A group of Trinity researchers have announced details of a novel treatment for leukaemia. The drug, called PBOX-15, works by causing leukaemia cells to die. The new research is particularly significant because the drug appears to be effective on cancerous cells that are resistant to fludarabine, the currently-used treatment.
The research was published in the journal Cancer Research on November 1, and was co-authored by Dr. Tony McElligott, a senior Research Fellow in the laboratory of Professor Mark Lawler in the School of Medicine, Trinity College Dublin.
PBOX-15 works by disrupting microtubules, which are key components of the internal structure or skeleton of the cancerous cells. This causes the cell to arrest its cycle of growth and subsequently induces apoptosis, or cell death, which is a normal process of healthy cells.Defects in apoptotic mechanisms are believed to be a primary cause of chronic lymphocytic leukaemia (CLL), the type of leukaemia that this drug targets.
The research is significant for a number of reasons. Firstly, PBOX-15 was effective on cells with poor prognostic markers, which are molecular indicators of aggressive disease. In the journal article, the authors write that the clinical course of CLL varies in patients, “with some patients displaying stable disease, which often requires no treatment other than ‘watchful waiting,’ whereas other patients have aggressive disease necessitating early intervention.”
Secondly, PBOX-15 was effective on cells that had developed resistance to fludarabine, the current “front-line”agent in CLL therapy. This is important according to the researchers because “the need for novel treatments is acute in CLL, especially for the subgroup of patients with poor clinical outcome and drug-resistant disease.”
Thirdly, the new drug was shown to be more potent at inducing apoptosis (cell death) than fludarabine in fludarabine-sensitive cells. Researchers administered just one-fiftieth the amount of PBOX-15 compared to fludarabine and saw significantly more potency in PBOX-15 inducing apoptosis than fludarabine, which has a different mode of action to PBOX-15. Fifty five patients from St. James’s Hospital were involved in the study, which represented collaboration between researchers both internationally and within Trinity.
Prof. Giuseppi Campiani (University of Siena, Italy) and Dr. Mark Catherwood (Belfast City Hospital, Northern Ireland) took part in the study, along with Dr. Daniela Zisterer (School of Biochemistry and Immunology), Prof. Clive Williams (School of Biochemistry and Immunology) and Dr. Elizabeth Vandenberghe (St James’s Hospital).
“This important discovery is the result of a truly collaborative approach, involving researchers across the different disciplines of chemistry, biochemistry and molecular medicine at TCD, together with our colleagues in Siena and Belfast,” said Professor Mark Lawler, School of Medicine, lead investigator on the study. “The complimentary expertise allowed us to approach the problem of killing CLL cells from a number of angles,” he added.