To kill a cancer cell… or not?
There’s a common adage that “the best cancer cell is a dead cancer cell”. However, as Allan Jordan, Sygnature Discovery’s Director of Oncology Drug Discovery, explains, it’s not always quite that simple…
We often assume that understanding the in vivo action of a novel cancer drug is relatively straightforward. A simple tumour growth model can usually be used to demonstrate that a drug can reduce the size of a tumour, and more detailed patient-derived tumour models can both confirm this action in ‘close to human’ tissues and help suggest the most responsive patient populations for a clinical trial.
But in many cases, the actual mechanism of this growth inhibition is overlooked. And this can be of critical importance as we think about how we design and monitor our clinical trials.
PUMP THE BRAKES
Cancer therapeutics generally act either as cytotoxic or cytostatic agents, which either kill the cell outright or put the brakes on further growth. Whilst the idea of outright killing of the cancer cell might appear attractive, it is not always simple, or indeed desirable, to achieve.
In some clinical cases, the use of these cytotoxics (particularly some antibody-based therapies) have led to catastrophic and sudden cell death. While this sounds ideal in regard to a tumour, it also results in ejecting the cells’ contents into the wider circulation. This floods the system with toxins, leading to an effect known as tumour lysis syndrome. Whilst manageable in most patients, it’s become increasingly clear that an understanding of the mechanism, and rate, of cell death can be important to avoid sepsis and, sometimes, death.
Adding further woe, it’s also been shown that quickly reducing the size of the tumour in this way suddenly leads to less competition for nutrients and oxygen across the remaining tumour cells, and this feeding frenzy can lead to an explosive re-growth and rapid return of the tumour.
On the other hand, simply stopping the tumour growing might be a real option for some patients. If the tumour is not causing other bodily systems to struggle, perhaps we can maintain what’s known as ‘stable disease’. For many patients, holding the tumour at bay with a well-tolerated medicine may be an attractive option. Tumour lysis syndrome is avoided, as is rapid re-growth.
However, our current generations of cytostatic agents are not entirely effective, and the (very) slow but determined reproduction of tumour cells allows drug resistance to eventually occur, consigning the patient to a lifetime of worrisome ’watch and wait‘ until the tumour inexorably returns.
AVOIDING THE SCRAP HEAP
The mode of action we select for our experimental agents also has implications for how we measure success, or failure, in clinical trials. Match the wrong mechanism with the wrong trial endpoint, and a potentially useful agent can be inadvertently consigned to the scrap heap.
That’s because, for most clinical trials, measurement of tumour size is the key to determining drug effectiveness. And this measure can be unhelpful for both cytostatic and cytotoxic agents.
For a cytostatic drug, the tumour size may remain largely unaltered as we shut down cell growth. So only looking for the shrinkage of the tumour could mean that potentially effective drugs could be dismissed.
For a cytotoxic drug, tumour shrinkage as cells die would seem to be a clear measure of success. Once again, though, it’s not quite that simple. Many larger tumours possess a central core of dead cells and other detritus, surrounded by a layer of active cancer cells, and many of the methods we use to measure tumours fail to distinguish between this dead inner core and the outer layers of active cells. We might eliminate all these active cells, effectively eradicating cancer growth, but the apparent size of the residual mass may not really appear to shrink all that much.
Understanding how cancer cells respond to treatment, and how best to measure this in patients, is important as we think about the design of clinical trials and the evaluation of experimental new drugs. At Sygnature, we believe that integrating expert clinical advice early in the drug discovery process – so we better understand clinical trial design and measurement, and who our best responding patients are likely to be – can help increase the chances of success by ensuring we ask the right questions, of the right molecules, at the right time during the discovery process.
Sygnature Discovery’s scientists focus on delivering the highest quality, biologically active molecules, tailored to ask the right clinical questions. We carefully balance complex questions around drug discovery and clinical foresight in our drug discovery programmes, as we work to deliver the best therapies to our clinical colleagues and collaborators.
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