In the 1980s, an award-winning film written by and starring Andre Gregory and Wallace Shawn portrayed an open and lively dinner conversation between the two about art, the theater, and life in general. Recently, several of us had dinner with Dr. Gordon Mills for an equally open and lively conversation about cancer research, systems biology and brain tumors. “Our Dinner with Gordon” conversation provided the basis for our first interview of the series.
We are delighted that Dr. Mills was generous with his time and his insights. He is currently the Chairman, Department of Systems Biology at MD Anderson Cancer Center in Houston,Texas. He is also a Wiess Distinguished University Chair in Cancer Medicine and Head of the Kleberg Center for Molecular Markers. Dr. Mills received both his MD and a PhD in Biochemistry from the University of Alberta in Edmonton, Canada. Prior to joining MD Anderson he was an Associate Professor in the departments of Obstetrics and Gynecology, Immunology, and Clinical Biochemistry, and Director of Oncology Research at the University of Toronto Hospital. He is an author of more than 300 scientific publications and leads active research programs in cancer genomics and signal transduction pathway aberrations involved in driving cancer biology.
In addition to Dr. Mills and me, the dinner conversation included:
N. Paul TonThat, NBTS Executive Director
Dr. W.K. Alfred Yung, Chairman and Professor of Neurology (Department of Neuro-Oncology); Margaret and Ben Love Chair in Clinical Cancer
Dr. Oliver Bögler, Vice President, Global Academic Programs, Professor, Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, and Chair of the NBTS Scientific Advisory Council
We hope you find our Dinner with Gordon conversation helpful in your understanding of the systems biology research and that you enjoy reading it.
David R. Hurwitz, PhD
Richard B. Ross Chief Scientific Officer
National Brain Tumor Society
A Dinner Conversation with Dr. Gordon Mills
N. Paul TonThat
Dr. Mills, we would like to thank you for taking the time to share with us your expertise and insights into systems biology approaches to cancer research and how they apply to brain tumor research.
We’ve seen that there are vibrant discussions in the field about what types of studies constitute a systems biology approach to cancer research. We’d appreciate you sharing with us your way of thinking about this.
Dr. Gordon Mills
Different people in the field do have different perspectives on the defining of what constitutes a systems biology research approach. I think that the best way of looking at it is it fits the old expression that “you know it when you see it.”
Most biological research has taken a reductionist approach in which complex biological systems are divided and reduced into smaller components with the idea that by understanding the individual components and then adding them together you can understand the workings of the whole system.
But nothing works in isolation and anything taken out of context has no meaning for the whole. The parts have to be put into context.
What is central to a systems biology approach is that components are not studied in isolation but rather in the context of interconnecting and interacting systems. Biological events and processes need to be understood not in isolation but in the broader context of the biological system.
Let me give you a couple of metaphors.
Look at a car braking system. In a reductionist approach one could study a brake pedal by itself until you know everything about brake pedals. But alone it is just a pedal. What makes it work is its interconnection with the braking system behind it and how the components of the rest of the braking system interact with each other. Nothing happens in isolation.
Another example can be taken from the field of archeology. On a dig there might be a big pile of rubble with each of the pieces looked at individually. Only when you fit them together and see how they interact with each other do they make sense and emerge as a different whole, perhaps for example an arch. Only by understanding how all of the pieces of an arch fit together and interact can one know which piece or pieces need to be removed in order to have the entire arch fall apart.
Similarly, knowing how the components of a biochemical pathway (e.g. signal transduction pathway) that drives a cancer fit together and interact with other pathways in the broader biological context of the cancer may allow for the identification of specific components that if inhibited by drugs would cause the entire tumor cell system to fall apart resulting in the eradication of the cancer. We already know that it is not likely that a single drug directed at a single molecular target in brain tumors will be able to completely kill the tumor and that the tumor will recur. That’s due to a great extent to the complex interactions between the different pathways. Block one pathway and the biological system will fill in the hole and another pathway will take over and continue to drive the tumor growth. And so a combination of drugs will be required to interfere with more than one pathway.
