Clinical & Translational Research > Blood Malignancies > Professor Andy Pettitt

I have a longstanding clinical and research interest in lymphoid malignancy. I am Lead Clinician for lymphoma and chronic lymphocytic leukaemia (CLL) within the Merseyside and Cheshire Cancer Network (MCCN), a member of the National Cancer Research Institute (NCRI) Lymphoma Clinical Studies Group (CSG) and low-grade NHL sub-group, and a member of the NCRI Haematological Oncology CSG and CLL sub-group.

I am also Chairman of the UK CLL Forum, an umbrella organisation that brings together clinicians, scientists, patients and the pharmaceutical industry through its twice yearly scientific and educational meetings. My research is focussed on chronic lymphocytic leukaemia (CLL), the most common form of adult leukaemia, and also more recently on follicular lymphoma, the most common form of indolent non-Hodgkin’s lymphoma (NHL).

Both maligancies run a chronic relapsing course and result in significant morbidity and mortality, thereby placing a significant burden on the NHS. This research aims to improve the treatment of both diseases through clinical trials and, in the case of CLL, through a comprehensive programme of translational research incorporating biomarker and drug resistance studies, pre-clinical studies of novel agents, clinical trials and biobanking.

Biomarker studies
I began my research career by investigating p53 dysfunction in CLL. This work led to a series of studies exploring the various causes of p53 dysfunction and their relation to other prognostic biomarkers. It also led to the development of a functional assay that probes the integrity of the ATM-p53-p21 pathway using ionising radiation as a DNA-damaging agent. We have shown that p53 dysfunction detected in this way is a powerful predictor of disease progression in patients with early-stage disease. We have applied the test to a large number of samples from the LRF CLL4 trial and are awaiting analysis of the data by the co-ordinating centre. In addition I have secured CR-UK funding in collaboration with Professor Ross Sibson (Division of Surgery & Oncology) for targeted SNP analysis as part of the LRF CLL 4 trial. We are also planning to perform SNP analysis as part of the PACIFICO trial in follicular lymphoma (see below).

Drug resistance studies
In parallel with studies of p53 dysfunction, I have also investigated the mechanism of action of purine analogues in CLL. These drugs have emerged as important therapeutic agents in both CLL and indolent NHL yet a significant proportion of patients do not respond to therapy. Our studies have highlighted the importance of TP53 defects as a determinant of drug resistance. I am also the lead investigator for an ongoing LRF-funded project to investigate mechanisms of glucocorticoid resistance in CLL. The latter is of considerable clinical importance as high-dose glucocorticoids are one of the main treatment options for CLL patients who are resistant to fludarabine or who harbour a TP53 defect, yet not all patients respond.

Pre-clinical studies
Our group has conducted preclinical studies to investigate the potential therapeutic value of Hsp90 inhibition in CLL. Our findings indicate that this could be an effective therapeutic strategy not only for “ordinary” CLL but also for cases of CLL with TP53 defects. In addition, ongoing studies are examining the role of AKT as a potential therapeutic target.

Clinical trials
I am the chief investigator of three NCRI multicentre clinical trials, one in follicular lymphoma and two in CLL. The follicular lymphoma trial (PACIFICO) is a randomised phase III study comparing the current standard treatment with a novel drug combination that could be more effective. This trial, which is fully funded by CR-UK, is scheduled to open to recruitment in May 2009. The two CLL trials are both phase II studies for high-risk disease. One (CLL206) finished recruiting in February 2008 and will be presented at the 2009 meeting of the European Hematology Association in Berlin. The other (CLL210) is currently under development.

Biobanking
I am Director of the University of Liverpool Leukaemia Bank which supports the great majority of all laboratory research within the Division of Haematology. This biobank has supported a number of additional projects that have been conducted at other sites. In addition to leading our local biobank, I am also Director of the UK CLL Trials Biobank. This is a GCLP-compliant national resource, jointly funded by CR-UK and the LRF, which receives samples from all patients with CLL in the UK who are entered into NCRI clinical trials. Haematological Malignancies Diagnostic Service In addition to my clinical and research activities, I am also Acting Director of the Merseyside and Cheshire Cancer Network (MCCN)

Haematological Malignancies Diagnostic Service (HMDS).
The HMDS, which will become operational during 2009, will provide the network with a state-of-the-art diagnostic facility in which clinical, morphological, immunophenotypic, genetic and molecular information is integrated into a single diagnostic report. It will provide a major opportunity for biobanking and biomarkers studies involving the Divisions of Haematology and Histopathology.