Trinity Researchers Discover New Way to Kill Leukaemia Cells

Posted on: 02 November 2009

Researchers from Trinity College Dublin have identified a new way of killing leukaemia cells, including those resistant to current therapies.  Their findings have just been published  in the renowned international journal Cancer Research.  The researchers describe how a new drug, pyrrolo-1,5-benzoxazepine-15 (PBOX-15), is able to kill chronic lymphocytic leukaemia (CLL) cells, including those from patients with poor prognosis. The research project was funded by the Irish Cancer Society.

 PBOX-15 is one of a number of PBOX class of drugs which was developed by a team from Trinity College Dublin and the University of Siena.   Researchers from the School of Medicine in collaboration with the School of Biochemistry and Immunology in Trinity College Dublin then tested the PBOX drugs in the laboratory and discovered that PBOX-15 is highly effective at killing CLL cancer cells, and at the same time spares normal cells.  

CLL is the most common leukaemia in the western world.   While some progress has been made in developing new treatments for this disease, resistance and recurrence of the disease mean that new approaches need to be found.

“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, TCD and 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.  Professor Lawler was invited to present the work that led to this publication at a special session in the recent American Chemical Society Conference, one of the largest scientific meetings in the world, which took place in Washington DC, USA. 

The researchers showed that PBOX-15 is specifically active in cancerous cells and it works by interfering with the structure or architecture of the cancer cell.  They also found that PBOX-15 activates key targets in leukaemia cells that triggers the cells to die. Cancer cells become resistant to chemotherapy by evading or avoiding cell death.  The TCD researchers demonstrated that PBOX-15 can overcome this resistance and kill these cancer cells.

The researchers also conducted a laboratory study using CLL cells isolated from 55 CLL patients.  PBOX- 15 was more effective than the front-line therapy, fludarabine, in killing CLL cells.  The most exciting result was that PBOX-15 also killed CLL cells that were resistant to the existing treatment. 

The ability of PBOX-15 to kill leukaemia cells while sparing normal blood cells suggests that the PBOX drug may pave the way for new approaches for the treatment of this incurable cancer.

 “Its activity in malignant cells isolated from patients with this common form of leukaemia emphasises the potential of this approach,” said Dr Elizabeth Vandenberghe, consultant haematologist at St James’s Hospital and a collaborator on this study.

Speaking about this important publication Mr John McCormack, CEO of the Irish Cancer Society said: “The Irish Cancer Society welcomes these research findings and is proud to have funded this high quality research. The Society is the largest voluntary funder of cancer research in Ireland and one of our objectives is to fund researchers that will ultimately develop new and better treatments for cancer patients”. 
He also added: “The findings that are being published today emphasise the potential for basic science discoveries to translate to clinical benefit.  These findings now need to be brought from the laboratory to the bedside so that they will ultimately benefit patients with this common form of leukaemia.”

In addition to the current funding from the Irish Cancer Society to Professor Lawler’s group, funding of this research programme was also achieved through Science Foundation Ireland to Dr Zisterer’s group, while previous funding of the work was provided by Enterprise Ireland and the Higher Education Authorities Programme for Research in Third Level Institutions (PRTLI).

The paper is authored by Dr Tony McElligott, a senior postdoctoral fellow in the laboratory of Professor Mark Lawler (School of Medicine, TCD) in collaboration with Dr Daniela Zisterer (School of Biochemistry and Immunology, TCD), Prof Clive Williams (School of Biochemistry and Immunology, TCD) and Dr Elizabeth Vandenberghe (St James’s Hospital) along with international collaborators Prof Giuseppi Campiani (University of Siena, Italy) and Dr Mark Catherwood (Belfast City Hospital, Northern Ireland). Dr McElligott has also received a number of awards for presenting some of this data at national and international meetings.