A loss is felt

As I wing my way back home from San Diego, I've had a bit of time to digest what I saw and learned at the AACR meeting. Overall, it was an above average but definitely not outstanding meeting, and I may discuss specifics more at a later time. One key theme that seems to be increasingly emphasized is cancer prevention, and indeed the AACR launched a new journal, Cancer Prevention Research, dedicated to publishing high quality research on just that topic. This new emphasis on prevention is long overdue because once cancer has developed the cat is out of the bag, so to speak, and even our best and most sophisticated treatments are still depressingly limited in what they can offer to patients with advanced cancer. As vaccination did for infectious disease, effective strategies to prevent cancer before it develops have the potential to save far more lives than the incremental improvements in survival provided by the best new chemotherapy and biological therapy. Other prominent topics included the epigenetic control of cancer, which is definitely becoming more of a hot topic; the influence of the tumor microenvironment, an emphasis of which, given my interest in tumor angiogenesis, I heartily approve, of course); chromosomal aberrations and cancer; and the question of rapidly translating advances in basic science into effective treatments, which was the theme of the Presidential Address on Monday.

However, there was something definitely different this year. There was something missing.

I will readily admit that my perception of something different is influenced by my primary area of research interest, tumor angiogenesis. Attendees who do not share my area of expertise and research interest may not have felt it, but many of us did. It was driven home on Tuesday morning when I attended the largest session on tumor angiogenesis.

For the first time in my memory, for the first time since I first started attending AACR meetings about ten years ago, Judah Folkman was not at AACR. It was just hard to believe that he would never be there again, having died suddenly of a heart attack on January 14 in the Denver airport while on his way to a conference in Vancouver.

Those of you unfamiliar with Dr. Folkman might wonder what difference that would make, but, believe me, it made a big one, at least to his scientific offspring like me. For one thing, Dr. Folkman could be counted on to give plenary session talks nearly every year that would be stimulating and full of great science, but his contribution to the meeting every year went far beyond that. He was known to roam the poster halls, picking out posters and engaging the presenters on their science, particularly if they were young investigators. Ever approachable, he would be happy to talk to virtually anyone who wanted his advice, the same generosity he demonstrated to patients, whom he often spent evenings talking to and reassuring, particularly after his concept of antiangiogenic therapy, particularly his discoveries of angiostatin and endostatin, hit the media ten years ago. Such was the generosity of spirit that, according to all reports, he also demonstrated with his students, residents, and postdocs. Personally, I only met him two or three times, and only once was this for more than a few minutes, when he met with our lab and we presented our data to him. It was a great session, and he clearly relished just talking science with a bunch of young investigators. It was there that I got to show him a bit of data from a simple (but, I hope, clever) experiment that demonstrated how antiangiogenic therapy might potentiate radiation therapy, which resulted in a paper that Dr. Folkman cited not infrequently in talks for years after that.

I've discussed this before, but coming out of this meeting I think it's worth reiterating. There's no doubt that Dr. Folkman was a true giant among cancer researchers. I look at what I've accomplished thus far in my career, and it pales to utter insigificance compared to what Dr. Folkman had achieved by the time he was my age. Indeed, Dr. Folkman accomplished far more by the time he was my age than I am ever likely to accomplish in my entire career and was the very epitome of what a surgeon-researcher should be. That he never received the Nobel Prize for his contributions, which went far beyond his visionary hypothesis that inhibiting tumor angiogenesis could eventually result in effective anti-cancer therapies, is a travesty and oversight that surely must be among the worst in Nobel history. Indeed, Robert Kerbel, who eulogized Dr. Folkman before speakers presented their data, presented a list of what he called the "top ten" major contributions to cancer research made by Dr. Folkman and ten pointed out that it really should be at least a "top twenty" list, as, after proposing it, he kept getting e-mails pointing out important contributions by Dr. Folkman that he had forgotten to include. How many researchers can be honestly said to have birthed an entire field of investigation whose importance is apparent in many different fields? Dr. Folkman did just that.

