Mitsiades, Constantine

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Mitsiades, Constantine

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Mitsiades

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Constantine

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Mitsiades, Constantine

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Daratumumab augments alloreactive natural killer cell cytotoxicity towards CD38+ multiple myeloma cell lines in a biochemical context mimicking tumour microenvironment conditions
(Springer Berlin Heidelberg, 2018) Mahaweni, Niken M.; Bos, Gerard M. J.; Mitsiades, Constantine; Tilanus, Marcel G. J.; Wieten, Lotte
Natural killer (NK) cell-based immunotherapy is a promising novel approach to treat cancer. However, NK cell function has been shown to be potentially diminished by factors common in the tumor microenvironment (TME). In this study, we assessed the synergistic potential of antibody-dependent cell-mediated cytotoxicity (ADCC) and killer immunoglobin-like receptor (KIR)-ligand mismatched NK cells to potentiate NK cell antitumor reactivity in multiple myeloma (MM). Hypoxia, lactate, prostaglandin E2 (PGE2) or combinations were selected to mimic the TME. To investigate this, NK cells from healthy donors were isolated and NK cell ADCC capacity in response to MM cells was assessed in flow cytometry-based cytotoxicity and degranulation (CD107a) assays in the presence of TME factors. Hypoxia, lactate and PGE2 reduced cytotoxicity of NK cells against myeloma target cells. The addition of daratumumab (anti-CD38 antibody) augmented NK-cell cytotoxicity against target cells expressing high CD38, but not against CD38 low or negative target cells also in the presence of TME. Co-staining for inhibitory KIRs and NKG2A demonstrated that daratumumab enhanced degranulation of all NK cell subsets. Nevertheless, KIR-ligand mismatched NK cells were slightly better effector cells than KIR-ligand matched NK cells. In summary, our study shows that combination therapy using strategies to maximize activating NK cell signaling by triggering ADCC in combination with an approach to minimize inhibitory signaling through a selection of KIR-ligand mismatched donors, can help to overcome the NK-suppressive TME. This can serve as a platform to improve the clinical efficacy of NK cells. Electronic supplementary material The online version of this article (10.1007/s00262-018-2140-1) contains supplementary material, which is available to authorized users.
An epigenomic approach to therapy for tamoxifen-resistant breast cancer
(Nature Publishing Group, 2014) Feng, Qin; Zhang, Zheng; Shea, Martin J; Creighton, Chad J; Coarfa, Cristian; Hilsenbeck, Susan G; Lanz, Rainer; He, Bin; Wang, Lei; Fu, Xiaoyong; Nardone, Agostina; Song, Yongcheng; Bradner, James E; Mitsiades, Nicholas; Mitsiades, Constantine; Osborne, C Kent; Schiff, Rachel; O'Malley, Bert W
Tamoxifen has been a frontline treatment for estrogen receptor alpha (ERα)-positive breast tumors in premenopausal women. However, resistance to tamoxifen occurs in many patients. ER still plays a critical role in the growth of breast cancer cells with acquired tamoxifen resistance, suggesting that ERα remains a valid target for treatment of tamoxifen-resistant (Tam-R) breast cancer. In an effort to identify novel regulators of ERα signaling, through a small-scale siRNA screen against histone methyl modifiers, we found WHSC1, a histone H3K36 methyltransferase, as a positive regulator of ERα signaling in breast cancer cells. We demonstrated that WHSC1 is recruited to the ERα gene by the BET protein BRD3/4, and facilitates ERα gene expression. The small-molecule BET protein inhibitor JQ1 potently suppressed the classic ERα signaling pathway and the growth of Tam-R breast cancer cells in culture. Using a Tam-R breast cancer xenograft mouse model, we demonstrated in vivo anti-breast cancer activity by JQ1 and a strong long-lasting effect of combination therapy with JQ1 and the ER degrader fulvestrant. Taken together, we provide evidence that the epigenomic proteins BRD3/4 and WHSC1 are essential regulators of estrogen receptor signaling and are novel therapeutic targets for treatment of Tam-R breast cancer.
