A new drug developed in Israel for the treatment of one of the most aggressive types of cancer has shown promising results at the pre-clinical stage. The research, on mice infected by human tumors, was conducted by scientists at the Hebrew University of Jerusalem, led by Prof. Yinon Ben-Neriah, an expert in immunology and molecular biology. The results were published last week in the prestigious journal Cell.

Recently, the American company Bio TheryX has bought the rights for developing this drug from Yissum, the university’s research development company. The company, with a group of researchers, is seeking permission to conduct the first clinical trials on patients suffering from acute myeloid leukemia in the United States.

In contrast to other malignant diseases, patients suffering AML have had little good news over the last 40 years. “Only this year,” Ben-Neriah says, “have we started seeing some signs of innovative treatment, all of them still at the stage of chemotherapy that was developed 50 to 60 years ago. Even with those novel treatments the chances of a cure are still considered low.”

The results of the study showed a dramatic shrinking of tumors in the mice.

“We were very excited to see that the night after the drug was administered, nearly all signs of leukemia had disappeared in a very sick mouse,” related Waleed Minzel, a doctoral student who coordinated the research. All the mice in the study responded to the drug.

Open gallery view A mouse in an American lab. The Bio TheryX company in the U.S. has bought the rights to develop the new drug from the Hebrew University's research development company. Credit: Tom Gannam/AP

In the weeks following cessation of the treatment, the disease returned in half of the mice – but the other half was cured.

According to Ben-Neriah “Cancerous stem cells are very resistant to most treatments, both chemotherapy and biological ones. In this case, the attacking drug succeeded in selectively destroying leukemic stem cells. This explains why the disease did not re-appear even after the [affected] bone marrow underwent treatment and was implanted into healthy mice.”

In general, the pre-clinical stage of experimentation on animals does not necessarily presage success in clinical trials on humans, where safety and efficacy are tested with extreme care. So, while experimentation with the new substance is still in its early days, the chemically altered molecule developed by Ben-Neriah and his colleagues has surprised and impressed researchers by the way it seems to rapidly attack the disease.

This treatment may represent a new generation of anti-cancer drugs, sophisticated ones based on and implementing the enormous knowledge that has been amassed in recent years regarding the molecular biology of cancerous growths.

A leukemic cell produces proteins that are typically not present in normal blood cells. These proteins essentially act collectively to provide tumorous cells with optimal conditions for multiplying, protecting them against the body’s immune system or external intervention such as via chemotherapy or other means.

The biological agents used today to fight cancer, known as “targeted therapies,” are designed to attack one key protein, disrupting its activity while simultaneously preventing the spread of the disease. The attack on the vulnerable part of the protein affects its functioning at many levels and with varying success rates. However, at some point the cancerous cells can develop compensatory and evasive mechanisms by means of other proteins, thus surviving the assault.

In their research, Ben-Neriah and his colleagues developed a multi-pronged treatment designed to target several key proteins at important crossroads in the lifespan of the cancerous cell. This makes it hard for the cell to activate other proteins to block the effects of drug treatment.

The professor explains that one reason it is hard to destroy leukemic cells is the fact that they are typically effective in neutralizing a protein called p53, which is known to slow or suppress the development of malignant cells while also destroying defective ones. “Thus, for example, while chemotherapy attempts to bolster the activity of a protein such as p53, the affected cells know how to respond by augmenting the production of other proteins such as MDM2, which blocks p53.”

At the same time, adds Ben-Neriah, “the leukemic cell activates a protein called Myc, which accelerates cell division, as well as another protein called MCL1. The latter protects leukemic cells that have undergone mutations that protect them from apoptosis, or programmed cell death, which is caused by chemotherapy. The result is the survival and resistance of the infected cells.”

The researchers compare the action of the molecule they developed to chemically manipulate cancerous cells to that of a cluster bomb, which disperses numerous small projectiles that hit several targets at once.

Ben-Neriah: “This is a multi-pronged attack that combines three or four different drugs, without needing to pay the often intolerable price of combined therapy.”

In addition to Ben-Neriah and Minzel, other participants in the study were Evanthika Venkatchalam, Dr. Irit Alkalay and Dr. Avner Fink. Key partners in the field of drug treatment were Prof. Eli Pikarsky and Dr. Shlomo Elias of the Faculty of Medicine at the Hebrew University and Hadassah University Hospital, as well as Prof. Moshe Oren, Dr. Liran Shlush and Dr. Nathali Kaushansky from the Weizmann Institute of Science in Rehovot.