Breast Cancer

• Application of kinase antagonists to block the cross-talk between kinases and ER
• New endocrine agents: dual aromatase/ sulphatase inhibitors
• Inhibitors of Notch Pathway; inhibitors of Gamma Secretase

Prostate Cancer

• Inhibition of GSK 3
• Recombinant signal chain Fv antibodies

Lung Cancer

• Inhibition of FGFR signalling through S6K2
• Role of Statins and mTOR inhibitors

Ovarian Cancer

• Inhibition of P13K to reverse resistance to platinum
• Inhibition of XIAP-AF 1

CML

Application of novel inhibitors of RTK's: Dasatinib.

Epigenetics

Our aim is to measure molecular pharmacodynamics and biomarkers with the contents of Clinical Trials, and to develop assays commensurate with GCLP, and to develop assays appropriate to epigenetic therapy.

Molecular Imaging

PET - Development of novel pharmacodynamic read-outs of proliferation, apoptosis and cell signalling.
MRI - Imaging the extra-cellular matrix.
OCT - Imaging of neoplastic and preneoplastic changes in the oesophagus and bronchus.

Biomarkers and Omics

• Identification of novel kinases as responsible for chemoresistance in solid tumours and CML
• Discovery of novel inhibitors of drug transport and identification of resistance-associated genes
• Refinement of metabonomic profiles
• Markers of residual stem cells

Metabonomics

Metabonomics in medicine aims to generate biomarkers for better detection, to predict an individual's response to treatment and identify new avenues for therapy. It is also key technology in translational research, because the methods used, such as NMR spectroscopy of extracellular fluids, are minimally invasive, non-destructive and can be applied in similar fashion to clinical investigation and experimental models.

Within the ECMC, we are currently investigating the potential of metabolic profiling to deliver non-invasive biomarkers for prostate cancer detection and prognosis that are better than the use of PSA alone. Using an SOP developed for this project (Teahan et al, 2006); we have established a prospectively collected sample bank of serum and plasma from 102 patients with prostate cancer, and 90 patients with benign prostatic hyperplasia (BPH). Using multivariate regression analysis of plasma NMR data we have identified a panel of candidate biomarkers that appear to exhibit different levels between individuals with BPH and prostate cancer.

These clinical projects are supported by laboratory research aimed at characterising disease progression and hormone-insensitive phenotypes in experimental models. Future work will attempt to validate our biomarker panel and will include studies of other cancers.

Patients in Translational Studies

Getting patients enrolled into translational studies: Imaging trials, Biomarkers studies, Novel therapies/Reverse drug resistance, Phase I and Phase II Clinical trials.

Oncogenomics and Drug Resistant Team in Ovarian Cancer

The Oncogenomics and Drug Resistance team, which sits within the Ovarian Cancer Action Research Centre and Imperial College's Department of Oncology, is firmly focused on the clinical problem of acquired resistance to platinum based chemotherapy in ovarian cancer which is a critical determinant of the poor outcome associated with this condition.

Understanding and reversing this resistance is therefore of pivotal importance in improving the treatment options for ovarian cancer. We are approaching this problem from both basic and translational angles.

• We are coordinating a large, national multi-centre translational study based on the SCOTROC4 clinical trial, which aims to develop predictive signatures of response to carboplatin and to identify therapeutic targets and/or markers of platinum resistance using genome wide molecular analyses.
• We are also coordinating a translational study investigating the mechanism of action of the putative platinum resistance reversing agent phenoxodiol within the OVATURE clinical trial.
• In addition, we are using iso-genetically matched cell lines derived directly from the tumour cells of patients with advanced stage serous ovarian cancer, both before and after the onset of resistance to platinum in order to identify and mechanistically characterise modulators of platinum resistance.
• Key to all this work is the availability of high quality clinical material with associated clinico-pathological data and as such we have established routine collections on the Hammersmith site and are currently rolling our standard operating procedures out to our ovarian cancer action collaborative sites at the Royal Marsden Hospital.

Minimal Residual Disease in Breast Cancer

We have an expanding programme on the detection of micrometastases in breast cancer. Currently patients receive adjuvant therapy with no knowledge as to whether it has eradicated the disease. Monitoring for circulating tumour cells and DNA may provide a way forward. The ECMC is providing funds to monitor patients by blood sampling and bone marrow aspirations.

Biomarkers and Drug resistance in Lung Cancer

The key cause of death in lung cancer is from drug resistant metastatic disease. Consequently, we have adopted a translational biology/clinical approach to develop new therapies for lung cancer.

• This has already resulted in the identification of statins as agents which trigger apoptosis in vitro and in vivo and enhance chemotherapeutic effects. These and other results lead to a placebo controlled trial of statin added to standard therapy in SCLC-the LungStar trial.
• Our ability to compare normal lung with lung cancer cells/tissue has enabled us to identify several key signalling molecules which are highly upregulated in lung cancers. One such molecule, mTOR, is targeted by several agents one of which (RAD001) is in a phase I trial combined with chemotherapy in our unit.
• Our biology research involving high throughput RNAi library screens of the kinome and drugable genome has revealed multiple new targets involved in driving drug resistance, metastasis and cell proliferation. Our tissue and blood collection is enabling us to test whether these targets are relevant in patients with lung cancer.

In addition, there is a need to develop simple cheap tests that can accurately identify patients with early lung Cancer to improve the chances of CT screening being successful. To achieve this we are using our serum/urine collections to look for novel epigenetic/metabonomic markers of lung cancer.

Translational research in Gestational Trophoblastic Neoplasia

Although this cancer is now nearly always cured there is a need to:

• Develop less toxic and more effective salvage regimens.
• Eliminate false positive and negative results in hCG assays used as a biomarker for the disease.
• Identify at an early stage which patients with the premalignant forms of the disease will develop the active cancer so that curative treatment can be started as soon as possible.
• Identify the causative gene(s).

We are actively involved in all these research areas.

PET Scan Imaging

We are using ECMC funding to improve patients' recruitment into PET Imaging clinical studies of proliferation of cancer cells, Cholin metabolism and Angiogenesis.