Cincinnati Children's Hospital Medical Center Archives

2017

Scholar Grant

Dr. Ashish Kumar

Cincinnati, OH

Majority of infant leukemias involve rearrangements in the MLL gene and are most often fatal. Our long term goal is to improve the outcome for MLL-fusion gene leukemia by developing newer, more effective therapies. These leukemias are characterized by high expression of MBNL1, a regulator of alternative splicing. Preliminary studies from our laboratory show that depletion of MBNL1 impedes leukemia propagation, while normal tissues appear less affected. Separately, sequestration of MBNL1 and the ensuing splicing defects are pathogenic features in the disease myotonic dystrophy type 1 (DM1). Further, researchers in the DM1 field serendipitously identified a small molecule inhibitor of MBNL1.

We found that leukemia cells are more sensitive to this inhibitor as compared to normal hematopoietic cells. The objective of this application is to advance the development of MBNL1-inhibition as a therapeutic strategy in MLL-leukemia. The central hypothesis is that MBNL1 is a druggable therapeutic target essential for the maintenance of MLL-fusion leukemia, wherein it regulates splicing of key factors.

There are two specific aims proposed. In the first aim, using medicinal-chemistry approaches, we will modify the chemical structure of the prototype inhibitor, improving its efficacy, specificity, bioavailability and safety. The co-investigator Dr. William Seibel is an established medicinal-chemist with expertise in this arena. Additionally, we have access to a large library of compounds with backbone structures that meet the structural criteria as starting points.

The second specific aim is to identify the molecular functions of MBNL1 in leukemia. We have generated preliminary data from shRNA knockdown and genetic deletion studies. The central hypothesis is that MBNL1 is required for the regulation of key splicing events, essential for the propagation of MLL-leukemias. We will utilize RNAseq to determine gene-expression and alternative-splicing events that are affected by MBNL1-knockdown. These results will also serve as biomarkers to help determine the efficacy of compounds identified in the first specific aim.

The proposed studies are innovative since we are developing a novel therapeutic approach aimed at treating leukemia based on knowledge of the molecular mechanisms involved in disease pathogenesis. Additionally, the role of MBNL1 in hematopoiesis and cancer is unknown, so we will generate new knowledge in this regard. The proposed research is significant because infant-leukemia is currently an incurable,
almost universally fatal cancer.

Lay summary:

Leukemia occurring in infants is incurable, and most of these infants do not survive
The biology of leukemia in infants is different than that in older children, making the disease more resistant to current chemotherapies
We have identified a novel biologic vulnerability in this leukemia, called MBNL1
We are developing drugs that could block MBNL1 which would help treat this dreaded cancer

2014

Scholar Grant

Dr. Susanne Wells

Cincinnati, OH

A person’s genome, contained within each cell in our bodies, is continuously damaged by natural or artificial toxic chemicals. Resulting genome breaks must therefore be continuously repaired. Each of us is born with a distinct ability “better or worse” to repair breaks and therefore to keep their genome stable. Children with unstable genomes are at a high risk of early cancer development such as leukemia or solid tumors. Furthermore, once those children have cancer, they will experience very serious side effects of radiation and chemotherapy – all of which cause genome breaks. Knowing which children carry unstable genomes is critical so their doctors can screen them for cancer more often, and come up with lifestyle and prevention measures that support a stable genome. They can then also lower the chemotherapy dose for children who are unable to repair genome breaks. Unfortunately, clinical tests to diagnose genome instability are not available. Here we propose to develop such tests. The test results will help doctors decide which of their patients are prone to cancer and which ones are not, and will also help them treat those with cancer in the most effective way. Finally, we will discover what specific changes in the body’s chemical profiles occur in children with unstable genomes. Understanding how the body changes its production of chemicals in response to damage will ultimately allow us to manipulate this chemistry to promote optimal genome stability in all children. We believe that the discovery of biomarkers of genome instability as proposed here will result in major advances in our ability to prevent and treat childhood cancer.