A new treatment approach in the battle against blood cancers has been developed by researchers at Bar-Ilan University (BIU) in Ramat Gan (near Tel Aviv). The new method involves attacking the cytoskeletal protein called WASp, which has a unique structural condition in active hematologic cancer cells. The cytoskeleton is a structure that helps cells maintain their shape and internal organization and provides mechanical support that makes it possible for cells to carry out vital functions such as division and movement.
To carry out their malignant functions, cancer cells depend on actin – a protein that plays a key role in the cytoskeleton. Malignant cells need actin to be active, proliferate, migrate and invade. The WASp protein controls actin’s activity and structure.
The BIU team headed by Prof. Mira Barda-Saad and her research team from the Goodman Faculty of Life Sciences focused on destroying WASp in malignant cells and showed that the breakdown of WASp helps inhibit and destroy these cancerous cells. Their research was recently published in the journal Nature Communications under the title “Targeting the actin nucleation promoting factor WASp provides a therapeutic approach for hematopoietic malignancies.”
Until now, the involvement of WASp in cancer has not been completely understood, but it is known to be found in cancer cells in a unique “open” structure that allows it to be identified and manipulated. Inducing the degradation of “open” WASp can destroy mainly malignant cells without threatening healthy cells and can be used to treat most types of blood cancers.
To damage the cytoskeleton of the malignant cell, the BIU team performed screening to identify small molecule compounds (SMCs) that degrade the WASp compound in its “open” structural condition. To identify the SMCs, they used bio convergence technologies, which combine biology with various engineering technologies – in this case, artificial intelligence and machine learning (AI/ML).
Using a device developed by BIU Prof. Yanai Ofran, small molecules were identified in Barda-Saad’s lab that do, in fact, damage cancer cells without posing too much risk to healthy cells. The researchers proved the efficacy of using SMCs to inhibit proliferation and destroy the malignant cells in laboratory experiments using cells taken from actual patients, in cooperation with nearby Sheba Medical Center, as well as a mouse model carrying human blood cancer.
The WASp protein interacts with another protein named WIP, which binds to a specific point known as the “recognition site” and protects it against degradation. The SMCs bind to the recognition site and prevent the two proteins from binding together, thus promoting the breakdown of the WASp, which is no longer protected by WIP. “The idea arose in my lab when we discovered the process of WASp protection during a study that was published in 2014 in the journal Science Signaling,” recalled Barda-Saad. “This primary research led to the development of a new treatment strategy.”
This study, which has been carried out in the last six years with funding from the Israel Innovation Authority could provide a response for types of hematologic cancers for which treatment has not yet been discovered. The focused targeting of WASp, which aims to damage the cytoskeleton of the blood cancer cells, could replace treatments such as chemotherapy and other biological therapies which, because of their non-specificity, damage not only cancer cells but other cells in the body, or cause cancer cells to become resistant to treatment.
Previous knowledge of WASp degradation sites, also identified in Barda-Saad’s lab, allowed researchers to define the various properties of the binding sites and allowed them to predict the types of SMCs that would bind to the interphase between the WASp and WIP proteins, and separate them.
The research team used machine learning to predict the WASp interactions with its environment and identify molecules that would not block the WASp degradation sites. The moment these molecules were identified, the researchers verified their activity through molecular and biochemical experimental work with cell cultures, and later on with a mouse model carrying human malignant tumors.
Barda-Saad noted that SMCs are already being used for various medical purposes and can be given to patients through the blood system or by ingestion. One indicator of the safety of this new treatment strategy is the structure of WASp in normal blood cells; it is a “closed” structure, compared with the open structure found in malignant blood cells, which prevents the SMCs from binding to the recognition site.
As a result, in theory at least, using the SMCs does not pose any significant risk. Nevertheless, the concept must of course undergo pre-clinical and clinical safety trials as is standard procedure with any drug. This research focuses primarily on non-Hodgkin’s lymphoma, but since other types of hematologic cancers also express the target protein, which is not expressed in cells that are not blood cells, there is a good chance that this can work for them as well, the team said.
For Barda-Saad, development of this new therapeutic strategy is more than just a scientific achievement. “For many years during my doctoral and post-doctoral studies at the Weizmann Institute of Science in Rehovot, and later with the US National Institutes of Health in Maryland, I concentrated on basic research. Several cases of cancer discovered in my family caused me to adopt an applicative approach – how could I take the primary knowledge and use it to develop a therapeutic strategy,” she concluded. “The process is lengthy and drawn out because it demands a deep understanding of how cells work and how cancer cells are different from normal cells – what are their weak points that can be exploited? In this research we used the vast knowledge we acquired to design a strategy that can be applied clinically.”