Even with today’s safer and more targeted anti-cancer drugs, scientists have been unable to satisfactorily explain the phenomenon of why treated cancers so often recur. The common theory is that the cancer cell develops internal resistance to treatment, and overrides the toxic effects of the drug.
Now, a team of Israeli scientists provide the key for reducing recurrence, allowing anti-cancer drugs to do work as intended.
Led by Prof. Yuval Shaked of the Technion-Israel Institute, the study shows that tumor relapse occurs when the body, in effect, mobilizes itself in favor of the tumor, causing recurrence of the disease, increasing its aggressiveness and creating metastases (tumor spread). Even selective, highly focused treatments that almost exclusively harm cancer cells lead to a similar response.
“The administration of an anti-cancer drug is very aggressive intervention in the body,” Shaked said in a statement. “Therefore, the body responds to chemotherapy the way it responds to trauma. This creates the effect of a double-edged sword: although chemotherapy kills cancer cells, it also causes the secretion of substances that confer resistance to the tumor.”
The study, which was recently published in the scientific publication The Journal of Pathology, mice with multiple myeloma – a malignant disease of the plasma cells produced in bone marrow and spread throughout the body – were treated with the selective anti-cancer drug Velcade (bortezomib). Velcade is based on the discovery of ubiquitin, for which professors Avram Hershko and Aaron Ciechanover of the Technion won the Nobel Prize (along with the late American biologist Irwin Rose) in 2004.
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Shaked found that treatment with Velcade led to a physiological reaction that actually reinforced the intensity of the myeloma in the mice. According to Shaked, the drug caused inflammatory cells in the bone marrow to enhance the aggressiveness of the disease and provide the cancer cells with resistance to treatment. Still, “treatment with Velcade is essential and necessary,” says Shaked, “but its disadvantage is that along with the benefit there is damage.”
Next steps: Inhibiting the mechanism that enhances the tumor
Understanding the mechanisms that enhance the tumor and accelerate the spread of metastases “will enable us to develop methods to inhibit them,” he stresses. In fact, when the researchers inhibited the secreted factor related to the activity of inflammatory cells, they observed a decrease in the proliferation of cancer cells. Now, they are working on various ways to inhibit the body’s response to anti-cancer treatments.
“Ultimately, we are talking about a trade-off between the intensity of the treatment and the intensity of the physical response,” Shaked says. “The moment the ratio is in favor of the treatment, and to the detriment of the response, we will achieve effective treatment without a ‘fine’ in the form of enhanced metastasis. In addition, we can inhibit the body’s response using existing drugs, thereby enabling the anti-cancer drugs to get the job done.”
The study was conducted by Dr. Ofrat Beyar Katz, a doctoral student at Prof. Shaked’s lab, along with Prof. Irit Avivi from Israel’s Rambam Hospital, and Prof. Yosef Yarden from the Weizmann Institute of Science.