Cutting off the Oncogenic Signals that Cofactors Send to Notch in T-ALL
Notch was found to be the most frequent cancer-causing gene in T cell acute lymphoblastic leukemia (T-ALL). This discovery raised hopes for anti-Notch drugs. However, these drugs had too much toxicity, like diarrhea, and even promoted cancers. The reason for these side effects is that Notch is very important for keeping normal tissues healthy. How can we knock out Notch in cancer, but preserve Notch in normal cells? We believe that the answer may be proteins called cofactors that stick to Notch. We've noticed that some cofactors tell Notch to drive cancer. Other cofactors tell Notch to keep organs healthy. Our idea is that inhibiting the specific cofactors that tell Notch to drive cancer, but sparing other cofactors, could combat Notch without intolerable side effects. In support of our idea, we recently discovered that the cofactor Zmiz1 sticks to Notch and triggers its cancer-causing functions but not its normal functions. When we removed Zmiz1 from a leukemic mouse, the tumors shrank without damaging normal tissues or causing new cancers.
For the project, we will see what happens to tumors when we cut the physical connection between Zmiz1 and Notch1. In theory, disconnecting these proteins from each other should cripple the tumors. We will test human samples to ensure that our results are relevant to human cancer. We expect to show for the first time that cofactors send cancer-causing instructions to Notch. This information will be essential for developing anti-Notch cancer therapy without the intolerable side effects of total Notch blockade.