Exploiting the tumor-suppressing enzyme AHCY to target methionine-dependent cancer

A wide variety of cancer cells strictly require the amino acid methionine to survive and grow, while normal cells do not. This is being exploited to treat cancer by methionine starvation, but the underlying mechanism is unknown.

We recently discovered that the enzyme adenosylhomocysteinase (AHCY) is critical for growth without methionine, but also strongly suppresses tumor growth.

Oncogenes therefore modify and inactivate AHCY, causing methionine dependence.In this project, we will translate these discoveries towards therapeutics.

We will develop antibodies to detect the modified AHCY protein in tumors, enabling personalized treatment of methionine-dependent cancer. We will also create a mathematical model of methionine metabolism to enable rational design of dietary interventions.

In parallel, we will identify the AHCY-modifying protein (AMP) that inactivates AHCY in cancer, by integrated analysis of protein-protein interaction data, transcriptomics, and CRISPR screening in methionine dependent cells.

As proof-of-principle, we will show that knockout of AMP reactivates AHCY and prevents tumor formation in mice.We now have a unique opportunity to pioneer this research, as the only group world-wide with knowledge of the AHCY protein. This project will run over 4-years and involve collaborations with academics, industry and clinicians.

As AHCY inactivation is likely a common event in tumorigenesis, new therapeutics reactivating AHCY could have a major impact on cancer medicine.