Dr. Mortimer Poncz, Children’s Hospital of Philadelphia (CHOP), ‘Drug Screen for FPD/AML Therapeutics’
Dr. Poncz and his team propose to enhance RUNX1 levels with the target of correcting the platelet problem, expecting that correction will also correct the risk of getting leukemia. The group specializes in studies on how to make platelets from megakaryocytes and have already identified one drug called RepSox that can correct many of the megakaryocyte defects seen in FPD/AML cells. They will continue studies with RepSox and also do a screening of drugs looking for other compounds that correct FPD/AML megakaryocytes at doses that an individual might be able to take on a long-term basis. Drugs will also be tested in RUNX1-deficient mice, adjusting candidate drugs to the lowest level that corrects the platelet counts in these mice. The longer-term goal is to test whether that dose protects the mice from getting leukemia. The lab envisions applying this strategy to affected individuals who will take the drug at the lowest dose that corrects their platelet count, with the expectation that the dose will also protect the individual from AML with few side-effects. They believe that the proposed strategy offers a short-track for drug identification that both reduces the risk of bleeding and of developing AML.
Dr. Anupriya Agarwal, Oregon Health & Science University (OHSU), ‘Role of Inflammatory Microenvironment in Clonal Evolution and Progression from FPD to AML’
Dr. Agarwal has performed genetic sequencing and identified 16 patients with AML who have inherited RUNX1 mutations as well as additional mutations in known cancer-causing genes. The lab proposes to study how RUNX1 mutations create a “pre-leukemic” environment, to identify which inflammation-causing cytokines present in this “pre-leukemic” environment, and to determine which of these cytokines can then contribute to disease progression and to full-blown leukemia. The lab has found that samples from the 16 patients were sensitive to certain drugs, and this information will be used to help identify new treatment strategies for these patients. The knowledge gained in this study will help determine effective treatments to prevent FPD from transforming to AML, leading to improved outcomes for patients with FPD. In the long term, information gained from the study will be used to discover how to predict which people with FPD will develop AML and how best to monitor families with the RUNX1 mutation for early detection of AML, thereby expanding our database of FPD patients and families. This will also allow for the design of clinical trials to be aimed at early intervention in these patients.
Dr. Guy Sauvageau, University of Montreal, Canada, ‘RUNX1 mutations that confer exquisite sensitivity to glucocorticoids’
Dr. Sauvageau discovered that a class of steroid hormones called glucocorticoids selectively inhibits the growth of acute myeloid leukemia (AML) cells containing RUNX1 mutations in cell culture. He plans to determine how glucocorticoids inhibit the growth of RUNX1 mutant AML cells, and to test the ability of glucocorticoids to inhibit AML in a mouse model.