Synthesizing novel activators of PP2A in T-ALL cells
BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most prevalent cancer among children in the U.S. and about 6,000 new cases are reported annually. T-cell ALL (T-ALL) comprises 15% of ALL cases and forms a subgroup at high risk for treatment failure.
GAP: Despite continuous advances in the treatment protocols, T-ALL patients with unfavorable pretreatment signs or with recurrent disease still have a dismal prognosis and novel treatment options are needed.
HYPOTHESIS: We have recently identified perphenazine (PPZ) as a FDA-approved drug that unexpectedly kills T-ALL cells through its activation of protein phosphatase 2A (PP2A), which is a critical tumor suppressor. Yet, because of its other activities as an antagonist dopamine in the brain, PPZ can cause serious movement disorders and extrapyramidal symptoms, limiting its potential as an anti-leukemic agent. In this research, I will develop orally available analogues of PPZ with increased potency against T-ALL cells and with reduced off-target neurologic side effects.
METHODS: I will identify PP2A subunits responsible for PPZ’s activity in a cell-based assay. I will then clarify the effects of PPZ on PP2A activity and dopamine receptor antagonism in biochemical assays. Based on the findings, I will synthesize analogues of perphenazine and test them in vivo in zebrafish T-ALL models and also in vitro in human T-ALL cells. These experiments will be done under the supervision of Dr. Eric Fischer, Dr. Nathanael Gray and Dr. A. Thomas Look.
IMPACT: The most active PPZ analogues in killing T-ALL cells that have the least CNS toxicity that I discover during this grant project will be prioritized for further preclinical studies. The best molecule will then be developed as candidates for testing in clinical trials of T-ALL patients at the Dana-Farber Cancer Institute.
With the generous help from the Thrasher Research Fund, I will do my best to complete this project so that I can contribute to the health of children who are suffering from this illness.