New Investigator Grant Awarded to Sameer Agnihotri

Brain cancer is now one of the leading causes of cancer-related deaths in children in the United States. A tumor known as Diffuse intrinsic pontine glioma (DIPG) is one of the most deadly types. Even though children with DIPG get intense treatment, including surgery, radiation, and chemotherapy, most patients still die within two years of their initial brain cancer diagnosis. Part of the problem is that DIPG grows in an area that is extremely difficult to resect and DIPG cancer cells do not respond to standard therapies. Our ongoing research has identified that DIPG cells have an altered metabolism compared to normal cells. We have determined that DIPG cells are addicted to specific amino acids, which are the building blocks of protein and required for cells to rapidly grow. The particular amino acid we have identified that DIPG cells are overly reliant on is called methionine. Methionine acts as an anabolic stimulant and restriction of methionine in the diet has been used in human and animal studies to promote health. Methionine is unique among the essential amino acids as it is the only amino acid where long-term dietary restriction is still compatible with life. Methionine is used in the methionine cycle, a complex series of steps allowing DIPG cells to proliferate, produce anti-oxidants and make a substrate called S-adenosyl methionine (SAMe), which acts as an essential methyl donor for numerous cancer cell reactions. There is direct evidence that methionine restriction leads to the selective death of cancer cells versus normal cells and we hypothesize that methionine and specific enzymes that regulate this pathway are essential for DIPG growth. We propose a series of aims to test the effects of methionine restriction in our DIPG models and test novel emerging therapies targeting key proteins overexpressed in DIPG providing a novel and innovative way of targeting this aggressive cancer.