Screening Platform Is a Launch Pad for Novel Treatment Combinations
This grid shows the results of an assay that tested 10 concentrations of ibrutinib in combination with 10 concentrations of another drug called BKM-120. The bright red areas indicate drug combinations that killed all or most of the cancer cells, whereas the dark areas indicate combinations that did not affect survival of the cancer cells. (Staudt Laboratory/NCI Photo)
More often than not, current medical treatments for a variety of diseases — including cancer, tuberculosis and brain disorders — involve administering more than just one drug, an approach known as combination therapy. There are thousands of approved and investigational drugs that can be combined in millions of possible pairings and dose variations. Clinicians often must make decisions based on trial and error, which is not optimal for the patient or the clinician.
Enter NCATS, which develops, demonstrates and disseminates solutions to challenges just like this one. To fast-forward the drug combination research process, NCATS investigators recently developed a sophisticated combination drug screening platform. In the Jan. 27, 2014, early edition of the journal Proceedings of the National Academy of Sciences, the team published the results of a collaborative study with scientists from the National Cancer Institute (NCI). The study demonstrated how the platform can quickly narrow down a long list of potential drug combinations to find those with the most potential to help patients. Investigators chose a difficult-to-treat variety of diffuse large B-cell lymphoma (DLBCL), a type of blood cancer, as the model for the study.
"NCATS is unique in its dedication to improving the process of translational research," said NCATS Director Christopher P. Austin, M.D., also an author on the paper. "This project demonstrates how the platform developed at our Center can take years off the process of testing new treatments for cancer and countless other diseases."
MANY TALENTS DEVELOP AND DISSEMINATE A POWERFUL TOOL
Marc Ferrer, Ph.D., and Craig Thomas, Ph.D., research scientists in the NCATS Division of Pre-Clinical Innovation (DPI), lead the multidisciplinary team that developed a high-capacity robotic platform to screen drug combinations. In just a couple of days, the robots can perform a drug screen that would take human researchers months to complete.
The 3Ds of NCATS: Combination Drug Screening
Develop a platform to identify the most promising combinations of drugs to treat a disease
Demonstrate the power of the platform to find combinations using diffuse large B-cell lymphoma as a model
Disseminate the results of the screen to the broader scientific community
Demonstrate the power of the platform to find combinations using diffuse large B-cell lymphoma as a model
Disseminate the results of the screen to the broader scientific community
Lesley Mathews Griner, Ph.D., a DPI research scientist, develops and oversees the tests (called "assays") that run on the platform. The system performs the automated assays using diseased cells that are placed on plates in tiny indentations called wells. Cells are treated in each well with a unique combination of drugs, and the assays reveal the effects of the drugs on each group of cells.
The DPI team drew on diverse talents and experience in high-throughput screening and informatics to create this exceptionally powerful system. One feature that makes the platform stand out from previous combination drug screening efforts is the drug library it uses, called the Mechanism Interrogation PlatE (MIPE). All the drugs in the MIPE collection are relevant for clinical use in cancer and have mechanisms of action that scientists already understand. The observations of each drug pair’s effects on the target cells, coupled with the detailed knowledge about the compounds in the MIPE library, provide the researchers with insights into the interactions between various cellular processes. "This library will not only enable us to find compound combinations that can go rapidly into clinical trials, but also explore the biological processes that create the enhanced effect of a drug combination in a cell, leading to new drug targets," Ferrer explained.
Another distinctive characteristic of the platform is that it enables investigators to test not just pairs of drugs but also many different doses of each drug. The robotic system does thousands of these mini-experiments on plates with up to 1,536 separate wells packed into just a few inches of space. Paul Shinn, who oversees compound management in DPI, led the team that used a new technology to create combinations of compounds for screening in these plates. Before the work led by Shinn’s team, performing this type of screen on 1,536-well plates was practically impossible. Rajarshi Guha, Ph.D., a DPI research scientist with expertise in informatics, led another technical team at DPI that developed an automated Web-based interface as well as an in-depth and highly sophisticated data analysis package to help researchers analyze the vast amounts of data produced.
