CDK INHIBITION THERAPY AND POTENTIAL FOR NOVEL IMAGING BIOMARKERS IN IDIOPATHIC PULMONARY FIBROSIS

Idiopathic pulmonary fibrosis (IPF) affects some 4000 people a year in the UK. There is no effective therapy and the average survival is 3 years. This means that IPF has a worse prognosis than many common cancers. We do not know what causes the disease, but inflammation is part of the complex disease process. The neutrophil is an inflammatory blood cell present in excess amounts in the lungs of patients with IPF. Normally, neutrophils only live for a few hours before dying and being removed by ?clearing? cells. In some diseases such as IPF, we believe that the neutrophil is able to survive longer in the lung, thereby injuring tissue and cause scarring. Corticosteroids are powerful anti-inflammatory drugs that are often used, but appear to not work well in IPF.

Over the last 20 years, our group have studied how neutrophils are able to survive longer and crucially how we might overcome this to allow normal healing. We have now discovered that R-roscovitine, a drug that affects the cell survival, has the unique property of forcing activated neutrophils to die therefore preventing lung damage. R-roscovitine has been used recently in patients with cancers, since it may also be effective at killing tumour cells. These cancer studies show that the drug is safe to use in humans. We wish to perform a study of R-roscovitine in patients with IPF. We will firstly determine the optimum oral dose and side-effect profile in 20 patients with IPF. Next, we will perform a study in 40 patients with IPF randomly allocated receive a combination of R-roscovitine, no specific treatment or corticosteroids. We will measure neutrophils in lung fluid via bronchoscopy (a telescope into the lungs). We will also employ a non-invasive technique for measuring lung inflammation, the PET scan, which is able to detect neutrophils in the lung using X-rays.

Here in Edinburgh we have a constellation of facilities to ensure this study can be performed effectively and safely. Our large specialist clinic in which we see patients with IPF is within the same building as a Clinical Trials Facility with expertise in running trials of this nature. Adjacent to the main hospital is a state-of-the-art Research Institute in which the key discoveries of neutrophil survival and R-roscovitine properties were made, and which will house a PET scanning machine. These studies should provide the foundations for future definitive trials of R-roscovitine in IPF.

Idiopathic pulmonary fibrosis (IPF) is a disease of progressive scarring of the lung with a median survival time from diagnosis of just 3 years, a poorer prognosis than for cancer of the breast, colon or ovary. There are 4000 new cases of IPF diagnosed annually and in the absence of a proven effective treatment, novel therapies are urgently required. Furthermore, there is a need to identify biomarkers of disease activity and progression. Although there are contentious theories regarding the pathogenesis of IPF, there is ample evidence that persistent inflammation is an important component of disease pathogenesis. Our group has generated a unifying body of supportive evidence to show that normal inflammatory resolution is dependent upon neutrophil apoptosis, a process that is delayed an inflammatory milieu in situ; corticosteroids rather than overcoming inflammation-enhanced survival, actually retard neutrophil apoptosis. We have now identified that the CDK-inhibitor R-roscovitine exhibits the as yet unique property of over-riding pro-survival inflammatory signals and driving neutrophil apoptosis. We have shown in vivo that R-roscovitine promotes neutrophil apoptosis, enhances resolution of inflammation and attenuates lung injury in the bleomycin model of lung fibrosis.
Early human studies of R-roscovitine have demonstrated its safety in patients with cancer, and here we propose a novel experimental medicine study of R-roscovitine in patients with IPF. We will firstly undertake a phase 1 study to establish the pharmacokinetics, safety and suitable dosing regime of oral R-roscovitine in prevalent cases of IPF. Guided by data from this study, we propose a small (n=40) factorial design phase 2 study to determine the efficacy of R-roscovitine in reducing lung neutrophil burden in incident patients with IPF. The primary end-point of the phase 2 study will be a neutrophil apoptotic index in bronchoalveolar lavage fluid. Furthermore consistent with the premise that these are experimental medicine studies, we will employ 18F-FDG PET, a marker of neutrophil activity, in this study with a view to qualifying this modality as a novel non-invasive biomarker in IPF.
In Edinburgh we have built a research team possessing considerable expertise in inflammatory cell biology, the mechanisms of inflammatory/scarring processes in human diseases and their experimental models, and the design and execution of clinical trials. This translational study is based on our original discovery of the previously unsuspected pro-resolution properties of R-roscovitine, and will be carried out in our established Interstitial Lung Disease Clinic under the auspices of the Wellcome Trust Clinical Research Facility.