Adrian Harris, MD, D.Phil

2009-2010 BCRF Project:
Professor Harris and his team at Oxford are trying to understand which patients get the most benefits from a new treatment against tumour blood vessels (anti-angiogenesis therapy) using the drug Avastin. They have completed half of the study and have seen marked variation from one patient to another in how effective a two-week period of treatment is in reducing the blood supply to the tumor. They obtained biopsies to understand the mechanisms, and this has already provided preliminary information showing that certain new pathways switch on that could bypass the effect of the drug. Using a very sensitive technique that can detect many differences in blood samples between patients before and after treatment, the scientists would also want to correlate these with the outcome, which will be much easier than doing biopsies in the future.

In the coming year, they will continue the current project to complete accrual in the study to discover the mechanisms responsible for response and resistance to drugs targeting tumor blood supply. They will analyse biopsies by gene arrays from 40 patients before and after treatment, with the assessment of response by improved imaging techniques. They also have the results of very sensitive techniques for measuring proteins in the blood during therapy, which will provide important information about the mechanisms of response. Based on the results from the patients, the researchers want to test the new possible therapies in preclinical models as a prelude to offering that in the trials in the near future.

Mid-Year Progress Report:
This project was set up 18 months ago to develop ways to improve the treatment of breast cancer, by blocking the blood supply to tumors [angiogenesis]. The aims of this project are to define who is most likely to benefit from the therapy against the tumor-produced angiogenic factor, VEGF, and mechanisms of resistance that develop on treatment. This would allow us to be more selective in treating patients upfront and allow us to switch to additional drugs to overcome resistance and improve the outcome of therapy.

Professor Harris' group has made strong progress in recruiting patients and now has 32 patients entered out of 40 planned. Patients can be clearly classified by improved imaging techniques to those who show a very striking response, and those who show complete resistance. They have tumor biopsies on patients before and two weeks after starting the anti-angiogenic drug, Avastin. They have analysed over 5,000 genes in the samples and found which stress response pathways switched on. These include signalling pathways for cell growth and fat metabolism, which could help the cancer cells survive. They also have results from measuring dozens of different proteins in the blood of patients, with new technology involving mass spectrometry, which shows similar results. These results are important because there are now new drugs in clinical trial that could block the pathways and this would these provide new avenues for combination treatment.

Bio:
Adrian L. Harris, MD, DPhil, is the Professor of Medical Oncology at the University of Oxford and Director of the Cancer Research UK Medical Oncology Unit. He is a Consulting Medical Oncologist at the National Health Service, Oxford Radcliffe Hospital Trust. The Trust and the University have now combined resources as a unified Academic Foundation Trust, one of the first in the UK combining the expertise of the University with the patient resources and investigation resources of the Regional Cancer Centre. It is also a comprehensive Biomedical Research Centre designated for extra funding by the British Government for development of translational research programmes. Cancer Research UK has also designated this as an Experimental Cancer Medicine Centre, with rapid access to phase I and phase II drugs for clinical trials. Thus there is a strong emphasis on development of translational research from the laboratory to the clinic.

Professor Harris' research is on tumour angiogenesis and hypoxia as key targets for anti-cancer therapy. From his earliest training, he has been interested in understanding the basic biology and science of disease, how this could be applied to patient benefit, particularly in development of new treatments and selecting the right patients for the right therapies.

He received his Bachelors Degree in Medicine and Surgery in 1973 at Liverpool University, but undertook an intercalated Biochemistry degree (first class honours) in 1969, which first cemented his interest in the applicability of basic science to medicine. He worked with Professor David Weatherall in the Nuffield Department of Medicine, Oxford University, from 1975-1978, where he conducted research on mechanisms of resistance to anti-cancer drugs, particularly by enzyme pathways that could be targeted. He then took up a lectureship at the Royal Marsden Hospital where he conducted several studies in phase I and phase II, but particularly developed an interest in the endocrine therapy of breast cancer with Professor Ian Smith, and helped develop early aromatase inhibitors. This led to a long-term productive collaboration in endocrine biology with Professor Smith and Professor Mitch Dowsett at the same Institute.

In 1981 he was appointed as the Professor of Clinical Oncology at the University of Newcastle Upon Tyne in a newly founded chair and proceeded to set up a phase I and phase II research department investigating the biology of growth factor receptors in breast cancer, being the first to show the prognostic importance of epidermal growth factor receptor in both hormone sensitive and hormone resistant breast cancer.

In 1988 he was invited to Oxford to take up a new chair in Medical Oncology and lead the Cancer Research UK Molecular Oncology Laboratories at the Weatherall Institute of Molecular Medicine, one of the leading basic science Institutes in the United Kingdom. He is the Director of the Molecular Oncology Laboratories, which comprises 11 research groups working in the areas of tumour hypoxia and angiogenesis, signal transduction and DNA repair. The emphasis is on investigation of basic mechanisms that are relevant clinically.