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Article: Novel Anti-B-cell Maturation Antigen Alpha-Amanitin Antibody-drug Conjugate HDP-101 Shows Superior Activity to Belantamab Mafodotin and Enhanced Efficacy in Deletion 17p Myeloma Models.

Singh, Ram Kumar / Jones, Richard J / Shirazi, Fazal / Qin, Li / Zou, Jianxuan / Hong, Samuel / Wang, Hua / Lee, Hans C / Patel, Krina K / Wan, Jie / Choudhary, Rajan Kumar / Kuiatse, Isere / Pahl, Andreas / Orlowski, Robert Z

Research square

2024

Abstract: B-cell maturation antigen (BCMA) plays a pathobiologic role in myeloma and is a validated target with five BCMA-specific therapeutics having been approved for relapsed/refractory disease. However, these drugs are not curative, and responses are inferior ... ...

Abstract	B-cell maturation antigen (BCMA) plays a pathobiologic role in myeloma and is a validated target with five BCMA-specific therapeutics having been approved for relapsed/refractory disease. However, these drugs are not curative, and responses are inferior in patients with molecularly-defined high-risk disease, including those with deletion 17p (del17p) involving the tumor suppressor
Language	English
Publishing date	2024-01-11
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3843028/v1
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Article ; Online: Intravenous Immunoglobulin G Suppresses Heat Shock Protein (HSP)-70 Expression and Enhances the Activity of HSP90 and Proteasome Inhibitors.

Jones, Richard J / Singh, Ram K / Shirazi, Fazal / Wan, Jie / Wang, Hua / Wang, Xiaobin / Ha, Min Jin / Baljevic, Muhamed / Kuiatse, Isere / Davis, Richard E / Orlowski, Robert Z

Frontiers in immunology

2020 Volume 11, Page(s) 1816

Abstract: Intravenous immunoglobulin G (IVIgG) is approved for primary immunodeficiency syndromes but may induce anti-cancer effects, and while this has been attributed to its anti-inflammatory properties, IgG against specific tumor targets may play a role. We ... ...

Abstract	Intravenous immunoglobulin G (IVIgG) is approved for primary immunodeficiency syndromes but may induce anti-cancer effects, and while this has been attributed to its anti-inflammatory properties, IgG against specific tumor targets may play a role. We evaluated IVIgG alone, and with a Heat shock protein (HSP)-90 or proteasome inhibitor, using multiple myeloma and mantle cell lymphoma (MCL) cells
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Bortezomib/pharmacology ; Cell Line, Tumor ; HSP70 Heat-Shock Proteins/biosynthesis ; HSP70 Heat-Shock Proteins/drug effects ; HSP90 Heat-Shock Proteins/immunology ; Humans ; Immunoglobulins, Intravenous/pharmacology ; Lymphoma, Mantle-Cell/immunology ; Mice ; Mice, SCID ; Multiple Myeloma/immunology ; Proteasome Inhibitors/pharmacology ; Xenograft Model Antitumor Assays
Chemical Substances	Antineoplastic Agents ; HSP70 Heat-Shock Proteins ; HSP90 Heat-Shock Proteins ; Immunoglobulins, Intravenous ; Proteasome Inhibitors ; Bortezomib (69G8BD63PP)
Language	English
Publishing date	2020-08-13
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.01816
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Article ; Online: Activating

Shirazi, Fazal / Jones, Richard J / Singh, Ram K / Zou, Jianxuan / Kuiatse, Isere / Berkova, Zuzana / Wang, Hua / Lee, Hans C / Hong, Samuel / Dick, Larry / Chattopadhyay, Nibedita / Orlowski, Robert Z

Proceedings of the National Academy of Sciences of the United States of America

2020 Volume 117, Issue 33, Page(s) 20004–20014

Abstract: ... ...

Abstract	KRAS
MeSH term(s)	Apoptosis/drug effects ; Bortezomib/pharmacology ; Endoplasmic Reticulum Stress/drug effects ; GTP Phosphohydrolases/genetics ; GTP Phosphohydrolases/metabolism ; Humans ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Multiple Myeloma/genetics ; Multiple Myeloma/metabolism ; Multiple Myeloma/physiopathology ; Mutation ; Proteasome Endopeptidase Complex/genetics ; Proteasome Endopeptidase Complex/metabolism ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins B-raf/metabolism ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins p21(ras)/metabolism
Chemical Substances	KRAS protein, human ; Membrane Proteins ; Protein Kinase Inhibitors ; Bortezomib (69G8BD63PP) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; GTP Phosphohydrolases (EC 3.6.1.-) ; NRAS protein, human (EC 3.6.1.-) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Keywords	covid19
Language	English
Publishing date	2020-08-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2005052117
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Article ; Online: LFA-1 activation enriches tumor-specific T cells in a cold tumor model and synergizes with CTLA-4 blockade.