Finally, NCATS has given the broader scientific community access to the control software, interface and data generated in ongoing experiments. Any research group in the world can now build off the team’s work. "These results are hints that the broader community needs to further investigate," Thomas said. "Making the data public makes this possible."
A POWERFUL DEMONSTRATION IN CANCER
For the cancer study, the DPI team collaborated with the NCI laboratory of Louis Staudt, M.D., Ph.D., a world-recognized DLBCL expert. DLBCL is the most aggressive and common type of adult lymphoma, a cancer of the white blood cells. The current standard of care for people with DLBCL is a combination of chemotherapies discovered through a long process of trial and error in the clinic. "Because chemotherapy only cures roughly half of individuals with DLBCL, we urgently need new curative therapies," Staudt said.
Cancer cells from a patient with DLBCL. (Staudt Laboratory/NCI Photo)
The new screening platform helped the collaborators speed up the search for a second drug to combine with a promising new one called ibrutinib. The Food and Drug Administration already approved ibrutinib to treat two different forms of lymphoma. However, because the drug targets a molecular process that is a hallmark of DLBCL, it has demonstrated clinical efficacy as a single-drug treatment in this disease.
The team systematically tested cancer cells from Staudt's lab using combinations of ibrutinib and 459 different drugs. Preliminary assays generated baseline data and revealed the most promising compounds to test in combination with ibrutinib. Additional assays tested the action of up to 10 different doses of each drug in combination. Ryan Young, Ph.D., a staff scientist in Staudt's group, confirmed the results of the screen in cancer cells. The final product was a short list of 30 drug pairs, many with unique mechanisms that target the specific molecular signature of the cancer cells tested. "A deeper analysis of each discrete combination will be key because we want to determine what would not only eradicate a cancer cell but kill it in a way that's not just toxic for the patient," Mathews Griner said.
The Staudt group plans to publish more detailed information about the drugs’ molecular activity in an upcoming paper. Most important, these data provide a foundation for ongoing and future clinical trials. Staudt’s group also may pursue clinical trials of other suggested combinations. "We are fortunate to have a number of small molecules entering the clinic that target signaling and regulatory pathways that are relevant to DLBCL," Staudt explained. "However, we need guidance from these pre-clinical analyses to determine which of the many drug combinations to prioritize for testing in clinical trials."
A NEW APPROACH SPREADS
Now, NCI is integrating the new screening platform into other Institute research. "We believe that use of this platform to identify novel, rational combinations of targeted therapies in a variety of tumor types will provide the foundation for therapeutic studies in the future," said Lee Helman, M.D., NCI scientific director for clinical research. NCATS is collaborating on combination drug screening projects with NCI groups interested in cancers of the kidney, pancreas, ovaries and other organs. The DPI team also has joined forces with scientists from the National Institute of Allergy and Infectious Diseases on malaria and tuberculosis projects.
"This platform is a great example of NCATS' dedication to creating new solutions for problems in translational science, and it's proving its value for investigators at the Center, other NIH scientists and the rest of the research community," Austin said. With such investments in tools and expertise and a strong commitment to scientific collaboration, NCATS continues to accelerate and streamline the process of translational research to deliver new hope for patients.
In Memory
NCATS automation expert Dongbo Liu wrote the software code used to generate appropriate compounds for every combination drug screening project at NCATS to date. While working on the DLBCL project, Liu was diagnosed with glioblastoma, the most common and aggressive type of brain tumor in the United States. Sadly, he succumbed to the disease, but NCATS staff currently are working to find promising drug combinations for glioblastoma using the platform Liu helped establish, with an aim to prevent others from sharing his fate.
NCATS automation expert Dongbo Liu wrote the software code used to generate appropriate compounds for every combination drug screening project at NCATS to date. While working on the DLBCL project, Liu was diagnosed with glioblastoma, the most common and aggressive type of brain tumor in the United States. Sadly, he succumbed to the disease, but NCATS staff currently are working to find promising drug combinations for glioblastoma using the platform Liu helped establish, with an aim to prevent others from sharing his fate.
Posted February 2014
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