Fortunately, it was reward enough to him to see the fruits of his great idea finally make it into the clinic to produce real and tangible improvements in the survival rates of cancer patients. It was pointed out that if Dr. Folkman had died ten years ago, he would never known if his work would ever actually benefit patients. Ever humble, he always used to say, "If you are a mouse and have cancer, we can cure you," an implicit acknowledgment that the road from animal studies to human studies claims far more treatments as casualties than the small number of them that ever make the leap to become successful therapies. He also never forgot that the purpose of his research was to help patients, and reacted with characteristic humor to requests that his discoveries be accompanied by "more basic studies" before they could be translated, as described by Isaiah Fidler:

Judah's sense of humor and ability to withstand stress always amazed me. For example, his greatest ambition as a physician was to shepherd the study of angiogenesis into the realm of therapy, although this mission proved to be difficult. Joint studies from our two laboratories showed that the progressive growth of infantile, cutaneous hemangioma is directly correlated with hyperplasia and angiogenesis and inversely correlated with expression of the endogenous angiogenesis inhibitor, IFN-β. Attempts to translate these findings to the clinic were met with numerous requests for "more basic studies." To calm me down, Judah said, "You know, this reminds me of a story: A pediatric surgeon in Boston just finished a difficult operation. To relax, he went to the Charles River and sat down on a bench. Suddenly, he heard cries of 'Help! Help!' and saw a person drowning. The surgeon jumped into the river and pulled the person to safety. He lay exhausted on the banks of the river and again heard, 'Help! Help!' He glanced at the river and saw another person drowning. Despite his exhaustion, he jumped into the river and pulled the second drowning person to safety. Now, he was truly exhausted and lay on the ground huffing and puffing and again heard, 'Help! Help!' He raised his head to look toward the river and saw a third person drowning, but he also noticed two basic researchers walking by the river. The surgeon shouted, 'Colleagues, you must help! This is the third drowning person in the river in one afternoon!' The researchers looked at the river and then at the surgeon and said, 'Three people drowning in one afternoon? This is very interesting! We'll walk upstream to see who's throwing them in!'".

There's one other aspect of Dr. Folkman that can't be emphasized enough for young scientists: persistence in the face of adversity. Dr. Folkman first proposed his idea that targeting tumor angiogenesis could be means of treating cancer in 1971 in a NEJM article. The reaction was not particularly enthusiastic. Actually, that's a bit of an understatement. Actually, the reactions tended to be dismissal and sometimes even ridicule. To make his case required a daunting series of achievements. If you want to get an idea of just how much needed to be accomplished, consider this: In 1971, vascular endothelial cells (the cells lining the inside of blood vessels and, we now know, the cells that respond to angiogenic signals to form the basis of new capillaries and blood vessels) could not be isolated and cultured. The techniques to do this just didn't exist at the time. Before Dr. Folkman could make much progress on testing his hypothesis and using it to design anticancer treatments, he first had to figure out something as incredibly basic (in retrospect, at least) as how to isolate these cells and grow them in culture. This was something that he did not achieve until 1979--eight years later. In the meantime, his list of discoveries and accomplishments on the road to validating his hypothesis (summarized here) is impressive by any standard. Still, tt was not until 1994 when he published the blockbuster paper that made researchers take notice and start to think that maybe there might be something to this tumor angiogenesis stuff after all. I'm referring, of course, to the Cell paper that described the discovery of angiostatin. Three years later, Dr. Folkman discovered endostatin and a year after that reported how tumor dormancy could be induced in a mouse model using antiangiogenic therapy. The discoveries came fast and furious after that, and Dr. Folkman's lab and intellect ran full throttle until the very end. This persistence is the reason that I also like to use the example of Dr. Judah Folkman when discussing the Galileo gambit. While it is true that Dr. Folkman's detractors did indeed dismiss his hypothesis, unlike advocates of dubious science, Dr. Folkman did not whine about how he was being "persecuted" by the scientific establishment. Rather, he hit the lab, did the rigorous and difficult research required, and eventually reached the status he achieved before his death through copious quantities of excellent science. In other words, he was vindicated because his data and experiments showed that his hypothesis was correct.