Targeting transcription regulation in cancer with a covalent CDK7 inhibitor
(2014) Kwiatkowski, Nicholas; Zhang, Tinghu; Rahl, Peter B; Abraham, Brian J; Reddy, Jessica; Ficarro, Scott; Dastur, Anahita; Amzallag, Arnaud; Ramaswamy, Sridhar; Tesar, Bethany; Jenkins, Christopher R; Hannett, Nancy M; McMillin, Douglas; Sanda, Takaomi; Sim, Taebo; Kim, Nam Doo; Look, Thomas; Mitsiades, Constantine; Weng, Andrew P; Brown, Jennifer; Benes, Cyril; Marto, Jarrod; Young, Richard A; Gray, Nathanael
Tumor oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state1, but direct pharmacological inhibition of transcription factors has thus far proven difficult2. However, the transcriptional machinery contains various enzymatic co-factors that can be targeted for development of new therapeutic candidates3, including cyclin-dependent kinases (CDKs)4. Here we present the discovery and characterization of the first covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell line profiling indicates that a subset of cancer cell lines, including T-ALL, exhibit exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and this transcription factor’s key role in the core transcriptional regulatory circuitry of these tumor cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumor types exhibiting extreme dependencies on transcription for maintenance of the oncogenic state.
Identification of proteins found to be significantly altered when comparing the serum proteome from Multiple Myeloma patients with varying degrees of bone disease
(BioMed Central, 2014) Dowling, Paul; Hayes, Catriona; Ting, Kay Reen; Hameed, Abdul; Meiller, Justine; Mitsiades, Constantine; Anderson, Kenneth; Clynes, Martin; Clarke, Colin; Richardson, Paul; O’Gorman, Peter
Background: Bone destruction is a feature of multiple myeloma, characterised by osteolytic bone destruction due to increased osteoclast activity and suppressed or absent osteoblast activity. Almost all multiple myeloma patients develop osteolytic bone lesions associated with severe and debilitating bone pain, pathologic fractures, hypercalcemia, and spinal cord compression, as well as increased mortality. Biomarkers of bone remodelling are used to identify disease characteristics that can help select the optimal management of patients. However, more accurate biomarkers are needed to effectively mirror the dynamics of bone disease activity. Results: A label-free mass spectrometry-based strategy was employed for discovery phase analysis of fractionated patient serum samples associated with no or high bone disease. A number of proteins were identified which were statistically significantly correlated with bone disease, including enzymes, extracellular matrix glycoproteins, and components of the complement system. Conclusions: Enzyme-linked immunosorbent assay of complement C4 and serum paraoxonase/arylesterase 1 indicated that these proteins were associated with high bone disease in a larger independent cohort of patient samples. These biomolecules may therefore be clinically useful in assessing the extent of bone disease. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-904) contains supplementary material, which is available to authorized users.
Discovery of a Potent, Covalent BTK Inhibitor for B-Cell Lymphoma
(American Chemical Society, 2014) Wu, Hong; Wang, Wenchao; Liu, Feiyang; Weisberg, Ellen; Tian, Bei; Chen, Yongfei; Li, Binhua; Wang, Aoli; Wang, Beilei; Zhao, Zheng; McMillin, Douglas W.; Hu, Chen; Li, Hong; Wang, Jinhua; Liang, Yanke; Buhrlage, Sara J.; Liang, Junting; Liu, Jing; Yang, Guang; Brown, Jennifer R.; Treon, Steven; Mitsiades, Constantine; Griffin, James; Liu, Qingsong; Gray, Nathanael
BTK is a member of the TEC family of non-receptor tyrosine kinases whose deregulation has been implicated in a variety of B-cell-related diseases. We have used structure-based drug design in conjunction with kinome profiling and cellular assays to develop a potent, selective, and irreversible BTK kinase inhibitor, QL47, which covalently modifies Cys481. QL47 inhibits BTK kinase activity with an IC50 of 7 nM, inhibits autophosphorylation of BTK on Tyr223 in cells with an EC50 of 475 nM, and inhibits phosphorylation of a downstream effector PLCγ2 (Tyr759) with an EC50 of 318 nM. In Ramos cells QL47 induces a G1 cell cycle arrest that is associated with pronounced degradation of BTK protein. QL47 inhibits the proliferation of B-cell lymphoma cancer cell lines at submicromolar concentrations.
