Primary brain tumors, delta 24 and tumor metabolism

Abstract

Interview by Rona Williamson, Commissioning Editor

Mark R Gilbert studied medicine at the Johns Hopkins School of Medicine in Baltimore (MD, USA). He completed residency training in internal medicine and neurology at the Johns Hopkins Hospital, then was named the first Keck Foundation Fellow in Neuro-Oncology at Johns Hopkins. After 2 years on the faculty at Johns Hopkins, he moved to the University of Pittsburgh to head the Brain Tumor Program. During his tenure at Pittsburgh (PA, USA), he was named Chair of the Brain Tumor Committee of the Eastern Cooperative Oncology Group. In 1996, Dr Gilbert moved to the Emory University in Atlanta (GA, USA) to lead the Medical Neuro-Oncology Program and successfully competed for the program’s membership in the New Approaches to Brain Tumor Treatment consortium. Dr Gilbert moved to the MD Anderson Cancer Center in Houston (TX, USA) in 2000 as Deputy Chair of the Department of Neuro-Oncology. During his tenure at MD Anderson, he has created two brain tumor consortia. The Collaborative Ependymoma Research Network is an international effort that is focusing research efforts on patients, both adult and pediatric, with this uncommon central nervous system tumor. The Brain Tumor Trials Collaborative is a 23-institution consortium that focuses on innovative clinical trials for primary glial malignancies. In addition, Dr Gilbert holds a leadership position in the Radiation Therapy Oncology Group and has served as the principal investigator on several large randomized brain tumor clinical trials. His research focus has been in the area of clinical and translational research for primary brain tumors. This includes novel clinical trial designs and the integration of correlative tumor biology with these clinical studies.

You studied human biology and then received your doctorate of medicine at the prestigious Johns Hopkins University. How do you feel this training prepared and inspired you to specialize in the field of neuro-oncology?

My experience at Johns Hopkins encouraged me to explore academic medicine. At that institution, there were many faculty who effectively combined providing outstanding clinical care with a high level of clinical and laboratory research. My experiences early in medical school led to my participation in laboratory research in oncology. My clinical clerkship on my neurology rotation resulted in a clinical interest in neurology. Advice from the Chairman of Neurology at Johns Hopkins at that time, Guy McKhann, introduced the concept of combining neurology and oncology, leading to my advanced training in neuro-oncology.

Your current position is Professor of Neuro-Oncology at the University of Texas MD Anderson Cancer Center, what do you feel has been your greatest achievement to date in this role and what do you hope to achieve in the future?

From a research perspective, I feel that my greatest contribution has been in the area of clinical research for patients with primary brain tumors. I have been very fortunate to be a member of the Brain Committee of the Radiation Therapy Oncology Group that has recently successfully completed several pivotal randomized trials [1,2]. I was a major contributor to some of these efforts that have created a clinical trial platform that should enhance future studies. Similarly, I have been able to create two research consortia, the Collaborative Ependymoma Research Network [101] and the Brain Tumor Trials Collaborative [102], that are performing innovative studies for patients with ependymoma (an uncommon brain and spinal cord tumor) and malignant gliomas, respectively. My goals are to further advance our ability to rapidly and efficiently test new agents and combinations, and enhance our efforts to translate laboratory findings into clinical trials.

The MD Anderson Cancer Center is continuously ranked among the best hospitals in the world. What do you think the center offers its patients that other hospitals can learn from?

MD Anderson Cancer Center is a remarkable institution that has clearly excelled at both clinical and translational research while providing the highest level of care for patients with cancer. It is one of the largest cancer centers in the world and this provides an outstanding resource of patients who benefit from the state-of-the-art treatment. This is complemented by the high level of collaboration in disease centers. For example, the Brain and Spine Center is an outpatient clinic that sees patients with primary brain tumors, spine cancer and patients with neurologic complications of cancer. As a result, there is open communication between the medical staff including neuro-oncologists, neurologists, neurosurgeons, radiation oncologists and neuroradiologists who practice in the same facility. Patients therefore benefit from this collaborative arrangement, and there is the opportunity for creating new initiatives.

In your experience, what is the most effective method in reducing the time taken from diagnosis of a malignant brain tumor to initiation of therapy?

Recovery from surgery tends to be the limitation for initiating therapy. Collective experience suggests that we wait at least 2 weeks for good wound healing. Neurosurgeons with advanced training in brain tumor surgery probably have a lower likelihood of postoperative issues and better tumor resections. In addition, referral to a brain tumor center of excellence may further improve the treatment timeline.

