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Applied Biosystems and the Swedish Neuroscience Institute

A partnership for the advancement of science

Greg Foltz, M.D. & Anup Madan, Ph.D.

Seattle Neuroscience Institute
Swedish Medical Center

The Swedish Neuroscience Institute established the Center for Advanced Brain Tumor Treatment as the first multidisciplinary treatment and research center in the Pacific Northwest dedicated solely to the treatment of brain tumors. Located adjacent to world-class research facilities, the out-patient clinic provides instant access to promising new therapies, offering hope for patients with all stages of brain tumors, including brain cancer.

Genomics scientist Anup Madan and neurosurgeon Greg Foltz are co-directors of the Center for Advanced Brain Tumor Treatment, working together to translate the scientific discoveries made in the lab into new clinical approaches in the treatment center. We recently had the opportunity to talk with Dr. Madan and Dr. Foltz about the collaborative work they are doing and how Applied Biosystems is helping scientists and physicians better understand the genomics of brain tumors and more effectively treat the patients afflicted by them.

First off, please introduce yourselves and tell us a little about your areas of expertise.

[Dr. Madan] My area of expertise is genomics and bioinformatics. I work in the research lab performing the genetic analysis of tumors and looking at the gene expression changes and genetic changes that drive tumor formation.

[Dr. Foltz] I take care of patients with brain cancer, which involves surgically removing their tumors and post-operative care and counseling in terms of further treatments.

What drove each of you to pursue working on brain cancer?

[Dr. Madan] Greg and I first met in Lee Hood's lab where I was finishing up my work on human genome sequencing. I wanted that research to really benefit people, and teaming up with Greg in the area of brain tumors was a meaningful way to work toward that goal.

[Dr. Foltz] I've always had an interest in patients with brain cancer--in fact, that's why I went to medical school. Everything I do, from taking care of patients in the clinic to trying to come up with new advances in the lab, is really designed to bring them some hope. Today, it's still an incurable disease with no effective treatment, so anything we can do to understand these tumors and push the field forward just a little bit will be of great benefit to them.

During my post-doc with Dr. Leroy Hood, I got to know Anup and started to apply genomic approaches to understanding brain cancer. Ultimately the goal is to use the genomics discoveries we are making in the lab back to design and formulate new treatment approaches for patients. It's the combination of the clinical work on my side and the scientific work on Anup's side that I think is going to yield great advances in the future.

Why did the Swedish Neuroscience Institute choose the SOLiD system from Applied Biosystems?

[Dr. Foltz] We chose the SOLiD System because of our long-standing relationship with Applied Biosystems. We have always been very pleased with the platforms they have produced in the past, including real-time PCR, microarray, and gene sequencing technologies, and our ability to do cutting-edge science that had immediate clinical impact using those platforms. When AB announced the next-generation sequencing technology, it was a very easy choice for us because of that track record.

[Dr. Madan] One of the reasons we selected the SOLiD System was the great technical support we get from AB. They are always very responsive; if anything breaks they're here within a day or two, and that kind of support is very hard to get from other companies. The SOLiD System also has better accuracy compared to the competitors.

What is the nature of your current and future research, and what role does the SOLiD System play?

[Dr. Madan] In our genomics lab, we look at the modifications to DNA and RNA that affect a process such as cancer. Specifically, we are investigating the role of epigenetic mechanisms in tumor formation. For this, we will use ChIP-Seq and RNA-Seq to identify relationship between transcriptional activity and brain tumor initiation and progression.

[Dr. Foltz] I'll just add that there are occasions in a scientific lifetime when a new technology really opens the door to the possibility of discovery on a magnitude that's never been possible before. That's the role the SOLiD system plays-I have never seen a single technology that will move us forward as rapidly. For the first time, we can investigate every single aspect of the genomics of brain cancer, which is the key to improving our understanding of the disease and developing new treatment options. I'm very excited about having access to this system in our community hospital setting and the opportunity it's going to afford our patients.

