Christian Hurtz, PhD
Assistant Professor, Department of Medicine
Temple University
Research project
DYRK1A Inhibition Results in the Activation of the Proapoptotic Molecule BIM and Consequently Sensitizes KMT2A-R ALL cells to BCL2 Inhibition
Summary
KMT2A-rearranged acute lymphoblastic leukemia (KMT2A-R ALL) is the most common ALL subtype in infant ALL and also common in older children with ALL. KMT2A-R ALL is a deadly disease that does not respond well to chemotherapy treatments and often returns after being treated. Our goal is to identify molecules that are important for the health of KMT2A-R leukemia cells, which we can attack with specific medicines called inhibitors. We identified in our studies that KMT2A-R leukemia cells need the signaling molecule DYRK1A to multiply and grow, a process called cell proliferation. DYRK1A regulates proliferation by transmitting information to other signaling molecules, which regulate cell proliferation and cell health. Using a specific inhibitor that prevents DYRK1A from transmitting signals did not kill the leukemia cells because, as a protective mechanism, some molecules are able to inactivate cell death. Our study showed that one molecule in particular is important for protecting leukemia cells against DYRK1A inhibition. This molecule is called BCL2. We are now testing in mouse models that were generated from infant KMT2A-R leukemia cells whether using a two-medicine treatment approach to inhibit DYRK1A and BCL2 can kill KMT2A-R leukemia cells. If this two-medicine treatment approach proves to be better than the currently available chemotherapy treatments, we aim to test this new strategy in new pediatric clinical trials.
Impact
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Unfortunately, ALL consists of many different types of cancerous cells of which some can be treated with modern medicines, but unfortunately some have a protection mechanism, and they are not affected.
One of the ALL cells that is not affected are those with a KMT2A mutation. We have now found a specific molecule that helps KMT2A ALL cells to protect themselves from the different medicine treatments. This molecule is called DYRK1A. Our results demonstrate that using a new medicine that makes DYRK1A unfunctional can make modern medicines effective again to treat ALL. However, the DYRK1A medicine that was available until now had many side effects.
We have made a new DYRK1A medicine, which has very little side effects and based on our studies can help mice with ALL to live a significantly longer life.
I am a new principal investigator and the funding from the Leukemia Research Foundation allowed me to initiate important studies and to generate required resources to further pursue the importance of DYRK1A for KMT2A-R ALL. Novel therapeutics for ALL are desperately needed and our new findings provide a strong foundation to support the usage of DYRK1A inhibitors clinically.
I am now actively collaborating with physician scientists, who have the experience of bringing drugs into clinical testing. I hope that with further validations and additional financial support we will be able to start clinical testing of DYRK1A inhibitors for patients with KMT2A-R ALL soon.
Leukemia Research Foundation grant
$100K awarded in 2022
Disease focus
Acute lymphoblastic leukemia (ALL)
Research focus
Treatment (targeted therapy)