The study was recently published in the prestigious scientific journal "Blood" and has future therapeutic implications within the framework of personalization of chemotherapy treatment
Researchers from the Faculty of Biology at the Technion discovered why the popular drug methotrexate (MTX) does not work in some blood cancer patients. Their research was published in the prestigious scientific journal "Blood" last month.
"The basis of the drug treatment (chemotherapy) in many cancer diseases is the blocking of the DNA base creation pathway in the malignant cells," explains Professor Yehuda Asraf, head of the Fred Wiszkowski Cancer Research Laboratory at the Technion, and a world-renowned expert in cancer research and anti-cancer drugs. "Blocking the creation of the DNA bases in the cancer cell by drugs from the family of antidotes, including MTX, prevents DNA from doubling, and as a result, the cancer cells cannot reproduce and therefore die."
The anti-cancer drug MTX is the oldest of the anti-cancer drugs and is very popular in the treatment of various cancerous tumors, including leukemia (blood cancer). The drug MTX penetrates the cancer cell and there it undergoes a metabolic process at the end of which it becomes a molecule with a "tail" carrying a high negative charge, which prevents it from leaving the cancer cell. This "tail" charged with a negative electrical charge is also essential for the drug to bind to the target enzyme and inhibit its activity within the cancer cell, since this is how it achieves its activity, namely: inhibiting the creation of the hereditary material (DNA and destroying the cancer cells.
"It has been known for about two decades that in many leukemia patients the drug MTX does not work," emphasizes Professor Asraf. "In other words, in these patients the blood cancer cells are resistant to the drug. It turns out that among certain patients the "tail" essential to the activity of the drug MTX is not conjugated, and therefore it is thrown out by the cancer cells. The reason for the inability to conjugate the negative "tail" in these resistant leukemia cells is the loss of activity of an enzyme known as "FPGS" which is responsible for adding the tail essential for the drug's activity."
Researchers in the field of drug treatment for leukemia have been trying for about two decades to trace the solution to the puzzle of why the activity of the FPGS enzyme is lost in these patients and makes the blood cancer fatal due to its resistance to drug treatment. After three years of in-depth research, researcher Dr. Michal Stark from Professor Asraf's lab at the Technion recently succeeded in deciphering the mystery. In order to create a normal FPGS enzyme, the cell creates a kind of "template" called messenger RNA that is copied from the DNA in an exact way. Dr. Stark and Professor Asraf discovered that in a large part of leukemia patients, the process of copying this essential "pattern" is completely defective. As a result of this defect, an active FPGS enzyme is not formed, therefore the drug MTX does not have a negative "tail" attached to it, which is essential for its activity, the drug is discarded from the cancer cells and the patient does not respond to this drug at all, the leukemia worsens and often leads to the death of the patient.
As a result of this research, Dr. Stark and Professor Asraf recently developed a rapid genetic test (the results of which are obtained within a few hours), which identifies the set of defects in the "template" before the drug treatment with MTX. Professor Asraf clarifies that this discovery may have important therapeutic implications, since the identification of the defect created in the "pattern" in the blood cancer cells already at the stage of diagnosing the disease, will lead to treatment with alternative drugs to MTX, which do not require the addition of a negative "tail". Therefore, this innovative approach may be a breakthrough in adapting the drug treatment to the individual patient, just as antibiotics are adapted to a patient with a bacterial disease. This discovery may significantly increase the chance of curing leukemia patients in the future.
