Finding the right drug combination for chronic lymphocytic leukaemia patients
Professor Mark Cragg is searching for clues to how some current cancer drugs work, so we can identify the ideal drug combinations that deliver the best benefits for patients. Find out more about this exciting research here.
Over one hundred years ago, Paul Ehrlich – a doctor and immunologist – dreamt of creating 'magic bullets' to fight human diseases. He envisioned developing a chemical compound that would target and kill infectious bacteria, while leaving a patient’s normal cells unharmed.
Paul Ehrlich in his laboratory. Credit: Wikimedia Commons
Ehrlich’s vision spurred scientists to create a myriad of drugs that target specific cancer causing pathways. But although many of these selective molecularly targeted drugs developed in the modern era have been initially successful, the drugs often stop working in patients over time. We now know that cancer is made up of many different sub-types, each of which responds differently to treatment. Even these different pockets of cancer cells can be quite diverse within an individual patient. And as our understanding of the complexity of cancer has grown, so researchers have increasingly come to believe that combinations of targeted therapies, specifically hitting a number of pre-defined molecular targets at once, represent the best hope of defeating the disease.
Finding the right combination
With the rising number of new treatments, the challenge is to identify combinations that deliver the best benefits for patients. Researchers need to gain a deeper understanding of how drugs work to guide these selections.
Professor Mark Cragg – a cancer immunologist in the Faculty of Medicine at the University of Southampton – is searching for clues to how drugs work. He is interested in drugs that block the phosphoinositide 3-kinase (PI3K) signalling pathway, which is elevated in many cancer cells.
A signalling pathway is a group of molecules in a cell that work together to control one or more cell functions, for instance cell division. Key to the PI3K pathway is a group of enzymes, which are involved in kick-starting lots of cellular processes, such as growth, multiplication and survival. When these tightly regulated processes go out of control, we start to see cancer forming.
Molecular structure of the phosphoinositide 3-kinase enzyme. Credit: Wikimedia Commons
Researchers have been looking at ways to block the PI3K enzymes in cancer cells, shutting down the signalling pathway in the process. Idelalisib is a new PI3K inhibitor, and has shown impressive results in patients with chronic lymphocytic leukaemia (CLL). However, it is not entirely clear how they work and why they are so effective, so Professor Cragg wants to gain a firmer understanding of this.
How do PI3K inhibitors work?
Researchers have proposed that PI3K inhibitors could work by modifying the immune system, or they may stop cells signalling to each other, block the cancer growth, or cause the cell to self-destruct. Now, Professor Cragg and colleagues have shed some light on how PI3K inhibitors work in research that was partly supported by Bloodwise, and was published this month in the journal Leukaemia.
Cells from patients and mice with CLL were grown in the lab, and then exposed to idelalisib to see the effects. Mice with CLL were also studied, and the drug was given with another targeted therapy called a monoclonal antibody.
Image of CLL cells. Credit: Professor Mark Cragg
Both human and mouse cells were seen to self-destruct when exposed to idelalisib. The drug also disrupted the communication signals from surrounding cells that supported the survival of the CLL cells. In the mouse system, the drug boosted the killing power of the monoclonal antibody.
Is Bim the answer?
Upon further investigation, the response to idelalisib was linked to an increased production of a protein called Bim, which causes cells to die. When Bim is removed from the CLL cells, they became resistant to idelalisib and no longer died. And mice without Bim that were given the drug did not show the enhanced drug effects with antibody treatments.
By knowing how PI3K inhibitors work, researchers can begin to look at the different combinations of drugs that could deliver more effective treatments for patients.
What the future holds
I caught up with Professor Cragg, who said: "This piece of research has given us a fantastic grounding in helping us to understand the biology of how these drugs work. With this knowledge we can design better, more effective combination treatments. And in the future, we could even be looking at combinations that will give us a cure for some blood cancers where we don't currently have that possibility."
Perhaps it’s not a single magic bullet envisaged a hundred years ago that will fight disease, but a combination tailored to the individual patient that is needed. We certainly will be following this research closely to find out the next steps.
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