Tell us a little about the specific goals of your current research.

[Dr. Madan] Our goal is to use the SOLiD System to begin to understand how brain tumors develop and provide better therapies to patients. For example, by isolating the cancer stem cells from patients, we can study the genomic content and understand how these cancer stem cells differentiate. This analysis will allow us to identify drugs that will be effective in killing these cells along with differentiated cells.

[Dr. Foltz] At a fundamental level, we have to improve our understanding of the genomic changes that lead to brain cancer. The SOLiD System is going to help us do that by giving us a picture of the entire genome in an individual patient's tumor. This will allow us to understand the disease better in individual patients and design individualized therapies that will lead to better outcomes. That's the very first thing that we have to do today for near-term-even immediate-impact on patient care.

In the longer term, there is a large discovery component here as well. We are going to discover things that have never been seen before in brain cancer, and that's going to advance our understanding of the disease and lead to new ideas about how to treat it.

What kinds of things can you learn from the in-depth genomic information you get from SOLiD?

[Dr. Foltz] It's clear that if you're talking about cancer, you're talking about a disease that is rooted in the genome, meaning that changes in the genome are driving the disease process. All tumors look the same under the microscope but, when you look at them on the genomic level, there are tremendous differences and variabilities between patients. We believe that these differences correlate with how quickly an individual's disease will progress and how patients will respond to treatment.

The SOLiD system allows us to extract a tremendous amount of genomic information by interrogating a patient's tumor at many different levels. We put that information into a database and, after we've looked across several hundred patients, we're able to see patterns in genomic change that might indicate certain things, such as which tumors are particularly aggressive. It may be different genes that are expressed, it may be a mutation, it may be microRNA-all of these aspects of the genomic information are available to us using the SOLiD system.

What near-term impact do you expect your work to have on medical treatment?

[Dr. Foltz] Cancer never sleeps; it's a relentless foe and you have to stay ahead of the disease to be able to anticipate and predict its behavior. You do not want to fall behind. New technologies like SOLiD are giving us the ability to look ahead and make a prediction of what we think a patient's disease is going to do. Even if it's just six months' advance notice, that's a lot of time to identify patients that we think are going to do poorly and bring more advanced treatments to them sooner. We can use that time to mobilize our forces and prepare patients for the next steps, enroll them in clinical trials, and help them get their family and social support system in place in case they need to go through an intensive therapy.

Would you say that the SOLiD system is essential to your work and to the advancement of the science in general?

[Dr. Foltz] Yes. Prior to the SOLiD system, we had a variety of technologies and platforms, none of which could give us a complete and exact picture of the genome. The SOLiD System gives us a very exact, in-depth picture. We can look across the entire genome and see with a high degree of sensitivity what is happening at the level of gene expression or gene mutation. When you're looking at a disease as complex as cancer with so much variability between patients, you have to get that part right in order to make accurate predictions.

In fact, several recently published studies on genomic changes in brain cancer have used the SOLiD System to show that there's a tremendous heterogeneity across tumors-that we probably aren't talking about a single disease, but rather a whole spectrum of disease. These findings have really opened the eyes of clinicians who treat brain cancer patients, and started them thinking about how to tailor treatments to a specific patient instead of treating all patients as though they're the same. I think this represents a major breakthrough.

[Dr. Madan] I agree. It's like comparing analog information to digital information. Earlier technologies lacked the sensitivity we needed to study the lowly expressed transcripts. Using SOLiD system we can monitor the changes in the expression of these genes that opens the door to better understanding of perturbed pathways associated with various diseases. For example, let's say that a given gene that plays a significant role is expressed in five copies in normal state and tumors had ten copies-it's a two-fold change in expression. This change was not detectable by earlier technologies but with the SOLiD system we can detect it and this leads to better understand the biology.

Are there any specific advantages/benefits of using the SOLiD system for cancer research?

