Targeting Myeloid Malignancies through IRAK4 Synthetic Lethality Dependencies
Eric Vick
MD, PhDUniversity of Cincinnati
Project Term: July 1, 2024 - June 30, 2027
Based on our preliminary data, we hypothesize that IRAK4 inhibition leads to LSPC reprogramming in MDS and AML. Aim 1 will evaluate the mechanism by which IRAK4 inhibition leads to LSPC reprogramming in cell lines, mice, and PDX samples. Aim 2 will concentrate on understanding of how IRAK4 inhibition creates synthetic lethal dependencies with the CELMoD CC-885 and how neosubstrates of CC-885 mediate the synergy upon IRAK4 inhibition in leukemic cells.
Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) are cancers which affect hundreds of thousands of people around the world. They are classified for doctors as two cancers with many different types, but actually they are a spectrum of the same disease of the bone marrow caused by errors in the DNA. There are many reasons for these errors to occur, but most are related to aging, and because of that, they aren't very preventable.
When someone develops this type of disease, their bone marrow stops making more red blood cells which carry oxygen in your blood, white blood cells which fight infection, and platelets which stop bleeding. Instead, their bone marrow makes more of these cells with errors in their DNA, called stem cells. Healthy stem cells make all of the cells of your blood but these unhealthy stem cells only make more of themselves. Sometimes they make so many of themselves that they overload the bone marrow, and this results in leukemia. We study the errors that are made by these cancers to determine better therapies to treat them.
The errors we are looking at for this proposal causes the unhealthy cells to change the way they make proteins. Normally, proteins are responsible for all the work that happens in a cell like making energy from sugar or movement. We looked at proteins that normally help the immune system to fight infection, and found out they were using a protein called IRAK4 to divide faster. Using gene-editing technology we were able to delete the gene for that protein and thus prevent it from being made. We found that it made these unhealthy cells less able to cause leukemia, but it did not stop them entirely. Several pharmaceutical companies also created drugs to target IRAK4. Using these drugs on our cells, we found they acted similarly to the cells in which we edited out IRAK4. As a part of this proposal we want to know how this happens in the leukemia cells and how long that effect will last.
Using the cells we edited and the same cells without the edit for comparison, we compared 2800 drugs based on their effects in each type of cell. We found that the most successful compound in the edited cells was a compound called CC-885, which is a drug that causes proteins to be broken down differently. We think in these cells, changing IRAK4 changed the way proteins were broken down, and we want to know how. We think both of these questions will make it easier to treat patients with leukemia.