Grant: Project Grant

Traditional chemo- and radiation-therapy, though often effective, has serious side and long-term effects, particularly for children, who face significant life-long health problems and increased risk for secondary cancers. We need to develop new "targeted therapies" that selectively attack cancer cells and leave healthy organs untouched. Targeted therapies are drugs that interfere with a specific molecule, the 'target', in the cancer cell to block its growth or kill it. The most specific targets are 'abnormal' proteins created by mutation or fusion between two genes. These abnormal proteins are found only in cancer cells, and are distinguishable from normal proteins. But they are also rare. Therefore, most targeted therapies are directed at proteins that occur in both healthy and cancer cells, and so they cause side effects. When they are uncoiled, proteins are a long chain of amino acids that have a start and an end, called the termini. The process called proteolysis cuts the protein apart, creating fragments that have different termini. We have shown that we can identify and quantify these termini in healthy and unhealthy cells, and we could show that in cancer proteolysis creates new termini not found in healthy cells. We found that there are more differences between termini than between the proteins. We now propose to study bone marrow biopsies from children with leukemia to identify cancer specific termini that have the potential to work as drug target. In addition, we will test blood and spinal fluid from these children. If we can find the other part of the protein, that has been cleaved off and released from the cancer cell, we may be able to use this fragment as very specific marker, not only for leukemia in general, but for the presence of the specific drug target. We will also investigate the mechanisms leading to the cleavage that generates the terminus and fragment. Our work will help to develop therapies that target only cancer cells.