Overview: Developing Personalized Treatments for
Therapy-Related Leukemia

The University of Chicago has formed a unique leukemia research program to discover genetic susceptibility factors involved in the development of therapy-related acute myeloid leukemia (t-AML), a unique form of leukemia that occurs in patients who have already been treated successfully for another cancer.

Using a systems biology approach, the research team aims to develop a global perspective of the biological processes that underlie this disease to identify new targets for therapies. The end goal of the research is not a single discovery, but rather a series of major discoveries that will facilitate clinical trials and the discovery of more effective, genomically-personalized therapies for patients with t-AML.

The success of this project should save countless lives and demonstrate to researchers around the world how to harness systems biology to fight cancer and other complex diseases.

Researchers at the University of Chicago have formed multidisciplinary teams to unravel the complex network of molecular interactions that take place during the development of leukemia. The effort is remarkable, if not unprecedented, in cancer research. Their discoveries will lead to not only the development of new therapies for leukemia that can be tailored to the individual patient, but also improved prevention strategies for t-AML. Ultimately, the knowledge gained from this research will allow clinicians to:

  • Reduce the incidence of t-AML by identifying individuals who are at risk; and
  • Select the appropriate therapy for treatment of patients with a primary cancer to minimize their risk of developing secondary leukemia.

The success of this project should save countless lives and demonstrate to researchers around the world how to harness systems biology to fight cancer and other complex diseases.

Research Teams

The University of Chicago research program is organized into six highly-integrated research teams. Through these interrelated teams, researchers are making a coordinated effort to gain a detailed understanding of leukemia. The research strategies for each team of investigators are choreographed so that findings from one team yield results that can be immediately handed off to another team. Teams are analyzing biological samples from the same patients, so the results generated can guide the experiments performed by other teams. This highly-integrated research approach allows investigators to identify cellular networks that are deregulated in leukemia more effectively. Building from this information, they can then simulate the cellular response to single drugs or new combinations of drugs using computational biology approaches.

This coordinated research effort will lead to:

  • Genetic tests that identify cancer patients who may be at risk for t-AML, which would indicate to clinicians if their treatments should be modified to prevent the development of the disease;
  • Chemical compounds that kill leukemia stem cells which give rise to t-AML, cells that are untouched by current drugs; and
  • Clinical trials to prove the safety and effectiveness of promising new treatments and make them available to patients as soon as possible.

Research Organization

Team 1 – Identifying Genetic Susceptibilities and the Genetic Profile of Therapy-Related Leukemias Team 1 is developing a genetic profile of t-AML. Researchers are profiling the genetic signatures of both healthy and malignant cells from a large group of t-AML patients treated at the University of Chicago Medical Center and throughout the world. 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. Team 6 will then analyze these two sets of genetic signatures to discover the altered cellular pathways responsible for producing malignant bloods cells in myeloid leukemia.

Team 2 – Understanding the Molecular Pathways involved in the Production of Normal Blood Cells Researchers in Team 2 are performing work similar to those in Team 1, except they are identifying the molecular pathways involved in the production of healthy blood cells. These observations will have wide-ranging implications both for therapy-related AML, other leukemias, and inherited blood diseases. Team 6 will compare the newly discovered normal and abnormal pathways and pinpoint the molecular interactions that go awry in t-AML. This critical and comprehensive comparison will allow researchers to identify novel therapeutic targets.

Team 3 – Predicting Drug Response and Finding New Therapies Team 3 is screening samples from patients who have been genetically profiled to discover which drugs are most effective for their disease. The pharmacogenomics experts on the team are linking drug sensitivity data with genetic signature data to design individualized treatments. Other experts on the team are screening chemical libraries to identify new chemicals that inhibit leukemia cell growth.

Team 4 – Studying Therapy-Related Leukemia using Mouse Models Team 4 researchers will transplant t-AML cancer cells from patients into mouse models to isolate leukemia stem cells. The keys to these studies are the novel ability to expand human leukemia stem cells in a mouse model that recapitulates the environment in a patient. These stem cells will be used to identify targets for effective chemotherapy through collaborative work with Teams 1, 3, and 6. University of Chicago researchers believe that current t-AML treatments are unsuccessful because they fail to kill these leukemia stem cells, which quickly re-establish cancer. By modeling human leukemia in the mouse, the team can also use these in vivo models to validate new therapies rapidly before they are brought to clinical trials (Team 5).

Team 5 – Designing Clinical trials to Test New Therapies Researchers in Team 5 will 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.

Team 6 – Developing an Atlas of Therapies Team 6 researchers are using computational modeling to interpret the data generated from Teams 1-4 throughout the project. Their data analysis will identify how deregulated cellular processes cause leukemia, identify drugs that would inhibit newly-found therapeutic targets, and predict the response to single drugs or combinations of drugs, thereby informing clinical trials developed by Team 5.