Research led by Peter Mac has found a way to map, in unprecedented detail, all of a drug’s clinically important interactions in the body. The new tools can reveal how a small-molecule drug works at the cellular or genetic level, providing scientists with powerful new insights into what drives or - importantly - limits its anti-cancer effect.
Peter Mac’s Professor Mark Dawson says it was developed to address to an information gap that has long frustrated clinicians as they treat cancer and also scientists involved in the search for new, more effective treatments.
“The frustration behind this innovation is that for many of our most effective cancer drugs we cannot fully explain how they work or why, for some patients, they fail,” says Prof Dawson who is Head of the Cancer Epigenetics Laboratory, and Program Head of Translational Haematology, at the Peter MacCallum Cancer Centre.
“We can know a drug will benefit a patient – as indicated first in the lab and confirmed in clinical trials – but big gaps can remain in our understanding of how it does this at the molecular and cellular level.
“We wanted to change that, to develop methods for seeing all of these interactions, and that’s what we’ve achieved.”
Prof Dawson led the research, with international collaborators, which developed ways to attach fluorescent or other types of markers to a new class of anti-cancer drugs.
The key was to find a way to do this without altering, in any way, how the drug would ordinarily act. A paper describing how the team achieved this, and demonstrated this using a new drug – a BET bromodomain inhibitor - is published online by the journal Science today.
The research was undertaken in models of cancer in the petri dish and in mice, not humans. It confirmed BET bromodomain inhibitors are less effective at penetrating the bone marrow than other tissues – an important discovery as cancers can have reservoirs in the bone marrow.
The researchers were also able to gauge, for the first time, how much of the drug was present in different tissues and map in fine detail the array of genes it interacted with.
“Where we had a hypothesis or question about how this drug operated in the body we now have firm and scientifically verifiable answers,” Prof Dawson says.
“These point us to new avenues for research to improve this drug and, excitingly, there are many small molecule drugs we could apply these same methods to.”
Prof Dawson also said the new tools should aid the development of the next generation of cancer treatments, by allowing scientists better understand a potential drug candidate’s biological activity in the lab and before committing to costly and time consuming clinical trials.