Our long-term goal is to develop a novel therapeutic strategy for childhood acute lymphoblastic leukemia (ALL), with focus on relapsed T-cell leukemia. We intend to accomplish this by targeting a unique molecular master regulator using a new generation of compounds. ALL is the most frequent cancer of the childhood. Although significant progress has been achieved with conventional therapies, major therapeutic challenges remain, including infant ALL, leukemia relapse and refractory disease. Overall, relapsed ALL is associated with poor prognosis, is per se the fourth most frequent childhood cancer and remains the second leading cause of childhood death;therefore, more effective therapies are much needed. As for other cancers, increasing evidence indicates that effective therapies for relapsed ALL will require the targeting of distinct molecular pathways. The central hypotheses of this grant is that the redox factor Ref-1 regulates critical transcription programs mediating the survival of relapsed leukemia cells, and that the selective blockade of Ref-1 redox function effectively inhibits leukemia recurrence and progression in animal models of relapse childhood ALL. This is supported by multiple evidence on the regulatory role of Ref-1 on important downstream targets involved in cancer growth, metabolism and drug resistance (NF-?B, AP-1, HIF-1?, STAT3), coupled with our previous studies with E3330 as a specific Ref-1 redox inhibitor and our preliminary data on T-cell ALL and leukemia relapse. To attain our goals we propose the following specific aim:
Specific Aim 1. To determine the therapeutic efficacy of Ref-1 redox blockade in animal models of relapsed childhood ALL using novel Ref-1 inhibitors. We will perform studies to investigate the anti-leukemia efficacy of our novel Ref-1 redox inhibitors in two distinct models of childhood relapsed ALL: a) xenografts with T-ALL cells from relapsed patients and, b) model of Notch-induced T-cell leukemia with disease recurrence after Dexamethasone treatment. We anticipate that our newly identified Ref-1 selective redox inhibitors will show significant anti-leukemia efficacy in the in vivo models of relapsed T-cell leukemia, with increased animal survival. While our model and the focus in this application is relapsed childhood ALL, we anticipate that these inhibitors will have additional indications in other cancers where Ref-1 has been implicated, e.g. pancreatic cancer, glioblastoma, as well as in other relapsed childhood leukemia and in adult ALL.
Refractory and relapsed childhood leukemia are difficult to treat and currently the second leading cause of death in childhood. The ultimate goal of this project is to develop an anticancer therapeutic agent in the form of oral or injectable medicine to more effectively treat these leukemias and other tumors. The results of these studies are of particular translational interest since there is un-met medical need for effective therapy of refractory childhood leukemia.
|Kelley, Mark R; Logsdon, Derek; Fishel, Melissa L (2014) Targeting DNA repair pathways for cancer treatment: what's new? Future Oncol 10:1215-37|