Steven Grant

Southwestern University of Finance and Economics, Hua-yang, Sichuan, China

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Publications (399)2239.18 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Effects of concurrent inhibition of mTORC1/2 and Bcl-2/Bcl-xL in human acute myeloid leukemia cells were examined. Dual tetracycline-inducible Bcl-2/Bcl-xL knock-down markedly sensitized acute myeloid leukemia cells to the dual TORC1/2 inhibitor INK128 in vitro as well as in vivo. Moreover, INK128 co-administered with the Bcl-2/xL antagonist ABT-737 sharply induced cell death in multiple acute myeloid leukemia cell lines, including TKI-resistant FLT3-ITD mutants and primary acute myeloid leukemia blasts carrying various genetic aberrations e.g., FLT3, IDH2, NPM1, and Kras, while exerting minimal toxicity toward normal hematopoietic CD34+ cells. Combined treatment was particularly active against CD34+/CD38-/CD123+ primitive leukemia progenitor cells. The INK128/ABT-737 regimen was also effective in the presence of a protective stromal micro-environment. Notably, INK128 was more potent than the TORC1 inhibitor rapamycin in down-regulating Mcl-1, diminishing AKT and 4EBP1 phosphorylation, and potentiating ABT-737 activity. Mcl-1 ectopic expression dramatically attenuated INK128/ABT737 lethality, indicating an important functional role for Mcl-1 down-regulation in INK128/ABT-737 actions. Immunoprecipitation analysis revealed that combined treatment markedly diminished Bax, Bak, and Bim binding to all major anti-apoptotic Bcl-2 members (Bcl-2/Bcl-xL/Mcl-1), while Bax/Bak knock-down reduced cell death. Finally, INK128/ABT-737 co-administration sharply attenuated leukemia growth and significantly prolonged survival in a systemic acute myeloid leukemia xenograft model. Analysis of subcutaneous acute myeloid leukemia-derived tumors revealed significant decrease in 4EBP1 phosphorylation and Mcl-1 protein level, consistent with results obtained in vitro. These findings demonstrate that co-administration of dual mTORC1/mTORC2 inhibitors and BH3-mimetics exhibits potent anti-leukemic activity in vitro and in vivo, arguing that this strategy warrants attention in acute myeloid leukemia.
    Haematologica 10/2015; DOI:10.3324/haematol.2015.130351 · 5.81 Impact Factor
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    ABSTRACT: Purpose: AZD6244 is a MEK1/2 inhibitor with significant preclinical activity in multiple myeloma (MM) cells. This phase 2 study used a two-stage Simon design to determine the AZD6244 response rate in patients with relapsed or refractory MM. Experimental design: AZD6244 (75 mg) was administered orally, twice a day, continuously for 28-day cycles. Response was evaluated after 3 cycles. Results: Thirty-six patients received therapy. The median age was 65 years (range: 43-81) and the median number of prior therapies was 5 (range: 2-11). The most common grade 3 and 4 toxicities included anemia, neutropenia, thrombocytopenia, diarrhea, and fatigue. Three deaths occurred possibly related to AZD6244 (2 due to sepsis, 1 due to acute kidney injury). After AZD6244 discontinuation, 3 additional deaths occurred due to disease progression. The response rate (CR + PR) was 5.6% with a mean duration of response of 4.95 months and median progression-free survival time of 3.52 months. One patient had a very good partial response (VGPR), 1 patient had a partial response, 17 patients had stable disease, 13 patients had progressive disease, and 4 patients could not be assessed for response. Pharmacodynamic studies revealed variable effects on bone marrow CD138+ cell MEK1/2 and ERK1/2 phosphorylation. The best clinical response, a prolonged VGPR, occurred in a patient with an MMSET translocation. Conclusions: Single-agent AZD6244 was tolerable and had minimal activity in this heavily pre-treated population.
