The agile scientist: Q&A with Web Cavenee

If someone wrote your biography, what would the title be?

Prepared for Serendipity

You influenced how scientists now think about the onset of cancer and its progression when you demonstrated proof of tumor suppressor genes in humans. Was this a totally unexpected finding?
Actually, we had what we thought was a reasonable expectation based on epidemiological analyses by Al Knudson at Fox Chase, cytogenetic findings by Bob Sparkes at UCLA and a unique family that was reported by Louise Strong at MD Anderson. Putting all of that together and testing the hypothesis using the new tools that Ray White and I were developing was compelling to us, although not so much for most in the cancer genetics community. Thankfully, the three years of hard work it took to actually be able to do the experiment validated our expectations.

What is glioblastoma (GBM), and why is it so hard to treat?
GBM is the most common intracranial tumor and, unfortunately, one of the most lethal, with an average survival from diagnosis of about 14 months. This is because of some intrinsic features of GBM, including inherent radio-resistance, inherent and acquired chemo-resistance, the migratory nature of the cells that limits complete surgical resection, and the heterogeneity and genetic plasticity of the tumors.

What new treatments are being investigated for glioblastoma?
Most new treatments are targeted at specific mutations in GBM cells, although immunotherapies, radio-sensitization and viral or nanoparticle delivery are all being tested.

Does the heterogeneity of glioma cells limit the efficacy of immunotherapy?
GBM heterogeneity has been the major impediment to therapeutic progress with any modality. Another major issue is that the tumor resides behind the blood-brain barrier, which limits the distribution of therapeutic agents.

Tell us about the Defeat GBM Research Collaborative and your role in it.
There are several collaborative initiatives directed at GBM now, with the idea being that conjoint efforts by investigators with varying approaches and viewpoints are more likely to accelerate progress in understanding and treating the disease. The Defeat group, under the auspices of the National Brain Tumor Society (NBTS), was one of the first such efforts. I had the pleasure of being one of the instigators (Bob Strausberg was as well) of that multi-institutional initiative and one of its first investigators and leaders. In its first four years, the Defeat group has developed new agents and approaches that are now entering clinical trials. The NBTS has also announced that it will support Defeat #2, with some of the original investigators as well as some new ones. I fully believe that this has and will continue to accelerate progress.

What is GBM AGILE?
GBM AGILE arose from conversations I had nearly five years ago with Ann Barker, the former Deputy Director of the National Cancer Institute, who is now at Arizona State University and Al Yung, the Ludwig scientific advisor who was then chair of neuro-oncology at MD Anderson, in which we decried the lack of success in extending the survival of patients with GBM. We posited that a more unified approach might be an answer and held a series of brainstorming meetings over the following couple of years, soliciting and focusing the views of more than 150 international neurosurgeons, neuro-oncologists, neuroradiologists, researchers, mathematicians, bioinformaticians, pharma representatives, and FDA personnel and patients. A major issue identified through these meetings was the need to address the way that clinical trials are conducted. They were hamstrung with way too many restrictions. That included their serial nature; the requirement that half the enrolled patients be assigned to the control arm; the limited number of patients that could be enrolled at any one institution, which in turn limited the numbers of drugs that could be tested and which necessitated a very limited stratification of patients; and limited clinical or scientific follow-up.

What makes it different from other clinical trials?
GBM AGILE was developed as a new construct to address the shortcomings I’ve mentioned. It’s truly unique in its flexibility and adaptability, qualities that took three years to design. It encompasses several distinctive features: Bayesian algorithm-driven patient randomization and arm assignment that incorporates the use of biomarkers; a master protocol, which allows arms to enter or exit the trial without having to revise it and have it reapproved; an international agent selection group; multiple arms, so as to minimize the number of patients needed for the control arm; a common data analytic and tissue repository; and an FDA-approved design that allows seamless transition of succeeding drugs or combinations of drugs through randomized Phase 2 to registration quality Phase 3 trials. It is sponsored by a new 501(c)3 organization named the Global Consortium for Adaptive Research (GCAR), and I serve on its Board of Directors and as interim Chief Scientific Officer. Some 40 sites in the US are currently being evaluated and discussions are active with regulatory agencies in Canada, China, Australia, Europe and Israel. This extended network will provide a sufficient number of patients to rapidly test many agents singly and in combination.

