Ever since Nixon declared the “War on Cancer” in 1971 we have reported progress in fighting disease in the public domain as though we are slowly capturing ground against a nefarious but mostly unknown enemy. The trials and tribulations of the pharmaceutical industry, a financially-strained reimbursement landscape and profound new insights into human disease read like a CNN or Al Jazeera newsfeed from the world’s conflict hot spots.
Wins here, losses there, ground captured and … ultimately defeat resoundingly delivered.
In truth – at the risk of sounding trite – “Tricky Dick” coined a concept far closer to reality than he probably imagined. The problem is that the pharmaceutical industry has been slow to grasp a basic military concept : if you want to surgically fight an enemy, you have to have the best intelligence money can buy. Armed forces don’t throw billions of dollars’ worth of hardware at unknown insurgents – they prefer to deploy force rationally, economically and in a calculated fashion on the basis of all known information about the enemy. “Total War” is not the cornerstone of modern warfare – nor should it be for modern medicine.
The first generation of cancer therapies were essentially just toxins. They were the military equivalent of a nuclear strike – and not some kind of clever tactical nuke – but a kind of Hiroshima-style warhead (with no insensitivity to our Japanese brethren intended). The “diagnosis” of battle was whether the patient died, whether skin turned yellow due to organ failure, whether cardiac arrest seemed imminent. The goal was to simply dose the patient as far as possible in the hope that the “bad guys” responded and that somehow the patient survived.
The second generation of cancer therapy was a bit like CIA intelligence. You are informed, to a first approximation, where the target is but you don’t know really to what extent – and whether a single airstrike or a 3 year war is going to solve the problem. Drugs like Herceptin® (Genentech/Roche) are given to patients on the basis of a biopsy from a primary breast cancer or tumor resection specimen. There have been multiple very good academic papers that have illustrated the wide variability of target (Her2) expression in breast cancer tissue specimens, the difficulty in predicting response and the fallibility of pathology lab protocols. Arguably (patent expiration around the Her2 franchise aside) Roche produced a second-generation product (T-DM1) on the premise that diagnostic medicine wasn’t good enough to capture the full possible patient responder range – effectively the development of a more potent tactical “nuke.”
The problem is that patients don’t typically die from primary cancer, they die from metastatic disease. So therefore assessing the status of the “battlefield” on the basis of a primary cancer lesion is like sniffing the air in Baghdad to glean intelligence about skirmishes in Bazra, 600kms away. In the case of diseases where metastases are very heterogeneous and have distinct biochemistry, it’s about as useful as studying cultural characteristics of Thais living in Bangkok to formulate a strategy to contain Buddhist-Muslim ethnic violence in Southern Thailand or even Myanmar.
Kind of similar, but mostly different.
For the “third generation” of cancer therapeutics, we live in an exciting and promising world where we increasingly understand how to deliver targeted molecular medicine – the “strategic strike” of medicine. Hit the target, but minimal “collateral damage” to surrounding tissues and important organs. Even better, we are now starting to understand that inflammation and the immune system is essentially at the heart of almost all human diseases, whether it is cancer, cardiovascular disease or dementia. Sure there is genetics – and epigenetics – but this is just the battle plan of the enemy. We are starting to understand who the combatants are, and they are often just our own immune cells gone rogue.
In fact, they are a lot like the “sleeper cells” of Hollywood fame, insurgents that are invisible to the immune system but slowly go about undermining our health in the form of arthritis, Crohn’s disease and cancer. They are also a lot like an Al Qaeda terrorist cell – they may follow the destructive mission of the Supreme Leader (the primary cancer) but they will cause terror in their own unique, adaptive and sometimes unpredictable way.
So, to get back to the intelligence analogy, to direct our modern “war on cancer” (borrowing Nixon) we need to have the best intelligence money can buy. We need to have the satellite systems tracking the movement of the enemy and “friendly” troops alike. We need to have the medical technology equivalent of the Predator and Reaper drones circling the skies, watching everything and deploying small but powerful forces in highly directed ways.
This is why diagnostic medicine – and particularly molecular imaging – is so important. This is the crux of a new kind of medical intelligence that will direct the next generation of engineered therapies, both molecules and cells, into “battle”. Molecular imaging is the “eyes and ears” of the oncologist and immunologist “on the ground” inside the patient. Major late stage drug development failures have [slowly] woken up the pharmaceutical industry to the fact that throwing billions of dollars at drug development, without superb clinical intelligence and “companion diagnostics”, is not only wasteful but ineffectual.
Ultimately it also ends up bankrupting the healthcare economy with a prolonged and multi-front war.