    Clinical Cancer Research 10/2015; DOI:10.1158/1078-0432.CCR-15-1076 · 8.72 Impact Factor

  • Clinical Cancer Research 09/2015; 21(17 Supplement):B15-B15. DOI:10.1158/1557-3265.HEMMAL14-B15 · 8.72 Impact Factor
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    ABSTRACT: A phase 1 study with carfilzomib and vorinostat was conducted in 20 B-cell lymphoma patients. Vorinostat was given orally twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 followed by carfilzomib (given as a 30 min infusion) on days 1, 2, 8, 9, 15, and 16. A treatment cycle was 28 days. Dose escalation initially followed a standard 3+3 design, but adapted a more conservative accrual rule following dose de-escalation. The maximum tolerated dose was 20 mg/m2 carfilzomib and 100 mg vorinostat (twice daily). The dose-limiting toxicities were grade 3 pneumonitis, hyponatremia, and febrile neutropenia. One patient had a partial response and 2 patients had stable disease. Correlative studies showed a decrease in NF-κB activation and an increase in Bim levels in some patients, but these changes did not correlate with clinical response. Trial Registration ID: NCT01276717.
    Leukemia & lymphoma 08/2015; 2015. · 2.89 Impact Factor
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    ABSTRACT: Chromodomain Helicase DNA-binding protein 4 (CHD4) is an ATPase that alters the phasing of nucleosomes on DNA and has recently been implicated in DNA double stranded break (DSB) repair. Here, we show that depletion of CHD4 in Acute Myeloid Leukemia (AML) blasts induces a global relaxation of chromatin that renders cells more susceptible to DSB formation, while concurrently impeding their repair. Furthermore, CHD4 depletion renders AML blasts more sensitive both in vitro and in vivo to genotoxic agents used in clinical therapy: daunorubicin (DNR) and cytarabine (ara-C). Sensitization to DNR and ara-C is mediated in part by activation of the ATM pathway, which is preliminarily activated by a Tip60-dependent mechanism in response to chromatin relaxation and further activated by genotoxic-agent induced DSBs. This sensitization preferentially affects AML cells, as CHD4 depletion in normal CD34(+) hematopoetic progenitors does not increase their susceptibility to DNR or ara-C. Unexpectedly, we found that CHD4 is necessary for maintaining the tumor forming behavior of AML cells, as CHD4 depletion severely restricted the ability of AML cells to form xenografts in mice and colonies in soft agar. Taken together, these results provide evidence for CHD4 as a novel therapeutic target whose inhibition has the potential to enhance the effectiveness of genotoxic agents used in AML therapy. Copyright © 2015 American Society of Hematology.
    Blood 08/2015; 126(12). DOI:10.1182/blood-2015-03-631606 · 10.45 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):LB-258-LB-258. DOI:10.1158/1538-7445.AM2015-LB-258 · 9.33 Impact Factor
  • Victor Y Yazbeck · Steven Grant ·
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    ABSTRACT: Introduction: Patients with relapsed or refractory lymphoma remain a population with unmet medical needs. Histone deacetylase inhibitors (HDACIs) represent a novel class of anticancer drugs currently in development in several malignancies. Inhibition of HDACs leads to acetylation of histone and non-histone proteins, which in turn results in epigenetic modification of gene expression that leads to a plethora of effects, such as cell cycle arrest, apoptosis and inhibition of angiogenesis. Romidepsin is a novel HDACI that has demonstrated preclinical and clinical activity. Areas covered: This review discusses the different HDACs and epigenetic regulation with a particular focus on the preclinical and clinical development of romidepsin in lymphoma. The review of romidepsin includes: the mechanism of action, its synergistic interaction with novel agents, pivotal clinical trials that lead to its US FDA approval in cutaneous T-cell lymphoma and peripheral T-cell lymphoma as well as active combinations currently in clinical trials. Expert opinion: Romidepsin is a potent HDACI with clinical activity in T-cell lymphoma where novel agents and combinations are desperately needed. A deeper understanding of the molecular characteristics of this class of agents will allow the design of more potent drugs with improved toxicity profiles and future rational combinations that will expand the indication and benefit from these novel agents.