The Cyclophilin A-CD147 complex promotes bone marrow colonization of B-cell malignancies: implications for therapy
(2015) Zhu, Di; Wang, Zhongqiu; Zhao, Jian-Jun; Calimeri, Teresa; Meng, Jiang; Hideshima, Teru; Fulciniti, Mariateresa; Kang, Yue; Ficarro, Scott; Tai, Yu-Tzu; Hunter, Zachary; McMilin, Douglas; Tong, Haoxuan; Mitsiades, Constantine; Wu, Catherine; Treon, Steven; Dorfman, David M.; Pinkus, Geraldine; Munshi, Nikhil; Tassone, Pierfrancesco; Marto, Jarrod; Anderson, Kenneth; Carrasco, Ruben
B-cell malignancies frequently colonizes the bone marrow (BM). The mechanisms responsible for this preferential homing are not entirely known. Using multiple myeloma (MM) as a model of a terminally differentiated B-cell malignancy that selectively colonizes the BM, we demonstrated that BM endothelial cells (BMECs), secrete cyclophilin A (eCyPA), which promotes migration, proliferation, and BM colonization of MM cells via binding to its receptor, CD147, on MM cells. The clinical and translational implications of this work are highlighted by the observation of significantly higher eCyPA levels in BM serum than in peripheral blood (PB) in MM persons, and that eCyPA-CD147 blockade supresses BM-homing and tumor growth in a mouse xenograft model of MM. eCyPA also promoted migration of CLL and LPL cells, two other B-cell malignancies that colonize the BM and express CD147. These findings offer a compelling rationale for exploring the eCyPA-CD147 axis as therapeutic target for these malignancies.
High-throughput approaches to discover novel immunomodulatory agents for cancer
(Landes Bioscience, 2012) McMillin, Douglas; Mitsiades, Constantine
The clinical success of immunomodulatory thalidomide derivatives has renewed the general interest in immunomodulatory anticancer compounds and prompted us to develop a high-throughput system to quantify immune effector-cell activity. We documented that the interaction between cancer cells, their stroma, anticancer agents and cells from the innate system are critical for determining the response of tumors to immunomodulatory strategies.
Selective Akt Inhibitors Synergize with Tyrosine Kinase Inhibitors and Effectively Override Stroma-Associated Cytoprotection of Mutant FLT3-Positive AML Cells
(Public Library of Science, 2013) Weisberg, Ellen; Liu, Qingsong; Zhang, Xin; Nelson, Erik; Sattler, Martin; Liu, Feiyang; Nicolais, Maria; Zhang, Jianming; Mitsiades, Constantine; Smith, Robert Walsh; Stone, Richard; Galinsky, Ilene; Nonami, Atsushi; Griffin, James; Gray, Nathanael
Objectives: Tyrosine kinase inhibitor (TKI)-treated acute myeloid leukemia (AML) patients commonly show rapid and significant peripheral blood blast cell reduction, however a marginal decrease in bone marrow blasts. This suggests a protective environment and highlights the demand for a better understanding of stromal:leukemia cell communication. As a strategy to improve clinical efficacy, we searched for novel agents capable of potentiating the stroma-diminished effects of TKI treatment of mutant FLT3-expressing cells. Methods: We designed a combinatorial high throughput drug screen using well-characterized kinase inhibitor-focused libraries to identify novel kinase inhibitors capable of overriding stromal-mediated resistance to TKIs, such as PKC412 and AC220. Standard liquid culture proliferation assays, cell cycle and apoptosis analysis, and immunoblotting were carried out with cell lines or primary AML to validate putative candidates from the screen and characterize the mechanism(s) underlying observed synergy. Results and Conclusions Our study led to the observation of synergy between selective Akt inhibitors and FLT3 inhibitors against mutant FLT3-positive AML in either the absence or presence of stroma. Our findings are consistent with evidence that Akt activation is characteristic of mutant FLT3-transformed cells, as well as observed residual Akt activity following FLT3 inhibitor treatment. In conclusion, our study highlights the potential importance of Akt as a signaling factor in leukemia survival, and supports the use of the co-culture chemical screen to identify agents able to potentiate TKI anti-leukemia activity in a cytoprotective microenvironment.
