Seek and destroy - detecting and combatting leukaemia

3 November 2016



Scientists at the Jonsson Comprehensive Cancer Center have identified a new method of detecting and combatting leukaemia by tracing the cellular production of the enzyme deoxycytidine kinase (dCK). Greg Noone talks to Dr Caius Radu, the lead scientist on the project and a professor in molecular and medical pharmacology at UCLA, about the significance of the seven-year study and the extraordinary effort made by the university to bring the technique to market.


In the grand accounting of cancer in Hollywood filmmaking, leukaemia is the disease of choice. Writing in the journal Cancer Control, radiologist and presumed movie fanatic Robert A Clark, MD, found that, out of 20 films featuring cancer as a major plot point – starting with 1939’s Dark Victory and finishing with Stepmom in 1999 – a total of nine portrayed leukaemia and lymphoma, followed by four that included brain tumours and three unspecified terminal cancers.

For Susan Sontag, the reasons for the blood-borne cancer’s frequency in celluloid were clear enough. For all its associations with blood and a sudden deterioration in the condition of the patient, leukaemia was a ‘clean disease,’ the diagnosis of which was a romantic – and convenient – way for an innocent to skip neatly off the narrative precipice.

In reality, leukaemia is a hard disease.As the patient’s bone marrow starts to get clogged with leukaemia cells, the production of other blood cells suffers. During this process, the presented symptoms may include anaemia, tiredness, infections of greater frequency and longer duration, unexplained bruising, and bleeding gums. In 2013, the National Cancer Institute estimated that some 333,975 people were living with the cancer in the US. While five-year survival rates there have climbed from 33.1% in 1975 to 61.0%, treatment often requires prolonged periods of chemotherapy or steroid treatment, both of which ordain debilitating side-effects. Plainly stated, leukaemia is a disease in need of more efficient methods of detection before this point is even reached. To that end, a breakthrough just might have been found in southern California.

Light map

Dr Caius Radu is not about to admit complete knowledge of the processes behind leukaemia’s creation, which may be the reason why his lab team has been so successful in its PET imaging research. “I’m extremely lucky to work with very talented people who have experience with drug and probe development, as well as different areas of biology,” he says. “That makes it really fun: being part of a team, without having to be a kind of lone investigator in your own lab. The work has changed, and discoveries that can be made in isolation are fewer and fewer.”

Radu and his team at the Jonsson Comprehensive Cancer Center at UCLA are responsible for a series of discoveries about the properties of the enzyme deoxycytidine kinase (dCK), highly expressed in leukaemia cells and activated lymphocytes. After a seven-year study, they announced in March 2016 their creation of a new PET probe – [18F]CFA – able to fully detect the enzyme’s activity in the human body. Not only was this a new way of mapping the activity of the cancer in the patient, but thanks to dCK’s important role in allowing drug therapies such as Fludarabine, Cytarabine and Clofarabine to treat the disease at a cellular level, it also provided a new and more accurate way of identifying and combating the spread of leukaemia.

“The quality of the images is much better,” Radu explained back in March. “We are able to clearly see tissues, including tumour tissues, with high dCK activity that we haven’t seen before in humans using any of the other problems previously developed for this enzyme.”

This discovery followed on from a key milestone in his team’s work at UCLA. In a paper co-authored by Radu and Dr David Nathanson in the Journal of Experimental Medicine, they announced their formulation of a brand new drug that blocked two biosynthetic pathways in the leukaemia cells of mice. By doing so, the cells were unable to produce an essential nucleotide called deoxycytidine triphosphate, thereby halting their growth and triggering cell death. “All cancer cells utilise these two pathways, and they have a strong avidity for these nucleotides to synthesise their DNA or repair it,” Nathanson said, in a UCLA press release. “Thus, we believe that this treatment strategy might be applicable across other haematological malignancies besides leukaemia.”

Treatment path

Radu has spent almost the entirety of his career at UCLA, having climbed the academic ladder since the commencement of his post-doctorate in 2001. “I realised that my best chance to make an impact on patient care came from doing research, rather than practicing medicine for all of my time,” he explains. The field that interested Radu the most was cancer metabolism, but the would-be professor quickly realised that knowledge of that particular area would have to be complemented by a deep understanding of the confluence of imaging and complex human biology. It was this focus that led him towards his work with dCK.

