Adrian Harris, MD, D.Phil

Dr. Harris's clinical study of metformin, an old drug commonly prescribed for diabetes, and its effects on metabolism in patients' tumors before surgery or chemotherapy, has progressed well. His team has now found that there is an effect on the tumors directly, which varies between patients. This finding is not related previous ones made on standard markers of tumor activity.

Also, Dr. Harris's analysis of the previous study of Avastin® (bevacizumab), now completed, has shown that tumors rapidly adapt to therapy by metabolic changes. Preclinical studies of the two drugs together show that they may enhance each other's activity. This information will help Dr. Harris's team, as well as others, to integrate the use of this type of drug with anti-angiogenic therapy to increase patient benefit. Based on the enzyme changes Dr. Harris's team saw in the tumors in the clinic, the researchers are now investigating if inhibition of key enzymes will block growth of cancer cells grown in the laboratory. Understanding the mechanisms will help determine clinically which is the type of breast cancer most likely to benefit and to take new inhibitors into the clinic.

Mid-year Progress: Previously, Dr. Harris's team has investigated how primary breast cancers respond to bevacizumab (Avastin®), a drug that blocks tumor angiogenesis, and although increasing the response rate of breast cancer and time for the tumor to progress did not affect overall survival. In their study, they made two important discoveries. First, they found that analyzing a special type of baseline scan called a DCE-MRI (dynamic contrast enhanced magnetic resonance imaging) in a particular way that could quantify the images, the baseline scan was a good predictor of the initial response. Currently this is not incorporated into use of the therapy but could make an important difference in selection for future trials.

Furthermore, they found that the genes that were regulated in the cancer changed dramatically with this therapy within two weeks, and switched on metabolism in a way that helped the tumor survive. They therefore investigated ways of stopping the change in metabolism so that the tumor could not survive under the new stress of hypoxia (this is called induced essentiality, an important new way of approaching cancer treatment).

One of the findings was that an enzyme that regulates fat and carbohydrate metabolism normally in the liver was upregulated, and the researchers had also shown previously that the anti-diabetic drug metformin can block this induction, so there they are investigating possibility of combining the treatments.

The current study has now recruited 23 patients onto metformin, with detailed kinetic imaging of glucose uptake, which allows the researchers to analyze the stress mechanisms directly within the tumor. They have found that both the primary tumor and metastases respond in a similar way and a subset of patients show a marked induction of changes with metformin. They are still trying to understand what the mechanisms are that make the tumors respond, because this would be a potentially important way of treating and even preventing breast cancer in the future, but understanding the selectivity and mechanisms is essential.

Additional changes were found in the tumor related to storing glycogen in order to survive low oxygen concentrations. Dr. Harris's team therefore is taking new approaches to block glycogen utilization, which the tumors use to recover from block of angiogenesis. These are being investigated pre-clinically and the researchers now plan to take them forward into clinical trial, with novel drugs and measurement of metabolism in the tumor, to enable future selective and individualized therapy.

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 Center. It is also a comprehensive Biomedical Research Center designated for extra funding by the British Government for development of translational research programs. Cancer Research UK has also designated this as an Experimental Cancer Medicine Center, 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's research is on tumor 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 bachelor's degree in Medicine and Surgery in 1973 at Liverpool University, but undertook an intercalated Biochemistry degree (first class honors) 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 tumor hypoxia and angiogenesis, signal transduction and DNA repair. The emphasis is on investigation of basic mechanisms that are relevant clinically.