Patricia A. D'Amore

Dr. Patricia D’Amore received her Ph.D. in Biology from Boston University in 1977.  She was a postdoctoral fellow in Biological Chemistry and Ophthalmology at Johns Hopkins Medical School, and then became an Assistant Professor of Ophthalmology. 

In 1981, she moved to the Children’s Hospital in Boston as Assistant Professor and is currently a Research Associate in Surgery. In 1998, she became Professor of Ophthalmology and Pathology at Harvard Medical School and a Senior Scientist at the Schepens Eye Research Institute. She is currently the Associate Director of Research at the Institute and the Ankeny Scholar of Retinal Molecular Biology. Her research focuses on vascular growth and development, with an emphasis on blood-vessel growth in the retina.   She believes that in order to decipher how disease processes occur you must first have a thorough understanding of the normal processes. Work conducted in her laboratory, and in collaboration with investigators at Mass Eye and Ear, formed the basis for the current use of anti-angiogenic therapies for diabetic retinopathy.

You study the vasculature.  Can you describe it?

The vasculature can be compared to a plumbing system with the heart as the major pump and the blood vessels as the pipes that supply all parts of the body.  The architecture of blood vessels is like a tree, with the central trunk called the aorta, and the very smallest branches called capillaries.  It is at the level of the capillary that oxygen and nutrients diffuse out of the blood to nourish the tissues.

The term angiogenesis is in the news a lot.  What does angiogenesis mean?

Angiogenesis comes from the terms “angio”, meaning blood, and “genesis” meaning birth.  So angiogenesis is the growth of new blood vessels, specifically the smallest blood vessels (capillaries).

Why is there so much interest in angiogenesis?

Angiogenesis has become a topic of interest because of its central role in tumor growth.  All tissues, including tumors, require a vascular supply to deliver oxygen and nutrients, and to remove CO2 and toxins.  In the early 1970’s, Judah Folkman at Children’s Hospital in Boston hypothesized that tumor growth could be prevented by blocking the growth of blood vessels into tumors.  More importantly, most blood vessels in the adult are not growing so it should be possible to develop therapies that target only the blood vessels growing into the tumors.  With this, the idea of anti-angiogenic therapy was begun.

On the other hand, there are diseases that are characterized by insufficient blood flow.  Coronary artery disease, in which the vessels that nourish the heart are blocked, is a very common example.   In this case, the goal would be to stimulate the growth of new blood vessels that could circumvent the blocked arteries.   Therapies aimed at growing new blood vessels are called pro-angiogenic.

How does anti-angiogenic therapy differ from the standard tumor treatments?

Conventional anti-cancer treatment has generally utilized chemotherapy.  This type of treatment uses relatively non-specific agents that target growing cells.  Though tumors cells would most certainly be killed by this treatment, it also destroys other dividing cells such as hair follicles (which is why patients lose their hair), the cells that line the stomach (which is the cause of the nausea), and the blood-forming cells of the bone marrow (which is why people can become anemic, or have reduced numbers of white cells).  In contrast, the anti-angiogenic therapies should target only the growing blood vessels and therefore should have many fewer side effects. 

Another very important difference between conventional chemotherapy and anti-angiogenic therapy is that patients often develop “resistance” to specific chemotherapies.  Resistance develops when a subset of tumor cells acquires the ability to continue to grow in the presence of the chemotherapeutic agent.  When this happens the tumor stops responding to the therapy and continues to grow; that is, the tumor becomes “resistant”.  Different chemotherapies can be used but eventually the tumor develops a resistance to each one and the physician runs out of treatment options.  This resistance is avoided by targeting the blood vessels instead of the tumor cells.

So what does angiogenesis have to do with eye disease?

New blood-vessel growth is a complication of a number of common eye diseases, including very common pathologies such as diabetic retinopathy and the wet form of macular degeneration.  In both of these cases, new blood vessels grow in places where they normally do not grow.  Furthermore, these new blood vessels are very leaky and as a result fluid can accumulate and disrupt vision.

Do tumor angiogenesis and eye angiogenesis have anything in common?

In fact, they have quite a bit in common.  Perhaps not surprisingly, nature is very economical and uses the same molecules and mechanisms in many settings.  A protein called vascular endothelial growth factor (VEGF) has been shown to be involved in both tumor angiogenesis and the angiogenesis associated with diabetic retinopathy and macular degeneration.

Are there any anti-angiogenic therapies available now?

The first anti-angiogenic therapy for cancer, called Avastin (made by Genentech), was approved for the treatment of colorectal cancer (in combination with chemotherapy) by the FDA more than two year ago.  This drug is an antibody that can bind to VEGF and thereby block its action.  The clinical trials that preceded its approval showed that, when used in combination with chemotherapy, it led to a four-month increase in survival when compared to chemotherapy alone.  Since that time a number of trials have been conducted to assess its effectiveness against other kinds of cancer. 

Encouraged by the promising results against cancer, and knowing that VEGF had been shown to play a role in angiogenesis in the eye, ophthalmologists began to treat their patients with wet macular degeneration with Avastin -- first intravenously and later by injection into the eye.  Preliminary results to date have been extremely exciting; not only has the disease progression been halted but oftentimes there has been vision improvement.   Genentech is currently testing a form of the anti-VEGF antibody designed specifically for ocular use, called Lucentis.

You mentioned pro-angiogenesis.   Is there any on-going work to develop pro-angiogenic therapies?

Investigators are developing methods to deliver the angiogenic factor VEGF to tissues that need new blood vessels.  This is being done for heart disease as well as for conditions where patients have insufficient blood flow to their legs (also called peripheral vascular disease).