Novel Method for Diagnosis and Treating Cancer by Analyzing the Urea Cycle (No. T4-1872)
Lead Researcher: Dr. Ayelet Erez
The urea cycle (UC) is an important metabolic pathway that takes place in the liver. A variety of enzymes, such as argininosuccinate synthase 1 (ASS1) and the trifunctional enzyme CAD, are involved in the UC, which converts excess nitrogen into urea. The UC produces various metabolites based on the balance between its components, such as arginine-based metabolites on one hand and pyrimidines on the other. Mutations in urea cycle enzymes have been found in cancer patients and correlate with poor prognosis. Therefore, the UC can be used to both diagnose and treat multiple oncological indications.
The research group of Dr. Ayelet Erez uncovered a link between urea cycle enzymes and the metabolism of cancer cells. The Erez group discovered that shifts in the UC towards higher CAD activity, greater pyrimidine synthesis, and/or reduced urea production correlated with higher disease severity. These findings were used to create a tool for diagnosis and prognosis in cancer patients.
· Non-Invasive – Analysis of urine and plasma samples.
· Multiple Applications – treating cancer by shifting UC-related metabolism, determining the severity of the disease, predicting the outcome of treatments, and more.
The group found that changes in expression of UC enzymes are prevalent in over 90% of cancers. The subsequent specific rewiring of the UC pathway induces the activation of CAD enzyme, which is the bottle neck for pyrimidine synthesis. The enhanced pyrimidine synthesis following UC dysregulation, leads to nucleotide imbalance and promotes mutagenesis of specific transversion mutations in which pyrimidines replace purines. Higher pyrimidines result in more hydrophobic neo-antigens that increase the response to immunotherapy. Additionally, the Erez group demonstrated that in both patients with urea cycle disorders, as well as in cancer patients, there is increased secretion of pyrimidine metabolites in body fluids, which might provide early detection and cancer monitoring in patients. Hence, UC generates a genomic signature that can predict response to immunotherapy, and a biochemical signature that may be translationally utilized for early diagnosis and monitoring cancer progression.