A researcher from Bar-Ilan University has developed a molecular strategy to treat blood cancer * Prof. Mira Breda-Sied from the Faculty of Life Sciences led a study focusing on the breakdown of a protein that is characteristically present in blood cancer cells * The research combined biology with artificial intelligence and machine learning, which made it possible to identify the molecules that would be used to attack the target protein
Researchers at Bar-Ilan University have developed a new therapeutic approach to the fight against blood cancer. The method developed by Prof. Mira Barda-Saad And her research team is based on attacking a cytoskeletal protein called WASp and found in a unique structural state in active cancerous blood cells.
In order for their malignant functions to exist, cancer cells depend on the protein actin, which plays key roles in the cytoskeleton. Cancer cells need actin to be active, proliferate, migrate and spread. A protein called WASp controls actin activity and its structure. The research carried out at Bar-Ilan University focused on the destruction of WASp in cancer cells and showed that its breakdown helps to slow down and kill these cancer cells.
Until now, WASp's involvement in cancer has not been fully understood, but it is known that in cancer cells it is in a unique "open" structural state, which allows it to be identified and manipulated. This means that damage to WASp may mainly damage cancer cells without threatening normal cells, and may even be useful for the treatment of all types of blood cancer.
To damage the cancer cell skeleton, the research team performed a screening process and identified small molecules (Small Molecule Compounds - SMCs) that break down the WASp protein in an "open" structural state. To identify the small molecules, the research team used Bio convergence technologies, a field that combines biology with various engineering technologies, in this case artificial intelligence and machine learning (AI/ML). Through the use of a prediction tool developed by Prof. Yanai Ofran From Bar-Ilan, small molecules were found and identified in Prof. Barda-Saad's laboratory that do indeed damage cancer cells without causing much risk to normal cells. The researchers proved the effectiveness of using SMCs to stop the culture and kill cancer cells in laboratory experiments with cells taken from patients (in collaboration with Sheba Hospital) and also in a model of mice bearing tumors found in humans.
This research, which has been taking place since 2015 with the funding of the Innovation Authority, may provide an answer to the types of blood cancer for which an adequate treatment has not yet been found. The targeted attack on WASp, which is designed to damage the cell skeleton of cancer cells, may replace treatments such as chemotherapy and other biological treatments, which due to their lack of specificity damage not only the blood cancer cells, but also other cells in the body or cause the cancer cells to become resistant to the treatment.
This is how the small molecules SMCs work: the WASp protein is assisted by another protein, WIP, which connects to it at a specific point known as the "recognition site" and protects it from degradation. The small molecules bind to the recognition site and prevent the connection of the two aforementioned proteins and thus accelerate the breakdown of WASp which is no longer protected by WIP. "The idea came up when we uncovered the WASp defense process in my laboratory, during a study published in 2014 in the scientific journal Science Signaling," says Prof. Barda-Saad. "This basic research led to the opening of the new therapeutic strategy."
Prior knowledge of the WASp degradation sites, which were also identified in the Barda-Saad laboratory, enabled the definition of the various characteristics of the binding sites, and it was also possible to predict the type of small molecules that would bind to the mediator between the WIP and WASp proteins and separate them. The research team used machine learning to predict the interactions of WASp with its environment and to locate molecules that would not block WASp's degradation sites. Once these molecules were identified, the researchers verified their action in molecular and biochemical experimental work in cell culture and later in a model animal - mice that carry human cancerous tumors.
Prof. Barda-Saad points out that the use of small molecules already exists today for various medical purposes, and they can be given to the patient by intravenous injection, into the bloodstream or by ingestion. What indicates the safety of the new therapeutic strategy is the structure of WASp in normal blood cells: it is a "closed" structure, unlike the open structure present in cancerous blood cells, which prevents the connection of the small molecules to the recognition site. Therefore, theoretically, the use of the small molecules does not involve a significant risk. However, it is understood that the concept still needs to undergo preclinical and clinical safety tests as is customary for any drug. This study focused mainly on non-Hodgkin's lymphoma, but since other blood cancers also express the target protein, which is not expressed in non-blood cells, there is a high chance that it will work in them as well.
For Prof. Breda Saad, the development of the new therapeutic strategy is more than a scientific achievement. "For many years and also during my doctorate and postdocs at the Weizmann Institute and later at the NIH in Maryland in the USA, I focused on basic research. A number of cancer cases that were discovered in my family made me always think in an applied orientation - how to take the basic knowledge and use it to develop a therapeutic strategy," she says. "The process is long and protracted because it requires a thorough understanding of how cells work and how cancer cells differ from normal ones - what are the weak points that can be exploited? In this study, we used the extensive knowledge we acquired to plan an applied strategy."
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