Research Symposium, October 12
Innovation in the Midst of Challenges: New Paradigms in Cancer Research and Funding

• Introduction, Anna Barker, PhD
• Getting at the Complexity, Tyler Jacks, PhD
• Getting to the Clinic, Giullio Draetta, MD
• Getting Coalitions Together, Dennis Berman, JD
• Wrap-up, Anna Barker, PhD

The complexity of cancer presents researchers with great challenges. Even more challenging are the complex adaptive systems that are brain tumors. We at the National Brain Tumor Society brought prominent researchers together in this symposium to hear firsthand about the complexities and about new approaches to overcoming barriers to developing brain tumor treatments. According to the presenters, hope is on the horizon.

“We probably are at the most opportune time in the history of the world in terms of science.”
— Anna Barker, PhD, Professor and Director Transformative Healthcare Networks, and Co-Director, Complex Adaptive Systems Initiative Arizona State University

The Cancer Genome Atlas (TCGA) project has provided us with a “parts list” in terms of gene and genomic data that researchers can now use to better understand the deadly brain tumor glioblastoma multiforme (GBM). Involved in establishing TCGA at the National Institutes of Health when she was deputy director of the National Cancer Institute, Dr. Barker was the opening speaker at the 2012 National Brain Tumor Society Research Symposium on October 12.

“Personally, my inclination is to believe that innovation is far from dead. And even in times of constrained resources, we will proceed and we will actually take on this disease, GBM, and brain tumors overall, and I’m very optimistic that we will see some huge changes in the next five to ten years, not just in this disease but in all cancers,” Dr. Barker said.

Science has become extraordinarily complex, “And that requires different thinking, different paradigms, different research models, and—ultimately—I think entirely new approaches. We’re creating a lot of data in science today, but taking that and turning it into actionable information for patients is a huge challenge for us,” she said.

Cancer is a complex scenario that starts out with a single mutation and evolves over time. “They don’t all become malignant, but when they do, this is where we lose our way in science. We study malignancy a lot, but it is still the biggest problem we have,” she said.

Genomic alterations drive dysregulation in cancer, which is a complex adaptive system. “I would argue that over the next five to ten years that systems biology is going to become complex systems biology. If you start to think of a system like this as a complex adaptive system, you will treat it differently and you will behave differently in terms of the way you address diagnostics and therapeutics,” she predicted.

TCGA chose GBM as one of the first tumors to sequence. During that research, GBM proved to be significantly different from other cancers in terms of genetic makeup. “I would posit that as we start to really interrogate this database that we are going to make discoveries we only dreamed about a few years ago,” she said.

Getting at the Complexity

“We’ve gone beyond our roots, which are in discovery research figuring out how things work, to the current emphasis on translating those discoveries and new technologies into solutions.”
— Tyler Jacks, PhD, Director and Professor, David H. Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology (MIT)

The Koch Institute is a new model for conducting cancer research. It houses the intersection of cancer biologists and cancer-oriented engineers working together under one roof. “Watchwords for us are integration, bringing these disciplines together, and collaboration, inspiring researchers from different disciplines to work together on common problems,” Dr. Jacks explained.

The research labs at Koch Institute are different in many ways from traditional research labs. Biology and engineering labs rim the outer walls, and common areas in the middle promote spontaneous discussion among researchers. “Because we’ve got a very interdisciplinary mix of individuals, who come from very specialized and distinct backgrounds, they don’t really speak each other’s language,” Dr. Jacks said. “It’s a little bit like Ellis Island. People show up and they can’t really talk to each other at the outset. And so we’ve worked very hard to try to create structures and mechanisms to overcome those barriers, create a new culture. And I’m pleased to say that this is working extremely well, better than I anticipated even.”

One example of Koch research is systems biology. “The National Brain Tumor Society has focused a lot of attention on this area, and I think they should,” Dr. Jacks said. The complexity of a cell looks like an integrated circuit of transistors, which has a lot of network behavior. Cancer biologists have been unable to explain the complex cell’s behavior so far, because, “we just haven’t been equipped to do so until recently,” Dr. Jacks said.

“My colleague, Michael Yaffe, has published recently a paper that demonstrates that use of two approved chemotherapeutic drugs, not given together but given in sequence allows for a much better treatment of a form of breast cancer, triple negative breast cancer, at least in cell-based models and animal models. And the appreciation that this combination would work in this fashion was made solely by the systems biology approach.”

One attendee’s reaction to Dr. Jacks’ presentation: “I just want to say, wow! [laughter in the room] What you are doing is so brilliant, probably so different than the average model. And I believe that different perspectives are critical to finding new answers. So, just keep up the great work.”

Getting to the Clinic

“We need to be applying high-level stringency to what is headed into the clinic.”
— Giulio Draetta, MD, Director, Institute for Applied Cancer Science, and Professor, University of Texas MD Anderson Cancer Center

The Institute for Applied Cancer Science is pushing forward to overcome barriers to overall progress in cancer prevention and improve the research ecosystem. The biggest barriers to treatment progress include limited insight into what drives cancer and the biology of potential drug targets, plus elemental knowledge so far of the cancer genomes and appropriate combinations of therapies to use.

Currently, the research ecosystem cycles consist of basic research in academia, then drug, diagnostic, and technology development in industry, and then back to academia for clinical trials. That center stage, industry development, however, has been shrinking. MD Anderson Cancer Center, through the Institute for Applied Cancer Science, is stepping in to “industrialize academic research to fill a key gap in the drug discovery and development continuum.”

“We have to catalog new medicines to understand more factors such as the microenvironment and immunotherapy,” Dr. Draetta said. “And when we’re thinking of the complexity, we’re dealing with the need to improve the interactivity among academia and industry.”

The quality of new therapeutic agents needs to be improved through such methods as pharmacokinetics and testing in healthy patients for Phase I safety trials. An improved understanding of the disease at the time of treatment is needed, which can come from tumor genetic fingerprinting. “We need a better understanding of the disease and its sensitivity and resistance to agents,” he said.

Much of this improvement can come from earlier evaluation and validation of the effects of therapies in clinical trials. “We need to be applying high-level stringency toward what is headed into the clinic,” Dr. Draetta said. “Clinical research needs to be more transparent.”

Such transparency can become reality in the academic world such as at the Institute for Applied Cancer Science, where collaboration is easier and where coalitions can be built with industry.

Getting Coalitions Together

“Having a coalition is critical to what we’re trying to accomplish.”
— Dennis Berman, JD, Director and Executive Vice President, Tocagen, Inc.

Tocagen, a privately held company, has been able to get its combination high-grade glioma therapy, Toca 511 and Toca FC, into clinical trials because the company has developed a coalition of funding sources that go beyond traditional funding of clinical trials. The coalition consists of government, private investors, and nonprofit sources, including the National Brain Tumor Society. If everything goes according to plans, Tocagen may be looking toward Food and Drug Administration approval within three years, a much shorter time span than traditional approaches.

Toca 511 is a novel retrovirus that is inserted into the tumor by stereotactic injection. “It goes into the tumor but not into the surrounding tissue,” Mr. Berman said.

Wrap-Up

“We have reached a point where we’re gathering enough data to start to think quantitatively about cancer,” Dr. Barker said in a wrap-up session after the presentations. “Cancer is digital information, which means it’s discernable. It’s also a complex adaptive, evolving system. However, the good news is you don’t have to know everything about a complex adaptive system to be able to control it.”

She concluded, “Systems biology, or complex adaptive systems biology, is essentially the next wave of science. And I think we are starting to think like that, but we should not underestimate the extent to which this will be difficult, because you do have to take an entire community out of their comfort zone.”

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