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illuminate the malignancy

A new MRI method developed by Weizmann Institute of Science scientists is expected to pave the way for early diagnosis of pancreatic cancer

A normal MRI scan is unable to detect a pancreatic tumor (left). After injecting a transgenic sugar and improving the sensitivity of the scan, the tumor appears clearly in the new MRI approach developed by the researchers (right)
A normal MRI scan is unable to detect a pancreatic tumor (left). After injecting a transgenic sugar and improving the sensitivity of the scan, the tumor appears clearly in the new MRI approach developed by the researchers (right)

The pancreas resides in the depths of the abdominal cavity and its exact location may vary from person to person. This fact, along with the lack of biomarkers and sufficiently sensitive imaging methods, are the reasons why pancreatic cancer tumors are particularly difficult to detect, and are often discovered only in an advanced and terminal stage. Recently, Weizmann Institute of Science scientists showed that A new imaging approach can illuminate pancreatic tumors in a new light and make them appear clearly in MRI examinations. The new method is expected to make it possible to harness MRI technology for the early diagnosis of pancreatic cancer, thus allowing treatment at earlier stages in this deadly disease, and hopefully - leading to higher survival rates.

"Standard MRI scans currently fail to detect pancreatic tumors, even when contrast agents are used, because the test is simply not specific enough," says Prof. Lucio Friedman from the Weizmann Institute of Science who led the development of the method in collaboration with the group of Prof. Avigdor Sartz from the institute. "In fact, even when MRI scans indicate deviations from the norm, it is often difficult to tell whether it is a tumor, inflammation or a benign cyst. As a result, pancreatic cancer is usually diagnosed only at the late stage when the patient already feels the symptoms." Prof. Friedman emphasizes that not only MRI technology has difficulty distinguishing pancreatic tumors, other imaging methods such as positron emission tomography (PET) also have difficulty confirming or denying the presence of cancer. Moreover, even the currently accepted diagnosis for detecting pancreatic cancer - a combination of periodic MRI and CT examinations as well as, in many cases, invasive biopsy examinations - is not necessarily reliable.

For these reasons and in light of the lethality of the disease, Prof. Friedman and his partners set out to search for innovative ways to identify pancreatic tumors. The search led them to Otto Warburg - a Jewish-German scientist and Nobel laureate who discovered almost a century ago that cancer cells are "addicted" to sugar, and that the breakdown of sugar in these cells produces different and distinct products. The researchers believed that it is possible to harness the "Warburg effect" and MRI technology to map specific metabolic products that characterize cancer cells, thus shedding new light on MRI scans and revealing the existence of cancerous tumors in the pancreas.

"In healthy cells, the final product of glucose breakdown is carbon dioxide," explains Prof. Friedman. "But Warburg discovered that in cancer cells, the breakdown of glucose stops at an intermediate station and therefore leads to the production of the lactate molecule. This interim stop means that the cancer cells produce less energy compared to normal cells, seemingly a significant disadvantage, but it also gives them a survival advantage: the presence of lactate helps them multiply and cause damage to the tissues around them. Our goal was to use MRI to identify where lactate is produced in the body, thus revealing the cancerous tumors."

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But there was only one problem with the promising idea: the amount of lactate produced by cancer cells does not meet the threshold necessary for detection through a standard MRI scan. MRI technology is based on measuring the protons in the nuclei of hydrogen atoms in the water molecules in the tissues being scanned. Since the concentration of protons in the water molecule in the tissues is 100,000 times greater than their quantity in the lactate molecules produced by the cancer cells, to detect the lactate one must first overcome the tremendous signal produced by the water. "The signal received from the water and fats in the body in a normal MRI scan is simply dazzling," says Prof. Friedman, "and the lactate - the hallmark of cancer cells - slips under the radar."

Prof. Friedman and the members of his group managed to solve the problem using two bypasses: first, they replaced the protons in the glucose molecules with deuterium - a hydrogen isotope that is not radioactive and whose natural concentration is negligible, providing a clean background free of confounding signals - and injected the labeled sugar into mice with pancreatic cancer. When the cancer cells broke down the engineered glucose, the resulting lactate produced a signal that was significantly stronger during the scan and was not completely drowned out by the surge of signals obtained from the proton MRI. However, the signal - however clear - was still too dim and, except in cases of particularly large tumors, remained undetectable. To improve the sensitivity of the scans, the scientists combined state-of-the-art image processing methods adapted to unique experimental approaches, and managed to increase the sensitivity considerably, so that even the smallest amount of deuterium-bearing lactate was clearly visible. Thanks to the improvement in the sensitivity of the scans and the use of labeled sugar, the researchers were able to clearly and prominently see even millimeter-sized tumors in animals in a non-invasive manner. The researchers even showed that the approach they developed is much more sensitive than competing techniques, which monitor only the final stage of glucose breakdown using MRI with hyperpolarization.

Prof. Friedman emphasizes that the experiment was performed on mice only, and that the findings must be confirmed in humans. "Future clinical studies, which are expected to begin soon using the excellent MRI infrastructure available at the Weizmann Institute, will be able to show whether the new method is a life-saving diagnostic tool - especially for those who have a genetic predisposition to this serious disease," he says. Even regardless of early diagnosis, the new method is expected to make it possible to measure the conversion rates from glucose to lactate, thus being an important factor in determining the effectiveness of various treatments.

The research was led by Prof. Lucio Friedman and Dr. Elton Monterzi from the Department of Chemical and Biological Physics at the Weizmann Institute of Science, and Dr. Keren Sasson and Dr. Lilach Agami from Prof. Shertz's group in the Department of Plant and Environmental Sciences participated in it.

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