Researchers at the Department of Oncology-Pathology at Karolinska Institutet have published a paper in Nature Communications. They created a cell line resource dataset and analysis tool that could be used to identify the traits that make specific leukaemias sensitive to new types of targeted therapies.
A hospital. Image credit: Max Pixel, CC0 Public Domain
The researchers used cell lines from childhood acute lymphoblastic leukaemia (ALL) patients with different forms of the disease. They analysed proteins, RNAs, and sensitivity to 528 drugs clinically approved or under investigation. Comparing cell lines that responded to medications in different ways could identify drug mechanisms and the traits that made leukaemias sensitive or resistant to those therapies.
For some drugs, the researchers determined that they might work through secondary off-target means. In a higher-risk ALL subtype, which response poorly to standard chemotherapy, they identified unexpected sensitivity to a type of immunotherapy drug which increases the strength of the molecular signals that activate immune cells.
ALL is the most common childhood cancer. Most patients can be treated with chemotherapy and stem cell transplantation, but 15-20% will respond poorly, and this patient group lacks treatment options and has high mortality risk. Additionally, current standard treatments can have a long-term health burden for children who survive cancer.
There is a need to identify less severe therapeutics than traditional treatments and could help patients who don't respond to current options. The researcher's results provide a foundation for exploring biological differences and new targeted therapies in childhood ALL and serve as a comprehensive public resource that will support other research projects.
The researchers used a panel of 49 childhood ALL cell lines and acquired mass-spectrometry based on in-depth proteome measurements, RNA sequencing, high-throughput drug screening, and fusion gene analysis. They created a web-based platform that allows the public to explore and analyze the dataset.
They performed analyses that integrated these data types and improved their understanding of biological differences. They performed analyses to profile the mechanisms of effective drugs on the screen. They performed validation experiments to understand drug mechanisms in depth.
We will further validate the results in the dataset with the highest potential for future clinical benefit, says Rozbeh Jafari, senior researcher at the Department of Oncology-Pathology and the last author of the paper.
We hope to expand the represented subtypes of childhood leukaemia in the dataset and explore further characterisations of our drug sensitivity and biological mechanism results in clinical samples and other models. We are also interested in developing new methods to understand drug activity and analyze and interpret similar comprehensive datasets measuring multiple molecular parameters.
Source: Karolinska Institutet