There were bumps along the way, though. Dr. Folkman's results ten years ago were so impressive that more than a few researchers wondered how they could possibly be correct. Worse, other labs could not replicate the same impressive tumor shrinkage that Dr. Folkman had observed in his mouse models. In fact, we ourselves initially had trouble duplicating Folkman's results ourselves when I was first started looking at the possibility of combining antiangiogenic therapy and radiation in a mouse model. Dr. Folkman was more than happy to provide us with reagents (including angiostatin and endostatin made and purified in his own lab), the strain of Lewis Lung carcinoma cells that he used, and any advice needed. In the case of other labs, he would sometimes go there personally (or send one of his many minions) to help investigators troubleshoot. Eventually, other labs started to replicate his results, and over time skepticism diminished. Looking back I like to think of these incidents as examples as science working at its best, with Dr. Folkman helping investigators who, he knew, could well turn into his competitors soon. He did it, as Dr. Kerbel pointed out, because he believed that we are all working towards the same goal of eradicating cancer and that collaboration is a better way to achieve this end than competition. To that end, he was even known to give of his unpublished data, arguably the most precious resource a scientist has.

Perhaps the most scientifically satisfying aspect of Dr. Folkman's legacy is just where his big idea has taken us. His original idea from 37 years ago, it must be admitted, was a bit simplistic, namely that blocking the development of new blood vessels would "starve" tumors. Early results in the 1990s were consistent with just such a concept, but now we're starting to see that the story, as is true of many things in biology, is far more complex than that. One example is the very example of what I worked on ten years ago. Radiation toxicity in cancer cells requires oxygen. Cells living in areas of low oxygen tension, as many do in the poorly perfused central regions of tumors, tend to be resistant to radiation. This is Radiobiology 101. Yet, I and others showed that combining radiation with antiangiogenic therapy actually produced a greater than additive antitumor response. According to the original model of how antiangiogenic therapy worked, if anything antiangiogenic therapy should have made radiation therapy less effective, not potentiated it. This paradoxical observation has led the field to grow in fascinating new directions. Indeed, this paradox in one model system showed that, under some conditions, antiangiogenic therapy could result in increased tumor growth, data that was presented in another session!

There are now a number of hypotheses that could explain this paradox, and some of them were presented in the talks during the session dedicated to Dr. Folkman. I won't go into many details other than to describe one hypothesis briefly. To understand it, you need to know that tumor blood vessels are quite abnormal and "leaky." They allow fluid to leak out and increase the interstitial pressure in tumors, and consequently blood does not flow through them as well as it does through normal capillaries. Because of this, even though there are more blood vessels, tumors often get less actually useful bloodflow than normal organs. There is now data, originally from Rakesh Jain's lab and now from several others (some of which was presented at this AACR meeting), that implicate a process dubbed blood vessel "normalization." When antiangiogenic treatment "normalizes" blood vessels, extra blood vessels are "pruned," leaving behind "normalized" blood vessels that are less leaky. Paradoxically, this process can lead (initially, at least, before continued pruning causes regression of more vessels) to better blood flow into the tumor and more oxygenation, making radiation therapy more effective. It turns out that this effect works with chemotherapy as well, where antiangiogenic therapy can paradoxically result in improved delivery of drug to the tumor because of "normalized" vessels and decreased interstitial pressure. Indeed, this effect is probably behind the survival benefit that bevicuzimab (Avastin) produces when added to chemotherapy for colorectal cancer metastatic to the liver, and it should be pointed out that "normalization" appears to be most prominent . Of course, the blood vessel "normalization" hypothesis is not the only one out there (it doesn't explain everything), but it appears to be the predominant one now to explain how antiangiogenic therapy can seemingly be a "universal" sensitizer to radiation therapy and chemotherapy.

Before I wrap up, it has to be emphasized that angiogenesis is important not just for cancer, but in several other diseases. Active research is ongoing in trying to find out ways to induce angiogenesis in cardiovascular or peripheral vascular disease to try to revascularize areas of cardiac or skeletal muscle that have inadequate blood flow due to blockages in the arteries feeding them. Excessive angiogenesis is also part of the pathology of eye diseases such as macular degeneration, and antiangiogenic therapy has been shown to slow down the progression of this dreaded sight-robbing disease. Indeed, it was pointed out that one of the awards that Dr. Folkman was most proud of was an award for his contribution to developing treatments that prevent blindness. Truly, the implications of Dr. Folkman's work reach into a mindbogglingly huge number of diseases!

Although we who admired Dr. Folkman remain saddened by his passing three months ago, we are comforted by the knowledge that, although Dr. Folkman may be dead, his legacy lives on. It lives on in the lives of the patients he helped, in the researchers he trained, and in those of us whose scientific careers were influenced by his work and his example.