Is there any advice you can provide neuro-oncologists currently working in the field on the most effective methods to treat one patient when collaborating with numerous departments?

The concept of a multidisciplinary clinic has been in place for well over two decades at the Brain and Spine Center. Working in close proximity has been very beneficial in this regard. This facilitates communications and improves the efficiency of care. Complicated imaging studies can be reviewed in person with an expert in neuroimaging studies. Similarly, having neurosurgeons with expertise in brain tumor management in close proximity allows easy dialogue as either a ‘curb-side consult’ or a logistically easy formal consultation.

Delta 24 is an oncolytic adenovirus currently in trials for therapy of malignant glioma. Can you give us a little more background information on this adenovirus & your hopes for its potential therapeutic application?

The delta 24 is a novel therapy for malignant brain tumors. It was developed by several of my colleagues at MD Anderson, most notably Juan Fueyo, Cande Gomez-Manzano, Fred Lang and Charles Conrad [3]. The unique aspect of this virus is that it has been engineered to only infect and proliferate in cells with an abnormal retinoblastoma pathway, which is restricted to the cancer cells. As a replication-competent virus, once it is injected into the tumor it should be self-propagating. The selective nature allows it to spread to tumor cells, but avoiding the normal brain cells. It is currently being tested in clinical trials at MD Anderson.

Currently you are the principal investigator of a Phase III trial looking at the addition of bevacizumab to the standard treatment of glioblastoma at the MD Anderson Cancer Center. Can you update our readers on the progress of this trial & what your ultimate goal for the trial is?

This study was designed to determine if the addition of bevacizumab to chemoradiation with temozolomide improves outcome for patients with newly diagnosed glioblastoma. This study was run by the Radiation Therapy Oncology Group and completed accrual in 2011. We expect to be able to present the outcomes later this year. Bevacizumab is currently approved for patients with recurrent glioblastoma and this trial will address the question of whether there is additional benefit as a first-line treatment.

From your experience leading & collaborating in clinical trials, what would you say are the major obstacles to advancing therapeutic research for glioblastoma?

There are several obstacles that slow our progress. First, only a very small percentage of patients with malignant brain tumors are treated on clinical trials. There are many reasons for this including patients’ unwillingness to participate, often because of misconceptions about clinical trials; lack of interest on the part of the treating physicians given the modest financial compensation and extra effort required for trial participation; and limited access to clinical trials, particularly for community-based practices. Second, pharmaceutical companies often consider brain tumors as an orphan disease so that financial investment likely has a smaller return than equally successful treatments in diseases such as lung and breast cancer. In addition, it is a time-consuming process to get access to new agent pipelines and very difficult to get pharmaceutical companies to collaborate so that the best agents can be used in combination when they are owned by different companies.

How do you feel that these obstacles are to be overcome in order to ensure advances are made in the research?

Overcoming the obstacles will require a concerted effort to reward the pharmaceutical industry for both investing in relatively low-incidence cancers such as brain tumors and likewise, to generate a system whereby intellectual property is protected in the setting where multiple companies allow combination therapies that take full advantage of our ever-increasing knowledge of tumor biology. Patient accrual can be improved through marketing and education.

Is there a particular area of research you are interested in working in that you currently are not?

Recent discoveries have clearly demonstrated that the cancer problem is even more complex than we had envisioned. Although first reported in the 1930s, tumor metabolism is an area that has recently re-emerged as a potential anticancer target. In the brain tumor field, I feel that this area has great potential, so I have recently begun to consider generating some research projects in this field [4]. For example, the recent discovery reported in 2009 of the high rate of mutation of the isocitrate dehydrogenase 1 gene has led to a widespread effort to find modulators of tumor metabolism that will specifically target cells with the mutation and establish the isocitrate dehydrogenase 1 as a predictive biologic marker [5].

Finally, do you have any words of advice you would give a young researcher entering the field of neuro-oncology?

I would encourage young investigators to seriously consider devoting their career to trying to make advances in the brain tumor field. From the standpoint of science, there are many important recent discoveries and advances in technology such that the possibility of bringing these avenues of research together makes it a very exciting time. There are great opportunities to see individual efforts lead to advances in knowledge and treatment. The field overall is remarkable in the level of collegiality and collaboration.

Financial & competing interests disclosure

MR Gilbert has received honoraria form Genentech, and is on the advisory boards of Genentech/Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.