Novel Therapeutic Targets in Relapse T-cell Acute Lymphoblastic Leukemia
The aggressive and unpredictable behavior of relapsed T-cell acute lymphoblastic leukemia (T-ALL) presents a major clinical challenge, as relapsed disease continues to have a dismal prognosis in both children and adults. A major hurdle in the development of new chemotherapies is identifying drugs that specifically kill malignant T cells, while leaving normal cells untouched.
Moreover, new therapies must be effective against T-ALL cells that have acquired resistance to front-line therapies like dexamethasone. Using zebrafish and human T-ALL, we have recently uncovered a prominent role for PRL3, a protein tyrosine phosphatase, in relapse. Moreover, PRL3 inhibition using a small molecule inhibitor rapidly and specifically killed zebrafish and human T-ALL cells but had no effect on normal blood stem cells.
Importantly, T-ALL cells that had become resistant to dexamethasone could be effectively killed using this inhibitor.
The goal of this proposal will be to extend these studies to FDA approved compounds that inhibit PRL3 and assess their efficacy in suppressing tumor growth in preclinical xenograft models of human disease. Additional work will identify the function of PRL3 in T-ALL malignancy. The long-term goal of this project is to provide a novel therapeutic approach for relapsed T-ALL.