[Dr. Madan] The SOLiD System will allow us to investigate the transcription profiles of any cancer, or any other disease, at an unprecedented level in a very cost-effective manner. With a better understanding of the biological networks-including microRNA, transcription factors, and gene expression and mutation-that are perturbed in association with a disease, we will be able to develop targeted therapies for individual patients.

[Dr. Foltz] Very simply, I think the SOLiD System has moved us to a whole new level in two major ways: scientific discovery and genome description as it relates to brain cancer. An example of scientific discovery is in the area of microRNA. Prior to the SOLiD System, doing a large-scale microRNA sequencing project was difficult. With SOLiD, it's trivial, which will allow us to detect new species of microRNA in brain cancer. That's pure discovery.

Along with that, there's the incredible benefit of using the SOLiD System in a descriptive fashion to understand the genome and how it's expressed in cancer. Before, you could spend a lot of time trying to figure out which genes are expressed in a given patient. The SOLiD System lets us do that quickly and easily across a large number of patients. This is going to allow us to understand how this disease varies across patients and then to design our treatments tailored to a specific patient or group of patients. That's going to be a tremendous advance.

What excites you most about the work you are doing now?

[Dr. Madan] Our research is always evolving. As soon as the SOLiD System came to market, we were among the first to adopt it because it will help us give brain cancer patients the best possible treatment options based upon their individual genetic or proteome analysis. I'm gratified coming to work every day knowing that I'm helping somebody else to live a longer, better-quality life.

[Dr. Foltz] If you take a look at the history of this disease, for a hundred years there were no advances-a diagnosis of the most common form of brain cancer, glioblastoma, was a death sentence. When I first started in this field 15 years ago, survival was about a year and that was it. Today, we fully expect to give patients two or even three years because of our ability to understand the disease a lot better up front, which allows us to tailor therapies and bring some of the more advanced treatments to play as they're needed. What's really exciting to me is the possibility of adding many more years to that number and ultimately contributing to finding a cure.

What direction do you see your future work taking with the SOLiD System?

[Dr. Madan] We will be using the SOLiD System to investigate cancer at the genomic level and identify new molecules, like microRNA molecules, new transcription factors, new maculation marks, and new epigenetic alterations. By better understanding cancer, we will be able to better treat patients.

[Dr. Foltz] I think we're going to be having a lot more fun and be even more excited about the results we're getting because the SOLiD System is going to give us insights and new discoveries that will lead to entirely new approaches to treating brain cancer. We are going to use it as a unifying platform to take a look at many important aspects of brain cancer biology-mutations in patients and how they vary across patients, whole genome gene expression, microRNA, how genes and networks are regulated, analysis of promoter regions, and the list goes on. These are all questions that we are currently investigating in the lab, but we've never had a platform that's allowed us to look at with the depth and the accuracy the SOLiD System will allow us.

Finally, how would you describe your relationship with Applied Biosystems, and how has it affected your research and your results?

[Dr. Foltz] From the very first day our lab opened, we have had a great collaborative relationship with AB. We have been using the entire AB platform to do genomic analysis on patients with brain cancer for several years, and have always been very pleased with the technology and the support we get from the company.

We're also very pleased with the results we get using AB technologies. That's critically important because, at the end of the day, if you're a clinician and a scientist trying to make a difference in the lives of people with a terrible disease like brain cancer, it's really all about the results. I can tell you that we have never failed to get the answers we need using AB technologies. That is why we are so excited about the SOLiD System and the work we have ahead of us. I have complete confidence that we are going to be able to make a difference.

For Research Use Only. Not for use in diagnostic procedures. Applera, Applied Biosystems, and AB (Design) are registered trademarks and SNPlex and SOLiD are trademarks of Applera Corporation or its subsidiaries in the US and/or certain other countries. TaqMan is a registered trademark of Roche Molecular Systems, Inc.

©Copyright 2008. Applied Biosystems. All rights reserved.