    Expert Opinion on Investigational Drugs 05/2015; 24(7):1-15. DOI:10.1517/13543784.2015.1041586 · 5.53 Impact Factor
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    Prithviraj Bose · Steven Grant ·
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    ABSTRACT: Despite modest improvements in survival over the last several decades, the treatment of AML continues to present a formidable challenge. Most patients are elderly, and these individuals, as well as those with secondary, therapy-related, or relapsed/refractory AML, are particularly difficult to treat, owing to both aggressive disease biology and the high toxicity of current chemotherapeutic regimens. It has become increasingly apparent in recent years that coordinated interruption of cooperative survival signaling pathways in malignant cells is necessary for optimal therapeutic results. The modest efficacy of monotherapy with both cytotoxic and targeted agents in AML testifies to this. As the complex biology of AML continues to be elucidated, many " synthetic lethal " strategies involving rational combinations of targeted agents have been developed. Unfortunately, relatively few of these have been tested clinically, although there is growing interest in this area. In this article, the preclinical and, where available, clinical data on some of the most promising rational combinations of targeted agents in AML are summarized. While new molecules should continue to be combined with conventional genotoxic drugs of proven efficacy, there is perhaps a need to OPEN ACCESS J. Clin. Med. 2015, 4 635 rethink traditional philosophies of clinical trial development and regulatory approval with a focus on mechanism-based, synergistic strategies.
    Journal of Clinical Medicine 04/2015; 2015(4):634-664. DOI:10.3390/jcm4040634
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    Hong-Bin Fang · Xuerong Chen · Xin-Yan Pei · Steven Grant · Ming Tan ·
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    ABSTRACT: Drug combination is a critically important therapeutic approach for complex diseases such as cancer and HIV due to its potential for efficacy at lower, less toxic doses and the need to move new therapies rapidly into clinical trials. One of the key issues is to identify which combinations are additive, synergistic, or antagonistic. While the value of multidrug combinations has been well recognized in the cancer research community, to our best knowledge, all existing experimental studies rely on fixing the dose of one drug to reduce the dimensionality, e.g. looking at pairwise two-drug combinations, a suboptimal design. Hence, there is an urgent need to develop experimental design and analysis methods for studying multidrug combinations directly. Because the complexity of the problem increases exponentially with the number of constituent drugs, there has been little progress in the development of methods for the design and analysis of high-dimensional drug combinations. In fact, contrary to common mathematical reasoning, the case of three-drug combinations is fundamentally more difficult than two-drug combinations. Apparently, finding doses of the combination, number of combinations, and replicates needed to detect departures from additivity depends on dose-response shapes of individual constituent drugs. Thus, different classes of drugs of different dose-response shapes need to be treated as a separate case. Our application and case studies develop dose finding and sample size method for detecting departures from additivity with several common (linear and log-linear) classes of single dose-response curves. Furthermore, utilizing the geometric features of the interaction index, we propose a nonparametric model to estimate the interaction index surface by B-spine approximation and derive its asymptotic properties. Utilizing the method, we designed and analyzed a combination study of three anticancer drugs, PD184, HA14-1, and CEP3891 inhibiting myeloma H929 cell line. To our best knowledge, this is the first ever three drug combinations study performed based on the original 4D dose-response surface formed by dose ranges of three drugs. © The Author(s) 2015 Reprints and permissions:
    Statistical Methods in Medical Research 03/2015; DOI:10.1177/0962280215574320 · 4.47 Impact Factor
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    Yun Dai · Steven Grant ·
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    ABSTRACT: A variety of anticancer agents employed in standard chemotherapy or novel targeted therapy induce autophagy. A cytoprotective autophagic response often counteracts apoptosis triggered by such agents, potentially contributing to acquired drug-resistance. It is recognized that autophagy and apoptosis share molecular regulatory mechanisms primarily governed by multidomain anti-apoptotic members (e.g., BCL2/Bcl-2 and BCL2L1/Bcl-xL) of the BCL2 family. However, the role of pro-apoptotic BH3-only proteins (e.g.,, BCL2L11/Bim), another class of BCL2 family proteins that critically determine therapeutic responses, in autophagy regulation remains largely unexplored, particularly with respect to mechanisms of acquired drug resistance.
