Laboratory of Steven Grant, M.D.
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.
Shuang Chen, M.D., Ph.D.
Yun Dai, M.D., Ph.D.
Girija Dasmahapatra, Ph.D.
Beata Holkova, M.D.
Life/Physical Science Technician II
Tri Nguyen, M.D., Ph.D.
Xin-Yan Pei, Ph.D.
Mohamed Rahmani, Ph.D.
Grant S "Rational combination strategies to enhance venetoclax activity and overcome resistance in hematologic malignancies." 2017 Aug 24 Leukemia & lymphoma Volume: Issue: Pg: 1-8 ISSN: 1042-8194 PMID: 28838268
Nguyen T, Parker R, Hawkins E, Holkova B, Yazbeck V, Kolluri A, Kmieciak M, Rahmani M, Grant S "Synergistic interactions between PLK1 and HDAC inhibitors in non-Hodgkin's lymphoma cells occur in vitro and in vivo and proceed through multiple mechanisms." 2017 May 9 Oncotarget Volume: 8 Issue: 19 Pg: 31478-31493 ISSN: PMID: 28416758
Zhou L, Zhang Y, Sampath D, Leverson J, Dai Y, Kmieciak M, Nguyen M, Orlowski RZ, Grant S "Flavopiridol enhances ABT-199 sensitivity in unfavourable-risk multiple myeloma cells in vitro and in vivo." 2017 Dec 14 British journal of cancer Volume: Issue: Pg: ISSN: 0007-0920 PMID: 29241222
Holkova B, Yazbeck V, Kmieciak M, Bose P, Ma S, Kimball A, Tombes MB, Shrader E, Wan W, Weir-Wiggin "A phase 1 study of bortezomib and romidepsin in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, indolent B-cell lymphoma, peripheral T-cell lymphoma, or cutaneous T-cell lymphoma." 2017 Jun Leukemia & lymphoma Volume: 58 Issue: 6 Pg: 1349-1357 ISSN: 1042-8194 PMID: 28103725
Wan W, Pei XY, Grant S, Birch JB, Felthousen J, Dai Y, Fang HB, Tan M, Sun S "Nonlinear response surface in the study of interaction analysis of three combination drugs." 2017 Jan Biometrical journal. Biometrische Zeitschrift Volume: 59 Issue: 1 Pg: 9-24 ISSN: 0323-3847 PMID: 27185067
Fang HB, Chen X, Pei XY, Grant S, Tan M "Experimental design and statistical analysis for three-drug combination studies." 2017 Jun Statistical methods in medical research Volume: 26 Issue: 3 Pg: 1261-1280 ISSN: 0962-2802 PMID: 25744107