Adrian Harris, MD, D.Phil
Professor of Medical Oncology
Director, Cancer Research UK Medical Oncology Unit
University of Oxford
Chairman, Scientific Advisory Board of Breakthrough Breast Cancer
Oxford, United Kingdom
2013-2014 BCRF Project:
(The Delta Air Lines Award)
Dr. Harris’s group continues their work to target the blood vessels of breast cancers and reduce their oxygen supply and ability to deliver nutrients, at the same time as targeting the changes in metabolism that help the cancer adapt and survive. This combination approach has shown marked additive effects in preclinical models, and this research team is now extending these studies into the clinic. Dr. Harris and colleagues are using a more sensitive type of PET scan to show the effects of metformin on glucose uptake in breast cancer, and they find patients’ metastases often show much more effect than the primary tumor. This has important implications for how clinicians use metformin therapy. To understand the direct effects on tumor metabolism, Dr. Harris has initiated a study where biopsies are taken from patients undergoing mastectomy or lumpectomy, before the blood supply is cut off, to measure the metabolic pathways in different types of breast cancer. This will give researchers very important new information about differences between patients and to enable clinicians to target their new therapies appropriately.
Dr. Harris has also continued his work on an important pathway of metabolism involving glycogen and, by blocking glycogen breakdown in cancers, it is possible to markedly slow tumor growth. It turns out that drugs to do this have been developed to treat diabetes, and so there is a ready source of new compounds to assess, to select ones appropriate for clinical trial. In addition, Dr. Harris’s group has started combining treatments blocking glycogen metabolism with chemotherapy and radiotherapy and shown in some cases very surprising beneficial effects in blocking growth.
Additionally, Dr. Harris wants to have better ways of blocking the blood supply to tumors, to maximize the combined effect. Through a bioinformatics method, his group has discovered a new pathway involved in angiogenesis for most types of cancer, including breast cancer, which has much more effect on tumor growth, when inhibited in preclinical models, and they are currently investigating this as a clinical target.
Dr. Harris’s recent work has discovered, for the first time, how metformin may affect cancer metabolism directly in patients’ tumors. His team has now found that it affects two fundamental metabolic pathways in cancer. One involves inhibiting mitochondria (small organelles in cells that generate energy) which are essential for cancer growth. The second affects the pathways that use a key amino acid called glutamine, and would greatly increase its uptake by cancer to compensate for the effects on mitochondria. In cell culture work with human breast cancer cell lines the researchers are finding that cells treated by metformin become dependent on glutamine and they therefore plan to to assess drugs that block glutamine use in combination with metformin. They hope that this will move into phase I studies (early clinical studies) to see which ones may be particularly useful in the targeting of triple negative breast cancer, which has many more of these metabolic pathways upregulated. This, therefore, may provide a way of selecting patients that will obtain the most benefit and how to combine modalities of treatment to obtain improved outcome.
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.