The Henry Ford Cancer Institute just enrolled its first patient in a GBM AGILE trial this past August. Tell us how being a part of AGILE makes a difference for this patient?
GBM AGILE was designed to allow candidate treatments to “fail fast” and “correct even faster.” That comes with many advantages to the patients as well. Just two: the testing of several drugs in separate arms of the trial permits the use of a common control arm, minimizing the numbers of patients who will not receive an experimental drug; and the longitudinal design of the trial means that the response of patients to a drug is followed carefully and in a highly prescribed manner, so that a patient who is not responding can be quickly moved to another arm, offering them a second chance at a potentially successful therapy.

How did joining Ludwig advance or change your career?
It is hard to believe, since Ludwig is now such a dominant force in cancer research, but when Hugh Butt and Donald Park first approached me in the early 1980s, it was still a small and relatively unknown entity. I was a young grant-funded faculty member, and, when we finally connected, they offered access to a newly developing Ludwig network that included some of the most renowned researchers in the world. Moreover, the Institute was international, interactive and well-supported. I clearly remember asking Hugh what the catch was, and he told me to look in the mirror and understand that my success or failure depended on me alone. No excuses. I relished this challenge and it turned out to be exactly right as, over the years, Ludwig has afforded me the opportunity to do science at the highest level, to develop and exercise abilities in constructing teams for scientific inquiry and to participate on the international stage. I am very grateful for the 33 years of support that Ludwig has provided to me and proud of the two outstanding and widely recognized Branches that I assembled in Montreal and San Diego. It has been a wonderful run!

What scientific finding of yours has been most surprising to you?
The most surprising and gratifying finding arose from work we were doing tracking the origins of recessive mutations in families. This gave us the idea in the early 1980s that we could use parents, siblings and/or their tumors to predict if a child in the family would develop disease—before it was even diagnosed—simply by following genotypes with the DNA markers I had developed and identifying those associated with affected members. We were elated when we were able to say very accurately that a child would not develop the tumor. In fact, even being able to identify kids who were very likely to develop the disease was also useful because they could be examined even earlier knowing that the risks of anesthesia were justified by the possibility of earlier radiotherapy or surgery. Our (my friends Magnus Nordenskjold at the Clinical Genetics Department at the Karolinska Institute in Stockholm, Brenda Gallie at the Hospital for Sick Children in Toronto and Linn Murphree at the Children’s Hospital of Los Angeles) report of this hit like a bombshell because it showed for the first time that it was becoming increasingly possible to identify extremely high-risk individuals and offer them curative therapies in many cases.

Parenthetically, Magnus and I and our families were staying at his summer house in the Stockholm archipelago writing this paper in the evenings and building a tree house for the kids during the day. There were only a couple of phones on the small island but, even so, I was receiving mysterious phone calls from a Dr. Butt who seemed to be all over the world and saying that he understood “I was interested in his job.” I had no clue what that was about and so simply ignored it until I returned to the U.S. (where Hugh called me at 6 am the morning after I landed). The rest is history!

Do you see a role for nutrition and microbiome research in GBM?
Sure. This is an exciting and promising area for cancer in general. It can be extended to intracellular metabolism, where several Ludwig investigators have made advances showing that cancer cell metabolism can be influenced by oncogenic mutations and thereby affect the growth of those cells or even the normal cells surrounding them.

What do you see in your post-Ludwig career? Will you remain in GBM research or pursue new opportunities, or both?
Definitely both. I want to be sure that the several reviewers who called me “unfocused” continue to be right! Fortunately, there are several other international organizations, including the Global Coalition for Adaptive Research and institutes, universities and companies that value my views. Consulting for them will continue to keep me busy.

What are you most proud of in your career?
My greatest accomplishment is contributing to the training, scientific maturation and ongoing success of the more than 120 students and fellows who have been members of my group, as well as the many hundreds of trainees who have been resident in the other laboratories in the Ludwig Montreal and San Diego Branches. I am proud of every one of them!

What advice would you give to young investigators today?
Read everything you can, work hard and trust your intuition, but with an open mind.

Who in your life influenced you the most?
There have been so many. Those who immediately come to mind are my father, Jim Cavenee, a career Air Force officer, and my uncle Max Ryan, who was a rodeo rider, dirt-track car racer and interstate truck driver. Both of them actively instilled in me the belief that being honest and standing up for what I believed—regardless of consequence—was how I was expected to lead my life. From a scientific standpoint, another uncle, Web Sawyer, who was head of chemistry for Shell Oil and taught at the University of California, Berkeley, piqued my imagination about the power of science when I was very young. Also, my postdoctoral mentor and friend, Ray White, who demonstrated every day that strength of conviction coupled with healthy skepticism about what are “true facts”; and Lloyd Old, who taught me that anything is possible when dreaming big and then actualizing those dreams. I am, and will be, eternally grateful to them all.