Citrin - a novel target for ASS1 depleted cancers (Yeda)

Many cancer cells hijack and remodel existing metabolic pathways for their benefit. Specific targeting of these metabolic dependencies offers cancer patients increased efficiency and minimized side effects. Yet, the complexity of these pathways hinders the identification of targets.
The present discovery elucidates the pathway by which argininosuccinate synthase (ASS1) down-regulation confer cancer progression. It shows that decreased activity of ASS1 in cancers supports proliferation by linking excess aspartate to pyrimidines synthesis. Importantly, these studies highlight Citrin (a mitochondrial aspartate transporter) inhibition as a potential method to decrease aspartate levels and selectively target this metabolic pathway in ASS1 depleted cancers. Cancer cells hijack and remodel existing metabolic pathways for their benefit in what is termed the Warburg effect. Researchers from Dr. Ayelet Erez's lab, at the Weizmann institute of Science, have delineated the metabolic benefit(s) conferred by loss of ASS1 to cancers. In agreement with previous experience, they found that ASS1 deficiency has an additional arginine- independent effect that is directly related to its substrate, aspartate.
By focusing on the relevant physiological and pathological model systems, it was found that ASS1 deficiency-mediated increase in aspartate levels lead to excessive proliferation through pyrimidine synthesis. The link between the two is provided by CAD (carbamoyl-phosphate synthase 2, aspartate transcarbamylase, dihydroorotase complex) and the mTOR signaling pathway.
Importantly, the present inventors have found that blocking Citrin, the mitochondrial aspartate transporter, rescues cell proliferation by reducing aspartate levels. Citrin may thus serve as a strong candidate for targeted therapy of ASS1 depleted cancers.
Supporting this model, retrospective survival analysis of several cancers reveal that cancers with both decreased ASS1 expression and high Citrin levels have a trend for significantly worse prognosis.

Targeted therapy, against a well defined pathway, increases the prospects for success.
Selective – targeting cancer metabolic dependency minimizes the chances for healthy cells damage that lead to side effects.

Targeted Treatment for ASS1 depleted cancers.

1751

Israel