    Autophagy 02/2015; 11(2). DOI:10.1080/15548627.2014.998892 · 11.75 Impact Factor
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    ABSTRACT: The present studies were to determine whether the multi-kinase inhibitor sorafenib or its derivative regorafenib interacted with the ERBB1/ERBB2 inhibitor lapatinib to kill CNS tumor cells. In multiple CNS tumor cell types sorafenib and lapatinib interacted in a greater than additive fashion to cause tumor cell death. Tumor cells lacking PTEN, and anoikis or lapatinib resistant cells were as sensitive to the drug combination as cells expressing PTEN or parental cells, respectively. Similar data were obtained using regorafenib. Treatment of brain cancer cells with [sorafenib + lapatinib] enhanced radiation toxicity. The drug combination increased the numbers of LC3-GFP vesicles; this correlated with a reduction in endogenous LC3II, and p62 and LAMP2 degradation. Knock down of Beclin1 or ATG5 significantly suppressed drug combination lethality. Expression of c-FLIP-s, BCL-XL, or dominant negative caspase 9 reduced drug combination toxicity; knock down of FADD or CD95 was protective. Expression of both activated AKT and activated MEK1 or activated mTOR was required to strongly suppress drug combination lethality. As both lapatinib and sorafenib are FDA approved agents, our data argue for further determination as to whether lapatinib and sorafenib is a useful glioblastoma therapy. J. Cell. Physiol. 230: 131-139, 2015. © 2014 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 01/2015; 230(1):131-139. DOI:10.1002/jcp.24689 · 3.84 Impact Factor
  • Prithviraj Bose · Steven Grant ·
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    ABSTRACT: The Bcl-2 family of antiapoptotic and proapoptotic proteins serve as key regulators of the mitochondrial pathway of apoptosis. Multiple signals from a variety of cell death stimuli converge upon mitochondria to trigger the intrinsic apoptotic cascade. Bcl-2 family proteins are intimately related to prognosis and therapeutic resistance in acute myeloid leukemia (AML), making them rational targets for drug development. Also, directly targeting Bcl-2 family proteins circumvents many of the problems associated with targeting upstream molecules. The Bcl-2 antisense oligonucleotide oblimersen failed to live up to its initial promise in large phase III trials. The discovery of ABT-737, a novel, small-molecule inhibitor of specific protein–protein interactions, gave a much-needed impetus to the field of “BH3 mimetic” research. The demonstration that Mcl-1, an antiapoptotic Bcl-2 family protein that is not inhibited by ABT-737 or its analogs, is of crucial importance in AML, underscores the need for rational drug combinations that simultaneously target multiple arms of the apoptotic regulatory machinery.
    Targeted therapy of acute myeloid leukemia, Edited by Michael Andreeff, 01/2015: chapter 4: pages 67-94; Springer-Verlag, New York., ISBN: 978-1-4939-1392-3

  • American Society of Hematology, San Francisco, CA; 12/2014
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    ABSTRACT: Interactions between the dual BCR/ABL and Src inhibitor bosutinib and the Chk1 inhibitor PF-00477736 were examined in BCR/ABL+ leukemia cells, particularly imatinib-resistant cells, including those with the T315I mutation. Bosutinib blocked PF-00477736-induced ERK1/2 activation and sharply increased apoptosis in association with Mcl-1 inhibition, p34(cdc2) dephosphorylation, BimEL up-regulation, and DNA damage in imatinib-resistant CML or Ph+ ALL cell lines. Inhibition of Src or MEK1 by shRNA significantly enhanced PF-0047736 lethality. Bosutinib/PF-00477736 co-treatment also potentiated cell death in CD34+ CML patient samples, including dasatinib-resistant blast crisis cells exhibiting both T315I and E355G mutations, but was minimally toxic to normal CD34+ cells. Finally, combined in vivo treatment significantly suppressed BaF3/T315I tumor growth and prolonged survival in an allogeneic mouse model. Together, these findings suggest that this targeted combination strategy warrants attention in IM-resistant CML or Ph+ ALL.
