Targeting the Unfolded Protein Response in Pediatric Leukemia
Abstract
To address the current gaps in the treatment of childhood leukemia – the most common form of cancer in children, adolescents, and young adults – the collective goals of this proposal are to first, identify molecular pathways that support childhood leukemia and then, second, develop rational therapeutic strategies for targeting such pathways. The deadliest form of childhood leukemia is pediatric acute myeloid leukemia (AML), which has a mortality rate greater than 40%. Pediatric AML can arise from distinct types of genetic mutations; however, those expressing genetic rearrangements of the MLL gene – commonly referred to as MLL-rearranged AML – are often resistant to conventional chemotherapies and therefore patients frequently have poor outcomes. These unsatisfactory outcomes highlight the immediate need for new, more-effective therapeutic strategies in childhood MLL-rearranged leukemia. We recently discovered that two components, called ATF4 and XBP1s, of a molecular pathway called the unfolded protein response (or UPR for short) are critically important for MLL-rearranged leukemia and therefore represent potential targets for the development of novel therapies. However, therapies directly targeting ATF4 and XBP1s currently do not exist; thus, we must identify alternative strategies for inhibiting the activities of ATF4 and XBP1s. The objectives of this proposal are to investigate two alternative strategies for blocking ATF4 and XBP1s in childhood MLL-rearranged leukemia: (1) The first alternative approach aims to exploit the abilities of ATF4 and XBP1s to regulate the levels of other genes to drive the progression of childhood MLL-rearranged leukemia. We have identified a gene called DDIT4, which is regulated by both ATF4 and XBP1s, that is associated with poor outcomes in AML. Furthermore, we have discovered that blocking DDIT4 expression impedes the growth of MLL-rearranged leukemia cells. Therefore, our objective here is to examine how blocking DDIT4 expression impacts leukemia progression in preclinical mouse models of MLL-rearranged AML. If successful, we will test therapeutic strategies for targeting DDIT4 in childhood leukemia. (2) The activity of ATF4 and XBP1s are regulated by two genes products called PERK and IRE1-alpha, respectively. Given the chemical inhibitors of PERK and IRE1-alpha are available, our second approach for targeting ATF4 and XBP1s is to assess whether these drugs can successfully block leukemia progression and possibly improve the effectiveness of existing chemotherapies in preclinical mouse models of MLL-rearranged AML. If successful, our future directions will focus on translating these therapeutic strategies into clinical trials. Given that this proposal focuses on childhood leukemia, the results of this proposal will have the greatest impact on the child beneficiaries of Service members who suffer from MLL-rearranged leukemia. However, since leukemia also affects adults, the results of this proposal may also impact Service members directly.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810472
Entities
People
- Stephen Sykes
Organizations
- United States Army