Hickman, Amber / Koetsier, Joost / Kurtanich, Trevin / Nielsen, Michael C / Winn, Glenn / Wang, Yunfei / Bentebibel, Salah-Eddine / Shi, Leilei / Punt, Simone / Williams, Leila / Haymaker, Cara / Chesson, Charles B / Fa'ak, Faisal / Dominguez, Ana L / Jones, Richard / Kuiatse, Isere / Caivano, Amy R / Khounlo, Sayadeth / Warier, Navin D /

Marathi, Upendra / Market, Robert V / Biediger, Ronald J / Craft, John W / Hwu, Patrick / Davies, Michael A / Woodside, Darren G / Vanderslice, Peter / Diab, Adi / Overwijk, Willem W / Hailemichael, Yared

The Journal of clinical investigation

2022 Volume 132, Issue 13

Abstract: The inability of CD8+ effector T cells (Teffs) to reach tumor cells is an important aspect of tumor resistance to cancer immunotherapy. The recruitment of these cells to the tumor microenvironment (TME) is regulated by integrins, a family of adhesion ... ...

Abstract	The inability of CD8+ effector T cells (Teffs) to reach tumor cells is an important aspect of tumor resistance to cancer immunotherapy. The recruitment of these cells to the tumor microenvironment (TME) is regulated by integrins, a family of adhesion molecules that are expressed on T cells. Here, we show that 7HP349, a small-molecule activator of lymphocyte function-associated antigen-1 (LFA-1) and very late activation antigen-4 (VLA-4) integrin cell-adhesion receptors, facilitated the preferential localization of tumor-specific T cells to the tumor and improved antitumor response. 7HP349 monotherapy had modest effects on anti-programmed death 1-resistant (anti-PD-1-resistant) tumors, whereas combinatorial treatment with anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) increased CD8+ Teff intratumoral sequestration and synergized in cooperation with neutrophils in inducing cancer regression. 7HP349 intratumoral CD8+ Teff enrichment activity depended on CXCL12. We analyzed gene expression profiles using RNA from baseline and on treatment tumor samples of 14 melanoma patients. We identified baseline CXCL12 gene expression as possibly improving the likelihood or response to anti-CTLA-4 therapies. Our results provide a proof-of-principle demonstration that LFA-1 activation could convert a T cell-exclusionary TME to a T cell-enriched TME through mechanisms involving cooperation with innate immune cells.
MeSH term(s)	CD8-Positive T-Lymphocytes ; CTLA-4 Antigen ; Humans ; Immunotherapy/methods ; Lymphocyte Function-Associated Antigen-1/genetics ; Lymphocyte Function-Associated Antigen-1/metabolism ; Lymphocytes, Tumor-Infiltrating ; Melanoma/drug therapy ; Melanoma/genetics ; Programmed Cell Death 1 Receptor ; T-Lymphocytes/metabolism ; Tumor Microenvironment
Chemical Substances	CTLA-4 Antigen ; Lymphocyte Function-Associated Antigen-1 ; Programmed Cell Death 1 Receptor
Language	English
Publishing date	2022-05-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI154152
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Article ; Online: LFA-1 activation enriches tumor-specific T cells in a cold tumor model and synergizes with CTLA-4 blockade

Amber Hickman / Joost Koetsier / Trevin Kurtanich / Michael C. Nielsen / Glenn Winn / Yunfei Wang / Salah-Eddine Bentebibel / Leilei Shi / Simone Punt / Leila Williams / Cara Haymaker / Charles B. Chesson / Faisal Fa’ak / Ana L. Dominguez / Richard Jones / Isere Kuiatse / Amy R. Caivano / Sayadeth Khounlo / Navin D. Warier /

Upendra Marathi / Robert V. Market / Ronald J. Biediger / John W. Craft Jr. / Patrick Hwu / Michael A. Davies / Darren G. Woodside / Peter Vanderslice / Adi Diab / Willem W. Overwijk / Yared Hailemichael

