Discovery of New Therapeutic Targets in ALL

Dana-Farber Cancer Inst, Boston MA

Investigators

Linked publications & trials

Abstract

In Project 1 we will identify and characterize new mutations in tyrosine kinases, and related signal[unreadable] transduction proteins, in ALL using novel genome-wide screening strategies. We have already identified[unreadable] mutations in tyrsoine kinases that demonstrate the validity of this approach. We will characterize mutant[unreadable] kinases in various models of transformation, and will develop small molecule inhibitors of these kinases in[unreadable] preclinical development. During the prior funding period, Dr. Gilliland and Dr. Armstrong, the coinvestigators[unreadable] on this proposal, developed extensive data demonstrating that ALL, like other human cancers, is[unreadable] the consequence of multiple mutations. Furthermore, they have identified several uncommon, but highly[unreadable] informative, examples that implicate mutant, constitutively activated tyrosine kinases in pathogenesis of ALL,[unreadable] including ABL gene rearrangements and FLT3 activating mutations. These data suggest that sensitive[unreadable] genome-wide screens for similar mutations in tyrosine kinases will provide additional insight into molecular[unreadable] pathophysiology disease, and will identify new targets for therapeutic intervention. Indeed, with the[unreadable] discovery of FLT3 mutations in a subset of cases of MLL rearranged infant leukemias, and of the NUP214-[unreadable] ABL fusion in a subset of T-ALL, targets have been identified that are suitable for immediate clinical[unreadable] translation in Project 6 with FLT3 inhibitors and the ABL inhibitor, imatinib.[unreadable] The Specific Aims are to 1. perform genome-wide screens for activating mutations in the kinome across[unreadable] the spectrum of pediatric leukemias. The screens will include (a) high-throughput DNA sequencing of the[unreadable] kinome and (b) high-density oligonucleotide array comparative genomic hybridization to screen for 5'[unreadable] activating deletions in the tyrosine kinome. 2. validate novel mutations by re-sequencing, and sensitive cell-based[unreadable] assays for kinase activation, and 3. develop and test small molecule inhibitors of mutant activated[unreadable] kinases. Project 1 will interact extensively with Projects 2 and 3 to test novel mutations mutations as[unreadable] cooperating events in TEL-AML1+ B-ALL, and in T-ALL, respectively; Project 4 to assess impact of kinase[unreadable] mutations on gene expression signatures; Project 5 to assess impact of these mutations on glucocorticoid[unreadable] induced apoptosis; and with Project 6 to test mutant kinases as targets for clinical therapy. As proof-of-principle for[unreadable] this approach, noted above, we have recently identified a novel NUP214-ABL fusion in a[unreadable] signfiicant proportion of cases of T-ALL due to a novel episomal fusion mechanisms that is a target for[unreadable] imatinib therapy Project 6, and activating mutations in FLT3 in MLL rearranged infant leukemias that are[unreadable] candidates for therapy with FLT3 inhibitors.