The Pennsylvania State University College of Medicine Penn State Children's Hospital Archives

2019

Scholar Grant

Sinisa Dovat

Hershey, PA

Title: Novel strategy to enhance thiopurine drug efficacy in pediatric T-cell leukemia

Executive Summary:
Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is a lethal disease, requiring intensive chemotherapy. Resistance to chemotherapy is the main cause of relapse and mortality in pediatric T-ALL. The development of treatment that overcomes chemotherapy resistance is essential for improving survival of T-ALL patients. The Ikaros protein is a transcription factor that regulates expression of its target genes and acts as a tumor suppressor in T-ALL. Impaired Ikaros function is associated with resistance to chemotherapy in leukemia. Our published results showed that Ikaros activity in leukemia is impaired by oncogenic Casein Kinase II (CK2). Inhibition of CK2 with a specific inhibitor, CX-4945, enhances Ikaros function in leukemia. Our preliminary data suggest that in T-ALL, Ikaros and CK2 regulate expression of the TPMT and NT5C2 genes. TPMT and NT5C2 encode proteins that directly counteracts the cytotoxic effects of 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). 6-MP and 6-TG are purine analogues, and potent cytotoxic drugs used as a part of T-ALL treatment. CK2 inhibition with CX-4945 treatment represses TPMT and NT5C2 expression in T-ALL, via enhancement of Ikaros function. In vitro, combination treatment with CX-4945 and 6-TG, exhibits a strong synergistic cytotoxic effect in primary T-ALL. Based on these data, we hypothesize that combination treatment with the CK2 inhibitor, CX-4945, and 6-MP, will achieve superior in vivo cytotoxicity in T-ALL cells, leading to much a stronger therapeutic effect against T-ALL as compared to a single drug. We hypothesize that the therapeutic mechanism will involve enhancement of Ikaros tumor suppressor function as a transcriptional repressor of the TPMT and NT5C2 genes in T-ALL. These hypotheses will be tested in vivo using patient-derived xenografts from patients with T-cell ALL. The project aims are:

Specific Aim 1: Establish the therapeutic efficacy of combination treatment with CK2 inhibitor (CX-4945) and 6-MP vs. single-drug therapy in a preclinical model of T-cell acute lymphoblastic leukemia.

Specific Aim 2: Determine the molecular mechanisms through which CK2 inhibition enhances the cytotoxicity of 6-MP in vivo.
Outcomes: Results of the proposed project would establish the therapeutic efficacy of combination treatment with CX-4945 and 6-mercaptopurine in T-cell acute lymphoblastic leukemia and provide mechanistic insights into drug efficacy during combination treatment.

Benefits to pediatric cancer: The proposed studies use precision medicine approach to develop a novel treatment for pediatric T-ALL. Results would provide the groundwork for use of this novel combination in clinical studies as a treatment for T-ALL.

The goals of our project are:
• To test a novel targeted combination therapy and establish the efficacy of this treatment using a preclinical model of high-risk T-cell leukemia
• To define the mechanisms through which the novel treatment exerts its anti-leukemia activity