Arbiser Jack L. (ed.) Angiogenesis-Based Dermatology

Springer, 2017. — 182 p. — ISBN: 978-1-4471-7312-0.This book is dedicated to the memory of Judah Folkman, MD, with whom I had the pleasure of spending a 4-year postdoctoral fellowship, between the years 1994 and 1998. There are several aspects to Dr. Folkman’s personality that made him so effective in advancing angiogenesis in medicine. First, his research was clinically driven. He wanted to use angiogenesis as a tool to cure human disease. Thus, he chose to use basic research to address clinical problems, not as an end to itself. There are two camps of people who perform basic research with regard to human disease. The first believes that we have to know everything in order to treat human disease. A corollary of that belief is that once we know everything, we will be able to design a specific targeted therapy that cures advanced cancer or other ailment, with no side effects. This will be accomplished because advanced cancers are addicted to an oncogene, and targeting that oncogene will lead to a painless cure. The second camp is the one that Dr. Folkman belonged to, in that he wanted to know how we could leverage the knowledge that we have today to help patients who are sick today. As a pediatric surgeon, he recognized that patients who are sick today need treatments today, and will likely not survive until that utopian time that we have magic bullets with no side effects. His concepts of angiogenesis inhibition, first expounded in The New England Journal of Medicine in 1971, were fiercely attacked both at home and in other institutions. He had the courage to take these to clinical trials, which were also controversial, but led to new treatments of cancer and disorders of excess vasculature. He was always in a hurry because he knew that time was short and that people are sick and don’t have infinite lifespans. He was also very open minded and allowed anyone to pursue their interests as long as they were related to angiogenesis.
In this vein, he provided critical advice to a generation of scientists in terms of career advancement. Finally, he was a total gentleman, and never disparaged those who attacked and ridiculed him, although we knew very well the identities of these individuals. The term “noble metal” refers to metals that are resistant to corrosion, like gold. Dr. Folkman was resistant to the corrosive environment that he lived in his entire professional life. This makes him noble.
Lab meetings in the Folkman lab were Friday mornings. I personally felt as if we were knights at the Round Table of Angiogenesis, each of us representing a separate field of angiogenesis. Studies from those heady times led to the development of thalidomide for myeloma, anti-VEGF therapy for macular degeneration, understanding of the relationship of oncogenic signaling, understanding of the biology of hemangiomas and vascular malformations, isolation of endogenous angiogenesis inhibitors, urinary detection of angiogenic biomarkers, angiogenesis and metabolism, and many other advances that are in the clinic today. Dr. Folkman had a way of quieting skeptics. When someone said, that won’t work, he gave him a pen and piece of paper and told him to write it down and commit to it. I never saw anyone actually committing their skepticism to paper. Many of us alumni in the Folkman lab wonder how he would view the world today. As someone who knew him from 1994 to the time of his untimely death in 2008 in the Denver airport, I can venture some predictions. He would be thrilled with the clinical discovery that propranolol, a very old drug, is highly effective against hemangiomas of infancy, and has been applied to this condition, even though the mechanism of propranolol against infantile hemangiomas is not fully understood. He would also be thrilled by the use of rapamycin against vascular malformations.
Part of the rationale for using rapamycin on vascular malformations was our discovery that mTOR is activated in vascular malformations, which we demonstrated on paraffin samples which I had acquired while in his laboratory. Dr. Folkman would not be surprised by the failure of the oncogene addiction hypothesis, because as a surgeon, he had seen numerous advanced tumors and intuitively knew that large solid tumors were not reliant on a single oncogene. Evidence of this are the numerous mutations and mechanisms that have been reported in Braf inhibitor resistance in advanced melanoma. He would be pleased with the use of Avastin as a treatment for macular degeneration and cancer, although he would recognize that our use of Avastin causes compensatory events in solid tumors that require further therapies, such as those that target NADPH oxidases and HIF2a, a response to chronic hypoxia. He would likely be disappointed in the failures of angiostatin and endostatin in the clinic, and would call for further studies to understand why these drugs didn’t show the same effect in humans as they did in mice.
He would be gratified about the role of angiogenesis inhibition in promoting antitumor immunity, and would call for combinations of angiogenesis inhibitors and checkpoint inhibitors against solid tumors. Finally, he would approve of the concept of angioprevention, the use of angiogenesis inhibitors to prevent the formation of cancer, which is widely practiced today by the public with natural products. Every dermatologist who prescribes a drug has a little bit of Dr. Folkman in them. When we prescribe a drug, we do not know the full mechanism of the action of the drug. Doxycycline kills bacteria but also inhibits matrix metalloproteinases. Which is more important for treatment of acne and rosacea? We don’t know, but we don’t let our lack of knowledge serve as an excuse not to treat patients. It is my hope that the well-written chapters in this book will serve to clarify to the practicing dermatologist a more full understanding of their every day actions. Once the dermatologist in the trenches has a better understanding of what they do, they too can contribute to the immediate advancement of knowledge through keen clinical observations which can be rapidly disseminated and aid treatment of patients today.