The Interdiscipinary Leukemia Project
The Interdisciplinary Leukemia Project
In 2009 the CRF pledged to give the University of Chicago $3 million dollars over the next three years to kick off a six-part, systems biology-based interdisciplinary attack on therapy-based Acute Myeloid Leukemia, a secondary cancer that strikes 8 to 10% of cancer survivors. The five year program will include high-throughput genomic screening, work in blood stem cells, clinical trials and high-level informatics, all focused on the same disease and pursued at the same time in a coordinated manner. While the primary goal of this project is to find answers surrounding this terrible disease, the hope is that by applying a systems-based approach to cancer research, the project will be able to change the way that cancer science is pursued.
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Harnessing Systems Biology to Fight a Fatal Cancer
Therapy-related acute myeloid leukemia (t-AML) is a particularly cruel and ironic cancer, one that is caused by cancer treatment itself. Typically, t-AML patients have celebrated success over their initial disease, only to learn that the treatment that wiped out their malignancy has actually caused a subsequent, uniformly fatal cancer. There are no treatment options and no survivors after five years. Average life expectancy after diagnosis is a scant eight months.
The University of Chicago has launched an all-out assault on t-AML that is unprecedented in its scope, sophistication, and integration. The quest is urgent. Thanks to medical advances, the population of cancer survivors has reached 14 million in the United States alone and is growing. But that success also means more people at risk for t-AML, the incidence of which peaks at 10 percent of "survivors" in the fifth year following initial treatment for adults, and in the second or third year of survival for children.
Using new methods of research, the University is employing a "systems biology'' approach to unravel t-AML's full genomic complexity. A highly coordinated series of experiments will yield:
- Genetic tests that identify cancer patients at risk for t-AML so their treatments can be modified to prevent it
- Chemical compounds that kill the leukemia stem cells that make t-AML deadly, cells that are untouched by current drugs
- Clinical trials to prove the safety and effectiveness of promising treatments and make them available to patients as soon as possible.
Systems biology increases the power of life sciences, enabling researchers to understand complex biological systems in order to pinpoint the slight variations in normal cellular regulation resulting from genetic abnormalities, external environmental influences, or both, that open the door to disease. Complex gene networks, biologists have realized, won't yield their secrets to the methods of traditional reductive science, which reduce problems to their basic elements and focus only on those discrete pieces of knowledge. At the forefront of the genomics revolution, a prime challenge is to master vast amounts of data describing thousands of interacting, interdependent genetic mechanisms.
As pioneered at the University of Chicago, systems biology is fast biology. Automated lab machines work round the clock to sequence DNA and track gene interactions, recording a census of the myriad molecular interactions involved in healthy and malignant blood production. The resulting set of raw data, however, is far too large for any person to analyze. That's done by fast computers programmed to model systems of molecular interactions, efficiently determine how they work, and predict ways to avoid or disrupt disease processes with new therapies.
Why the University of Chicago?
The University of Chicago Medical Center has an unmatched record in blood cancer research starting with the development of the first chemotherapy in 1943. For t-AML in particular, the University of Chicago Cancer Research Center (CRC) was first to identify the disease's main features and to discover how it arises from treatment-induced collateral damage to patients' DNA. For three decades, U of C clinicians have been treating patients with t-AML, amassing one of world's largest t-AML tissue banks. In short, the CRC knows t-AML better than anyone else.
Now the University of Chicago's grand legacy of basic discoveries and clinical experience will serve a high-powered, interdisciplinary cadre of 13 top scientists whose expertise knits together laboratory science, information technology and clinical treatment. CRC Director Michelle Le Beau, PhD, a pioneer in t-AML research, is quarterbacking a group that includes pediatric and adult oncologists who specialize in t-AML, world experts in blood stem cell biology, pioneers in systems biology and genomic profiling, leaders in pharmacogenomics, and renowned computational biologists, whose analysis of data sets is the glue holding the projects together. All of their expertise - covering molecules, cells, tumors, organ systems and, ultimately, patients - is required to meet the systems biology challenge.
Few other institutions in the world have the depth of expertise, culture of interdisciplinary collaboration, and technological resources available at the University of Chicago. "The stars are really aligned for this project,'' says Le Beau. "The entire cycle of translational research is represented right here in the group of scientists working together on this project.''
All Teams Drive toward Single Goal: Genomically Personalized Treatments
The research strategies for individual teams of t-AML investigators are choreographed so that findings from one team will yield results that can be immediately handed off to another group. The end goal is not a single discovery, but rather a series of major advances driving toward clinical trials and predictive, genomically personalized treatments.
One team has begun profiling the genetic signatures of both healthy and malignant cells from a large cohort of t-AML patients treated at the Medical Center. Their work will identify both the inherited genes that make cancer patients susceptible to t-AML and the acquired genetic mutations present in malignant t-AML cells. Our computational biology team will analyze those two sets of genetic signatures to discover the altered cellular regulatory pathways that produce malignant bloods cells in myeloid leukemia.
The ongoing work of a third team then comes into play. Researchers will identify the molecular pathways involved in normal hematopoiesis, the production of healthy blood cells. The computational team will compare these newly discovered normal and abnormal pathways and pinpoint the molecular interactions that go awry in t-AML.
Three more teams will:
- Transplant t-AML cancer cells into mouse models in order to isolate leukemia stem cells, which can then be studied to identify targets for effective chemotherapy. CRC researchers believe current t-AML treatments are unsuccessful because they fail to kill these "progenitor" leukemia stem cells, which quickly re-establish cancer.
- Screen samples from the patients we have genetically profiled to discover which drugs are most effective for their disease. University of Chicago pharmacogenomics experts will link drug sensitivity data with genetic signature data to design tests that individualize treatment.
- Design and conduct clinical trials of new t-AML drugs, starting with a current drug candidate that is ready for immediate trial, and extending to multiple new targets discovered along the way.
The integration of these multidisciplinary teams and the complexity of the network of interactions they will address within the scope of a consolidated effort are remarkable, if not unprecedented, in cancer research. The successes of this project should save thousands of lives and demonstrate to researchers around the world how to harness systems biology to beat cancer and other complex diseases such as diabetes.
"I owe a great deal to the Cancer Research Foundation for giving me a head start. This financial help made the difference between my getting a fast and successful start, and my other wise struggling to obtain the necessary funds to get my research program started."Elaine Fuchs, Ph.D.
Professor, Departments of Medicine and Molecular Genetics and Cell Biology and Human Genetics University of Chicago
April 30, 2010