Dr. Oliver Bögler
How many interventional points do you think would be required to shut down the entire tumor biology?
Dr. Gordon Mills
I think that a drug or combination of drugs that interfere with two interventional points would be sufficient. But it has to be the right two targets that are inhibited. Systems biology research holds the promise of identifying which two specific targets amongst all of the potential targets within the complex interacting pathways would be the right two targets. Of course it is still to be determined if two would be sufficient.
Dr. David Hurwitz
How about the issue of cellular heterogeneity within a tumor and how that impacts how many drugs would be required to kill the tumor and prevent it from recurring?
Dr. Gordon Mills
Tumor cell heterogeneity is the biggest challenge. I do believe that perhaps only two drugs directed at two targets in different pathways would be sufficient to disrupt the biological system of any particular sub-group of cells within a brain tumor. But it is true that a different set of two drugs might be required to kill another sub-group of cells within the tumor. That might mean that perhaps four different drugs would be required. Systems biology research focused on determining the molecular characteristics of not just the “tumor” but rather of all of the sub-groups of cells that make up the tumor and how they relate to each other will be important in figuring this out.
Dr. David Hurwitz
Do you think that even if only two drugs were required that it would be more effective to administer them concurrently or sequentially?
Dr. Gordon Mills
I think that definitely a sequential drug approach will be shown to be more effective. We are already obtaining results from studies that indicate that if a tumor is predominantly being driven through one signal transduction pathway that inhibiting that pathway with a single drug will allow some tumor cells to adapt allowing the tumor to recur because it is now utilizing a different pathway to drive its growth. A therapeutic strategy that calls upon using a second drug to inhibit the pathway to which tumor cells have switched will only be successful if the tumor cells have already made the switch.
If two drugs that target the first and second pathways are given concurrently to tumor cells that are being driven by just the first pathway, some tumor cells might still adapt and become driven by the second pathway when the drugs are withdrawn. But it could be much more effective if the drugs are given sequentially. Administration of the second drug that inhibits the second pathway could be effective against the tumor cells that have adapted to the first drug and switched dependence of its growth from the first to the second pathway.
N. Paul TonThat
Dr. Mills, what do you think is currently seen as growing importance in systems biology research for cancer in general and brain tumors specifically?
Dr. Alfred Yung
Gordon, your work with metastatic brain tumors that we are collaborating on is just such an important area.
Dr. Gordon Mills
Absolutely Al.
More and more, research is showing that an integral and influential part of the biological system of cancer in general and metastatic brain tumors specifically is the tumor microenvironment. The tumor microenvironment has substantial influence on the biology of the tumor and the power of this influence is dramatically seen in our work with metastatic brain tumors.
Up to and including now, it has generally been thought that the biology of metastatic brain tumors reflects the biology of the primary cancer from which they were derived. So metastatic brain tumors from breast cancer would have a biology reflecting breast cancer in the breast, brain tumors from lung cancer would have a biology reflecting lung cancer in the lung, and so forth and so on. What we are demonstrating in mouse models is that in fact when breast or lung or colon cancer tumors are implanted into the brain that their gene expression patterns change dramatically and they develop similar biological characteristics (phenotype) to each other and to primary brain tumors and that these characteristics are different than the biological characteristics of the tumor of origin. If these adapted tumors are put back into mice into their original sites of origin their biologies change back. You again put them back into brains and they again change into a similar biology.
What’s more, we have demonstrated that it is the brain microenvironment interacting with the tumor cells that is causing the change of tumor cell phenotype. We are currently investigating the mechanism by which the brain microenvironment has such a dramatic influence on the phenotype of brain metastases.
N. Paul TonThat
Dr. Mills, again we would like to thank you so very much for sharing with us your time and thoughts about systems biology and how it applies to brain tumor research.
Dr. Gordon Mills
You are most welcome. The Systems Biology program of NBTS is very important and I am pleased to help.
