Ever since DrugBaron studied biochemistry at the end of the 1980s, one question about cancer has always perplexed him: why can we induce almost complete remission and yet the cancer can come back stronger and invariably kill the patient? The answer now, as then, has always been selection of the rare, resistant mutant.
But DrugBaron was always left with a nagging doubt. Two observations seemed to call that obvious and simple answer into question.
Firstly, for the most part that is not what we see with infectious agents. Even viruses, which share with cancer cells a short generation time and a ready ability to mutate, can usually be cured as long as you hit them hard – because the chances of a resistant variant existing in the population is quite low. As long as you don’t give them time to find one over many generations, you can eliminate the infection. Since tumours typically have a much smaller cell population size than an infection, it follows that cancer should be easier to cure than it is.
Secondly, some cancers, such as some leukemias can be cured almost every time, while others, such as the brain cancer glioblastoma, are almost invariably lethal. Yet there is no obvious association between mutation rate or the cancer cell population size and tractability of the cancer type.
It’s hard to put a finger on it, but it has always felt like a key part of the puzzle was missing.
And then, a few years ago, DrugBaron was sitting in a bar in Cambridge, UK, enjoying a drink with my friend and colleague Professor Miro Radman, when in the space of an hour he suggested to me exactly why some tumours were essentially invincible. The missing piece, it turned out, was the ability of cells to form networks.
For sure, I was aware that cells often formed connections with each other. Indeed, skeletal muscle is made up of giant syncytia formed by the complete fusion of many individual cells that give up their autonomy to work together. In other tissues, the cells remain separate but communicate through numerous channels, such as the gap junctions between cardiac cells that ensure the contraction during a heartbeat is carefully co-ordinated. But, like most people, DrugBaron had never considered the full implications of such cell networks before – and certainly never imagined they had anything to do with cancer.
Prof Radman’s concept was logical enough: if cells are highly connected, then they cannot change phenotype very easily. Rather like a snake with two heads, if one wants to go left and the other right, it will continue down the middle. In the same way, networks of cells ensure phenotypic stability in normal tissues. For any cell to act …
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RxCelerate Ltd is an outsourced drug development platform based near Cambridge, UK. We specialize in delivering an entire road map of drug development services from discovery and medicinal chemistry through to formal preclinical development and clinical up to Phase IIa. In the last five years, we have witnessed dramatic changes in the drug development …