Research projects

The goal of this laboratory is to elucidate links that exist between survival signaling and cell cycle regulatory pathways, and to exploit this information to develop novel therapeutic approaches to the treatment of cancer, particularly hematopoietic malignancies.

In one project, researchers are exploring the factors that regulate activation of the NF-ĸB pathway by histone deacetylase inhibitors in human leukemia cells and determining the mechanisms by which interruption of this process may lead to enhanced cell killing. Dr. Grant’s team has recently reported that HDAC inhibitors trigger NF-ĸB activation through the atypical, “inside-out” ATM/NEMO/SUMOylation cascade, and that interference with this process, genetically or pharmacologically, dramatically increases HDAC inhibitor-mediated apoptosis.

In a related project, laboratory members are investigating the role of phosphorylation on RelA acetylation, nuclear translocation and activation, and the impact of disrupting IKK function in regulating these events as well as cell survival. These studies are also being extended to include other arms of the DNA damage response.

In another project, the Grant laboratory is exploiting their observation that interference with the DNA damage response at the level of Chk1 in human multiple myeloma cells elicits the potent activation of the Ras/Raf/MEK/ERK pathway, and that disabling of the latter cascade (e.g., by MEK1/2 shRNA or pharmacologic MEK1/2 inhibitors) leads to a striking increase in expression of the pro-apoptotic protein Bim accompanied by marked apoptosis. They have recently observed that Src inhibitors recapitulate these actions, and promote Chk1 inhibitor lethality both in vitro and in vivo — the latter in association with the pronounced inhibition of angiogenesis. Studies are currently underway extending these findings to include cytokinetically quiescent cells (G0G1), as well as myeloma cells with stem cell characteristics.

This group’s studies are also exploring strategies designed to enhance the activity of proteasome inhibitors in diffuse large B-cell and mantle cell lymphoma. They have observed that HDAC inhibitors and small molecule BH3 mimetics sharply increase proteasome inhibitor lethality in these cells via a process that involves activation of the stress-related kinase JNK, and in the former case, an inactivation of NF-ĸB. Recently, these studies have been extended to include a novel, irreversible proteasome inhibitor, carfilzomib, and have indicated that such regimens actively induce apoptosis in lymphoma cells highly resistant to standard proteasome inhibitors.

Another myeloma-related project seeks to exploit the observation that CDK inhibitors that disrupt CDK9 function act as transcriptional repressors as a consequence of their ability to inhibit the pTEBb/CDK9/cyclin T complex, and by extension, phosphorylation of the CTD of RNA Pol II. This leads to down-regulation of multiple short-lived proteins, including Mcl-1. These researchers have found that such CDK9 inhibitors potentially enhance the activity of BH3 mimetics toward multiple myeloma cells. They are in the process of extending these findings to animal models as a prelude to proposing novel treatment strategies involving CDK9 inhibitors and BH3 mimetics in patients with refractory multiple myeloma.

Additional projects are underway examining mechanisms by which HDAC inhibitors promote the activity of dual aurora kinase/Bcr/Abl inhibitors in Bcr/Abl+ leukemias, and interactions between the multi-kinase and Raf inhibitor sorafenib and BH3mimetics in human leukemia cells.

Laboratory members