Development of novel therapeutics: bench to bedside and consolidation of our Phase I trials unit:

1. We have shown that the mammalian target of rapamycin (mTOR) and it’s downstream target S6 kinase (S6K) are highly over-expressed in all lung cancer cell lines examined and many lung cancer biopsies. This lead to a Novartis multi-centre phase I trial of RAD001 combined with standard chemotherapy in patients with small cell lung cancer. This study is now completed and is being written up.
2. We have completed our Polo-like kinase-1 inhibitor (GSK4613564) study. Our results have shown that the compound is active regardless of p53 status or platinum resistance. Phase II planning of the drug in patients with ovarian cancer is underway.
3. We are developing CDK inhibitors relevant for hormone /drug refractory breast cancer and other cancer types with our new compound (BS-194) inhibiting CDK2, 7 and 9 being active in vitro and in vivo. We have also developed several novel CDK7 inhibitors and our lead molecule (BS-181) is active in vitro in breast and a wide panel of other cancer lines. BS-181 is the first example of a potent and selective CDK7 inhibitor with potential as an anti-cancer agent and is now being worked up for phase I clinical trials (Patent no: US 60/942,188 Filed June 2007).
4. We have led a phase I study of the newly formulated CRUK compound Coumate 667 in metastatic breast cancer.

We have developed bioinformatic algorithms and customised microarray approaches to analyse DNA methylation for future use in identifying prognostic/predictive methylation biomarkers in cancer patients. We have developed a novel algorithm, Methylation Linear Discriminant Analysis (MLDA) tailored to differentiated methylation hybridisation and made this available to other investigators (http://cran.r-project.org/). MLDA has identified 123 loci exhibiting differential methylation between drug-sensitive and resistant cancer cell lines, with the vast majority showing increased methylation, consistent with cisplatin selecting for CpG island hypermethylation and transcriptional silencing. We are currently applying this approach to the analysis of methylation patterns in ovarian tumours and and are uncovering associations of specific biochemical pathways with patient survival and response to therapy. These samples have been collected through an NCRN supported clinical study protocol run in collaboration with the Scottish Gynaecological Clinical Trials group and over 20 UK clinical centres. In addition,we have identified mTOR staining as a potential new biomarker for poor outcome in resected lung cancer and this could be used to identify a subset of patients for adjuvant therapy.

In 2008 we were awarded a CR-UK/EPSRC Imaging Centre grant and this bid was in part successful because of our ECMC funding. Several new imaging developments have taken place during 2008 including the publication of our Phase I Trial of the Positron Emitting Arg-Gly-Asp (RGD) Peptide Radioligand 18F-AH111585 in Breast Cancer Patients (Kenny et al J. Nucl. Med 2008). Our trial has shown that the radiopharmaceutical RGD (18F-AH111585) and PET procedures were well tolerated in all patients. Thus, 18F-AH111585 designed to bind the alpha v beta3 integrin is safe, metabolically stable, and retained in tumour tissues and detects breast cancer lesions by PET in most anatomic sites.

We have been working on the development of novel technology aimed at improving the utility and quality of T cell functional assays to test the T cell response to anti-cancer vaccination or other immunotherapeutic manipulations. The technology should prove very useful to several other ECMC centres performing immunological trials in cancer patients.

We have determined whether primary breast cancer patients show evidence of circulating tumour cells (CTCs) during follow-up as an alternative to monitoring disseminated bone marrow tumour cells (DTCs) for the detection of micrometastases in low-risk primary breast cancer patients or high risk of relapse who were being followed up after primary treatment. CTCs were identified using the CellSearch system. A significant proportion of poor prognosis primary breast cancer patients (group III) have evidence of CTCs on follow-up. Many also have evidence of DTCs, which are more often found in patients who were lymph node positive.

We showed that measurement of EGFR on the surface of CTCs, derived from individuals with metastatic breast cancer patients is possible using the CellSearch system and showed consistent positivity over time. The use of this system will now be validated in a prospective study aiming to identify patients for anti-EGFR therapy based on the expression profile of CTCs.