    Leukemia Research 11/2014; 39(1). DOI:10.1016/j.leukres.2014.10.009 · 2.35 Impact Factor

  • 2nd Annual Meeting of the International-Cytokine-and-Interferon-Society; 11/2014
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    Chunrong Yu · Yun Dai · Paul Dent · Steven Grant ·
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    ABSTRACT: Interactions between the PKC and Chk1 inhibitor UCN-01 and pharmacologic MEK1/2 inhibitors (e.g., U0126, PD184352) were examined in Bcr/Abl(+) = human leukemia cells (K562, LAMA 84) sensitive and resistant to the Bcr/Abl kinase inhibitor STI571. Coexposure of K562 cells to UCN-01 (e.g., 100 nM) or U0126 (30 microM) resulted in a marked increase in mitochondrial injury (e.g., release of cytochrome c; loss of deltapsi(m)) and apoptosis. Similar results were obtained in other Bcr/Abl(+) cells (e.g., LAMA 84, BV-173) and with other MEK1/2 inhibitors (e.g., PD184352). Exposure of K562 cells to UCN-01 resulted in activation of ERK, an effect that was abrogated by co-administration of MEK1/2 inhibitors. Coadminstration of UCN-01 with U0126 produced multiple perturbations in signal transduction/cell cycle regulatory pathways, including diminished expression of Bcr/Abl, Mcl-1, cylin D(1), and activation of JNK and p34(cdc2). Coadministration of the JNK inhibitor SP600125 attenuated UCN-01/MEK inhibitor- associated lethality, suggesting a functional role for JNK activation in enhanced lethality. Finally, UCN-01 and MEK1/2 inhibitors effectively induced apoptosis in Bcr/Abl(+) cells (e.g., K562 and LAMA 84) overexpressing Bcr/Abl and resistant to STI571. These findings indicate that BcrAbl(+) leukemia cells are sensitive to a strategy combining UCN-01 with MEK/ERK inhibitors that simultaneously disrupts two signaling pathways.
    Cancer biology & therapy 10/2014; 1(6):674-82. DOI:10.4161/cbt.319 · 3.07 Impact Factor
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    ABSTRACT: B-cell malignancies are a common type of cancer. One approach to cancer therapy is to either increase oxidative stress or inhibit the stress response systems on which cancer cells rely. In this study, we combined non-toxic concentrations of Auranofin (AUR), an inhibitor of the thioredoxin (Trx) system, with non-toxic concentrations of buthionine-sulfoximine (BSO), a compound that reduces intracellular glutathione (GSH) levels, and investigated the effect of this drug combination on multiple pathways critical for malignant B-cell survival. AUR interacted synergistically with BSO at low concentrations to trigger death in multiple malignant B-cell lines and primary mantle cell lymphoma (MCL) cells. Additionally, there was less toxicity toward normal B-cells. Low AUR concentrations inhibited Trx reductase (TrxR) activity, an effect significantly increased by BSO co-treatment. TrxR over-expression partially reversed AUR+BSO toxicity. Interestingly, the combination of AUR+BSO inhibited NF-κB signaling. Moreover, synergistic cell death induced by this regimen was attenuated in cells over-expressing NF-κB proteins, arguing for a functional role for NF-κB inhibition in AUR+BSO-mediated cell death. Together, these findings suggest that AUR+BSO synergistically induce malignant B-cell death, a process mediated by dual inhibition of TrxR and NF-κB, and such an approach warrants further investigation in B-cell malignancies.
