Aster awarded Marshall A. Lichtman Specialized Center of Research Grant

DF/HCC Member Jon Aster, MD, PhD (BWH), has received one of three new Marshall A. Lichtman Specialized Center of Research (SCOR) grants awarded by the Leukemia & Lymphoma Society in 2007. Aster will receive $6.25m in total costs over five years. The SCOR, entitled "Targeting the Notch Pathway,"  consists of four projects:

Targeting Extracellular Notch

Stephen Blacklow, MD, PhD (BWH)

Project One: Tanox's Notch3 antibodies prove that potent, selective molecules that bind the NRR can be developed. Blacklow and team will extend this effort to Notch1 through interactions with 1) Tanox, which will provide modulatory antibodies against Notch3; 2) Merck, which has recently funded an effort to develop monoclonal antibodies specific for the Notch1 NRR, and which will conduct a Fab library screen for lead antibodies with specificity against this region; 3) the Broad Institute, which has agreed to support screens for small molecules that bind the NRR.

Targeting Intracellular Notch

James Bradner, MD (DFCI)

Project Two: Bradner and Blacklow will develop stapled peptide inhibitors of the Notch transcription complex (NTC). Although nuclear complexes are not generally considered attractive therapeutic targets, several features of the NTC suggest that it may be an exception:

1) Recruitment of MAMLs. A MAML peptide consisting of just the residues that bind this site causes growth arrest of T-ALL cells (11), credentialing this interface as a plausible target of small molecules, peptidomimetics, and/or protease-resistant, cell-permeable peptides.

2) Existence of an interface between ANK domains in adjacent NTC complexes. ANK dimerization can occur, but its functional significance has been obscure. Blacklow noted that the spacing of the adjacent NTCs in the crystal lattice could accommodate loading of two NTCs onto tandem CSL binding sites (so-called sequence paired sites) that are found in certain important Notch target genes, such as Hes1. This insight led to studies showing that mutation of residues that participate in ANK:ANK contacts interfere with the binding of NTCs and the activation of transcription from promoters with sequence paired site, such as Hes1, but not promoters with NTC sites in other configurations.

3) Dimerization mutations abrogate the induction and maintenance of T-ALL cell growth. Blacklow will seek to identify lead compounds that abrogate NTC dimerization.

Novel Notch Inhibitors and Enhancers

Jon Aster, MD, PhD (BWH)

Project Three: Aster will use murine and human T-ALL cell lines to identify novel Notch pathway inhibitors and enhancers, and address the issue of resistance to Notch pathway inhibitors. Screens for new Notch inhibitors will rely on Gene Expression-High Throughput Screening (GE-HTS), a novel, cheap, effective luminex bead-based approach. A second set of screening studies will identify small molecules that synergize with Notch pathway inhibitors, both in GSI-sensitive and GSI-resistant cell lines. Aster will rely on access to the Broad Institute's extensive chemical libraries, and state-of-the art screening platforms. A third set of studies will be led by Adolfo Ferrando, PhD (Columbia University). Ferrando will seek to further understand the link between GSI resistance and increased PI3K/Akt signaling, and provide functional genomic expertise.

Identifying the Leukemia Initiating Cell in T-ALL

Warren Pear, MD, PhD (Abramson/UPenn)

Project Four: Pear will determine the identity of the leukemia-initiating cell in Notch-induced T-ALL, which is an unsettled issue of fundamental importance. In addition, he and his colleagues will provide relevant T-ALL models for preclinical testing of novel small molecules and antibodies that pass initial validation in Projects 1-3, playing a central role in moving therapies towards clinical trials.