kill cancer cells.
The biggest failure of all these treatments were that none were able to prevent or delay the spreading of cancer, metastasis, something that eventually kills 90% of all the cancer patients. Also, the approved state of the art personalized medicines were only able to increase progression free survival by a modest average of four to six months. Cancer medicines are toxic, responsible for inducing cancer, heart attacks, septicaemia, liver and renal failure, to name a few. Most importantly, no matter how effective these medicines were at the beginning of treatment, patients would eventually become resistant to them, within six months.
This phenomenon of acquired treatment resistance could be attributed to the fact that cancer is an evolutionary disease, where the cancer cell live by only one rule, survival of the fittest! Whenever they face new treatment and death, they genetically modify themselves and select another form that can bypass such treatments and beat death.
The main reasons behind cancer cells’ success in bypassing treatment and acquiring resistance can be attributed to two facts: 1) treatment was mostly targeted towards one specific target and 2) cancer cells are rapidly dividing, therefore selecting for resistance very rapidly. If one can address both these features and bring in a new paradigm of cancer treatment, its chances of success in beating the disease will exponentially increase. Moreover, if this new method can be applied to target cancer metastasis, it would take down two birds with one stone, achieving sustainable cancer remission and preventing any further spreading of the tumor, thus giving life a second chance.
This is however, easier said than done. World discovery landscape in cancer, with the advent of human genome sequencing, have become specialized and personalized, which have also increased the cost of drug development. From an era of 1970, when a billion US dollar would bring in 10 new drugs to the market we have come to a time when it takes more than 2 billion dollar to bring one single drug into the market. It is postulated that by 2020, the pharma industry will earn 1 dollar for every dollar it had spent, thereby compounding the fact that the time for traditional drug discovery is over. Focus for big pharma has definitely shifted from in-house research to in-licensing, enabling small biotech’s to come up with focused problems and solutions, wrapped in innovation. One can compare this to the success of guerrilla warfare from the traditional full-fledged wars, where the surprise element of the guerrilla warfare is mimicked by innovation in discovery.
The Indian drug discovery companies, albeit not having the deep pockets like their western counterparts, could not afford billions of dollars for discovery. They therefore focus on generic me-too and fast-follower approaches. The more adventurous ones did try their hand in discovery, but instead of focusing on novel first in class targets, they would work on targets that had some proof of concepts, that is targets that have at least progressed to phase 1 clinical trials in the west. The good side of this was if the company was successful in identifying something against that target, it could try to out license it. The bad part was since they were following something that had proof of concept, there were multiple other players already in the field thus diluting their chances of success. The ugly part of this was if the target failed in clinical trials, then even if the Indian company have had something around it, there would be no takers, as interest on that target had taken a hit. Caught in this conundrum of to-be or not-to-be, Indian discovery found it safer to keep themselves limited in the space of generics and biosimilars, thus forgoing innovation and inspiration for safer return on investments.
As a result of this, some lifesaving cancer drugs that have made substantial impact in the west, have no takers here in India. Sadly, this is only because they are too expensive. Enzalutamide, a drug approved for castration resistant prostate cancer, significantly increases life span by at least 6 months, but costs US$ 60,000 for a complete treatment (eight months) and is available in India for 3,35,000 INR per month! The lack of innovation has ensured that new cutting edge medicines will remain out of bounds for the average Indian diaspora.
The solution to this problem cannot be discounted medicine, which is a noble but non-viable model. India needs to make in India, its own drugs that will not only seal the gaps against cancer treatment, e.g. metastasis, but also offer sustainable remission, all in an affordable price-tag.
Is India ready for this challenge? What do we have now that we did not have a few decades earlier?
With the advent of the contract research organizations (CRO) in India, big pharma brought their scientific problems to collaborate with Indians, exposing Indian scientists to the high experimental standards of the west, educating and training them in the drug discovery process. For the first time, Indian scientists were exposed to the idea of what it takes to pursue novel first in class targets, how to mitigate risks and what questions to ask. The Indian CROs not only successfully created a workforce that was as good as international standards scientifically, but was also trained in all other aspects, from following the best safety practises to maintaining the highest standards of data integrity.
The success of the CROs created a demand for younger and well trained workforce, and as a result highly trained Indian scientists, returned from the west and joined Indian CROs in India. These people were motivated and did not carry the baggage of past failures or prejudices. They were quick learners with high self-belief and passionate about the quality of science that could be achieved in India. The simultaneous maturation of the Indian start up ecosystem with government grants such as BIG, and private public ventures, along with the foray of venture firms have successfully integrated this transition of India from service to innovation. Though it is early days, one can definitely see a clear picture emerging with multiple start-ups registering themselves and working in incubators. With the availability of all sorts of expertise from cell and molecular biologists to disease biologists to computational biologists, innovation can be achieved by collaborating between various disciplines with out of the box ideas.
The first targeted therapy in cancer, imatinib, was approved in 2001. Its target was characterized in 1980. The first immune therapy in cancer, ipilimumab, was approved in 2011. Its target was characterized from 1992. It takes two decades to come up with a successful first in class therapy, so if we are serious about targeting cancer metastasis in the near, we need to start now!
For a change, India can be the flagbearer of the new era of medicines in cancer. Let’s do it!