Lenalidomide for the Treatment of Relapsed and Refractory Multiple Myeloma
(Dove Medical Press, 2012) Görgün, Güllü; Nijhof, Inger S; Raymakers, Reinier A; Lokhorst, Henk M; Groen, Richard W.j.; Jakubikova, Jana; Mitsiades, Constantine; Hideshima, Teru; Laubach, Jacob; Richardson, Paul; Anderson, Kenneth; van de Donk, Niels WCJ
Lenalidomide is an amino-substituted derivative of thalidomide with direct antiproliferative and cytotoxic effects on the myeloma tumor cell, as well as antiangiogenic activity and immunomodulatory effects. Together with the introduction of bortezomib and thalidomide, lenalidomide has significantly improved the survival of patients with relapsed and refractory myeloma. The most common adverse events associated with lenalidomide include fatigue, skin rash, thrombocytopenia, and neutropenia. In addition, when lenalidomide is combined with dexamethasone or other conventional cytotoxic agents, there is an increase in the incidence of venous thromboembolic events. There is now evidence that continued treatment with lenalidomide has a significant impact on survival by improving the depth and duration of response. This highlights the value of adverse event management and appropriate dose adjustments to prevent toxicity, and of allowing continued treatment until disease progression. In this review, we will discuss the different lenalidomide-based treatment regimens for patients with relapsed/refractory myeloma. This is accompanied by recommendations of how to manage and prevent adverse events associated with lenalidomide-based therapy.
The Medical Research Council Myeloma IX Trial: The Impact on Treatment Paradigms
(Blackwell Publishing Ltd, 2011) Richardson, Paul; Laubach, Jacob; Schlossman, Robert Lawrence; Ghobrial, Irene; Mitsiades, Constantine; Rosenblatt, Jacalyn; Mahindra, Anuj; Raje, Noopur; Munshi, Nikhil; Anderson, Kenneth
Osteolytic bone disease is a hallmark of symptomatic multiple myeloma. Bisphosphonates have been the mainstay of treatment to preserve skeletal integrity and prevent skeletal-related events in patients with myeloma-related bone disease. Recently, the MRC Myeloma IX trial demonstrated for the first time improved survival and delayed disease progression with the use of an intravenous amino-bisphosphonate, zoledronic acid, vs. an oral agent, clodronate, with intensive and non-intensive anti-myeloma treatment regimens in patients with newly diagnosed multiple myeloma. These results validate a large body of preclinical, translational and other clinical data suggesting anti-myeloma effects of amino-bisphosphonates. In addition, this trial also provided the first head-to-head evidence for superiority of one bisphosphonate over another (zoledronic acid vs. clodronate) for reducing skeletal morbidity in patients with multiple myeloma, as well as a prospective comparison of toxicities. Despite the use of non-bortezomib containing anti-myeloma treatment regimens in the MRC Myeloma IX trial, these results are encouraging and provide an impetus to continue to evaluate current treatment guidelines for myeloma-associated bone disease.