“We got there by developing a PET probe,” Radu says, citing his work on the team at UCLA that developed the molecule FAC. By tinkering with the molecular structure of the cancer drug Gemcitabine and adding a radiolabel, the group created a probe that naturally gravitated towards the activation of DNA salvage pathways in cells. This occurred at its highest level in lymphocytes and macrophages, cells activated by the immune system that naturally took exception to leukaemia’s presence in the bloodstream. As the clumps of lymphocytes began to light up on the scanner, so Radu and his colleagues began to realise the potential of their discovery.

“What we didn’t know – although we had a suspicion – was that dCK was a target,” he explains. “Secondly, we didn’t know what dCK actually did in a living organism.” Finding out was a process of elimination. Leading a new team, Radu and his colleagues disabled the production of the enzyme in lab mice. The result was a dip in the number of lymphocytes produced. Nevertheless, the effect wasn’t actually radical enough to significantly impair the health of the mice, which weren’t being analysed in clean conditions anyway.

“The other line of evidence was that these lymphocytes that actually are essential for defence against pathogens can sometimes become tumours,” says Radu. “This gene, dCK, played a role in the development of lymphocytes. One could ask whether it also plays an even more important role when lymphocytes become leukaemia. That’s how we made the connection between the imaging probe that we developed earlier and the role of dCK as an enzyme expressed at high levels in leukaemia cells, and a potential target for a new drug that can be used to treat leukaemia.”

In 2010, Radu and his team began developing a screen to identify chemical structures that could suitably bind to dCK in the human body. “That gave us some candidate compounds, which then had to be optimised,” he adds. “You also have to apply some brute force, because it’s very difficult to predict how a certain chemical will actually behave once injected into a living organism. We’ve made many different compounds since 2010, and now we are at the point where we have something that has gone through the necessary approval steps at FDA to allow us to start Phase 1 clinical trials in May or June 2017.”

Assembly lines

It’s easy to say that the work being done by Radu and his team is at the vanguard of cancer imaging. However, were it not for their championing of a private-sector solution spun out of university resources to get the fruits of their labour out to market, it is conceivable that the seven-year study might have remained confined to the pages of academic journals.

“What we could do, up to that point, we did,” says Radu. “Then, soon after, we had to add an industry component to it, because beyond the point where you have shown proof of concept, the project becomes something that should not be done in academia any more. It will not be a good use of people’s time here, and certainly not something that students and post-docs will actually have to learn about.”

In situations like this, the clearest course of action is usually to license out the results of a study to a private company, necessarily losing ownership of the research and whatever direction it leads in terms of drug development. Instead, Radu and his colleagues advocated starting the companies that would monetise his research at UCLA itself. While it wouldn’t keep his team’s research within the boundaries of the university forever, matching their expertise closely with commercial investment is valuable to Radu, and, crucially, a trick that he believes many PET imaging researchers have missed at the culmination of their own studies.

“PET scanners were developed in the 1970s, and, since then, they’ve become a mainstay in hospitals,” he says. “Of course, since then, there have been so many groups in different parts of the world producing new probes. At one point, we tried to catalogue every probe that had been made. We counted about 3,000, most of which had been made by academic groups. However, if you track how many probes make it into clinical use, it’s only a fraction of that.”

Radu attributes this to a lack of clear guidance or knowledge of how to adequately commercialise most probes. By playing close attention to the approvals process, the professor hopes to avoid this pitfall. After all, bearing in mind the earlier breakthroughs made at UCLA in the inhibition of deoxycytidine triphosphate production in leukaemia cells, a tantalising possibility now exists for new types of cancer therapy. Although it must be said that research into the relationship between the inner workings of individual cells and cancer is still ongoing, it is certainly exciting to consider that Radu and his team, by mapping concentrations of dCK in the human body, may have sighted the quarry they’ve been hunting all these years. All they need to do now is find a way to shoot it.

Dr Caius Radu is a professor in molecular and medical pharmacology at the University of California Los Angeles. Radu’s primary research interest is cancer metabolism. He is a member of the UCLA Jonsson Comprehensive Cancer Centre and the UCLA Broad Stem Cell Research Center.
Radu and his team have discovered a possible way of treating leukaemia by targeting dCK.
Leukaemia treatment often requires prolonged periods of chemotherapy or steroid treatment, both of which have serious and debilitating side effects.


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