    Experimental Hematology 10/2014; 43(2). DOI:10.1016/j.exphem.2014.10.004 · 2.48 Impact Factor
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    ABSTRACT: AZD1775 targets the cell cycle checkpoint kinase Wee1 and potentiates genotoxic agent cytotoxicity through p53-dependent or -independent mechanisms. Here, we report that AZD1775 interacted synergistically with histone deacetylase inhibitors (HDACIs e.g., Vorinostat), which interrupt the DNA damage response (DDR), to kill p53-wild type or -deficient as well as FLT3-ITD leukemia cells in association with pronounced Wee1 inhibition and diminished cdc2/Cdk1 Y15 phosphorylation. Similarly, Wee1 shRNA knock-down significantly sensitized cells to HDACIs. While AZD1775 induced Chk1 activation, reflected by markedly increased Chk1 S296/S317/S345 phosphorylation leading to inhibitory T14 phosphorylation of cdc2/Cdk1, these compensatory responses were sharply abrogated by HDACIs. This was accompanied by premature mitotic entry, multiple mitotic abnormalities, and accumulation of early S-phase cells displaying increased newly replicated DNA, culminating in robust DNA damage and apoptosis. The regimen was active against patient-derived AML cells harboring either wild type or mutant p53, and various NGS-defined mutations. Primitive CD34(+)/CD123(+)/CD38(-) populations enriched for leukemia-initiating progenitors, but not normal CD34(+) hematopoietic cells, were highly susceptible to this regimen. Finally, combining AZD1775 with Vorinostat in AML murine xenografts significantly reduced tumor burden and prolonged animal survival. A strategy combining Wee1 with HDACI inhibition warrants further investigation in AML with poor prognostic genetic aberrations.Leukemia accepted article preview online, 06 October 2014. doi:10.1038/leu.2014.296.
    Leukemia 10/2014; 29(4). DOI:10.1038/leu.2014.296 · 10.43 Impact Factor
  • Tri K. Nguyen · Steven Grant ·

    Cancer Research 10/2014; 74(19 Supplement):2686-2686. DOI:10.1158/1538-7445.AM2014-2686 · 9.33 Impact Factor
  • Yu Zhang · Liang Zhou · Shuang Chen · Maciej Kmieciak · Hui Lin · Yun Dai · Steven Grant ·

    Cancer Research 10/2014; 74(19 Supplement):4556-4556. DOI:10.1158/1538-7445.AM2014-4556 · 9.33 Impact Factor

Publication Stats

16k Citations
2,239.18 Total Impact Points


  • 2015
    • Southwestern University of Finance and Economics
      Hua-yang, Sichuan, China
  • 2-2015
    • Virginia Commonwealth University
      • • Division of Hematology/Oncology
      • • School of Medicine
      • • Department of Biochemistry and Molecular Biology
      • • Massey Cancer Center
      • • Department of Radiation Oncology
      • • Department of Microbiology & Immunology
      • • Department of Pharmacology and Toxicology
      Ричмонд, Virginia, United States
  • 1994-2013
    • Richmond VA Medical Center
      Ричмонд, Virginia, United States
    • Arizona State University
      • Cancer Research Institute
      Phoenix, Arizona, United States
  • 2003
    • University of Richmond
      Ричмонд, Virginia, United States
  • 1991
    • Medical University of South Carolina
      • Division of Hematology/Oncology
      Charleston, South Carolina, United States
  • 1984-1987
    • CUNY Graduate Center
      New York, New York, United States
  • 1982-1985
    • Columbia University
      • • Department of Medicine
      • • College of Physicians and Surgeons
      New York, New York, United States