The Journal of Clinical Investigation, Vol 132, Iss

2022 Volume 13

Abstract	The inability of CD8+ effector T cells (Teffs) to reach tumor cells is an important aspect of tumor resistance to cancer immunotherapy. The recruitment of these cells to the tumor microenvironment (TME) is regulated by integrins, a family of adhesion molecules that are expressed on T cells. Here, we show that 7HP349, a small-molecule activator of lymphocyte function–associated antigen-1 (LFA-1) and very late activation antigen-4 (VLA-4) integrin cell-adhesion receptors, facilitated the preferential localization of tumor-specific T cells to the tumor and improved antitumor response. 7HP349 monotherapy had modest effects on anti–programmed death 1–resistant (anti–PD-1–resistant) tumors, whereas combinatorial treatment with anti–cytotoxic T lymphocyte–associated protein 4 (anti–CTLA-4) increased CD8+ Teff intratumoral sequestration and synergized in cooperation with neutrophils in inducing cancer regression. 7HP349 intratumoral CD8+ Teff enrichment activity depended on CXCL12. We analyzed gene expression profiles using RNA from baseline and on treatment tumor samples of 14 melanoma patients. We identified baseline CXCL12 gene expression as possibly improving the likelihood or response to anti–CTLA-4 therapies. Our results provide a proof-of-principle demonstration that LFA-1 activation could convert a T cell–exclusionary TME to a T cell–enriched TME through mechanisms involving cooperation with innate immune cells.
Keywords	Therapeutics ; Medicine ; R
Language	English
Publishing date	2022-07-01T00:00:00Z
Publisher	American Society for Clinical Investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Activating KRAS, NRAS, and BRAF mutants enhance proteasome capacity and reduce endoplasmic reticulum stress in multiple myeloma

Proc. Natl. Acad. Sci. U. S. A

Abstract: KRAS, NRAS, and BRAF mutations which activate p44/42 mitogen-activated protein kinase (MAPK) signaling are found in half of myeloma patients and contribute to proteasome inhibitor (PI) resistance, but the underlying mechanisms are not fully understood. ... ...

Abstract	KRAS, NRAS, and BRAF mutations which activate p44/42 mitogen-activated protein kinase (MAPK) signaling are found in half of myeloma patients and contribute to proteasome inhibitor (PI) resistance, but the underlying mechanisms are not fully understood. We established myeloma cell lines expressing wild-type (WT), constitutively active (CA) (G12V/G13D/Q61H), or dominant-negative (DN) (S17N)-KRAS and -NRAS, or BRAF-V600E. Cells expressing CA mutants showed increased proteasome maturation protein (POMP) and nuclear factor (erythroid-derived 2)-like 2 (NRF2) expression. This correlated with an increase in catalytically active proteasome subunit ß (PSMB)-8, PSMB9, and PSMB10, which occurred in an ETS transcription factor-dependent manner. Proteasome chymotrypsin-like, trypsin-like, and caspase-like activities were increased, and this enhanced capacity reduced PI sensitivity, while DN-KRAS and DN-NRAS did the opposite. Pharmacologic RAF or MAPK kinase (MEK) inhibitors decreased proteasome activity, and sensitized myeloma cells to PIs. CA-KRAS, CA-NRAS, and CA-BRAF down-regulated expression of endoplasmic reticulum (ER) stress proteins, and reduced unfolded protein response activation, while DN mutations increased both. Finally, a bortezomib (BTZ)/MEK inhibitor combination showed enhanced activity in vivo specifically in CA-NRAS models. Taken together, the data support the hypothesis that activating MAPK pathway mutations enhance PI resistance by increasing proteasome capacity, and provide a rationale for targeting such patients with PI/RAF or PI/MEK inhibitor combinations. Moreover, they argue these mutations promote myeloma survival by reducing cellular stress, thereby distancing plasma cells from the apoptotic threshold, potentially explaining their high frequency in myeloma.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #32747568
Database	COVID19

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Article ; Online: Ubiquitin-activating enzyme inhibition induces an unfolded protein response and overcomes drug resistance in myeloma.

Zhuang, Junling / Shirazi, Fazal / Singh, Ram Kumar / Kuiatse, Isere / Wang, Hua / Lee, Hans C / Berkova, Zuzana / Berger, Allison / Hyer, Marc / Chattopadhyay, Nibedita / Syed, Sakeena / Shi, Judy Qiuju / Yu, Jie / Shinde, Vaishali / Tirrell, Stephen / Jones, Richard Julian / Wang, Zhiqiang / Davis, R Eric / Orlowski, Robert Z

Blood

2019 Volume 133, Issue 14, Page(s) 1572–1584

Abstract: Three proteasome inhibitors have garnered regulatory approvals in various multiple myeloma settings; but drug resistance is an emerging challenge, prompting interest in blocking upstream components of the ubiquitin-proteasome pathway. One such attractive ...

Abstract	Three proteasome inhibitors have garnered regulatory approvals in various multiple myeloma settings; but drug resistance is an emerging challenge, prompting interest in blocking upstream components of the ubiquitin-proteasome pathway. One such attractive target is the E1 ubiquitin-activating enzyme (UAE); we therefore evaluated the activity of TAK-243, a novel and specific UAE inhibitor. TAK-243 potently suppressed myeloma cell line growth, induced apoptosis, and activated caspases while decreasing the abundance of ubiquitin-protein conjugates. This was accompanied by stabilization of many short-lived proteins, including p53, myeloid cell leukemia 1 (MCL-1), and c-MYC, and activation of the activating transcription factor 6 (ATF-6), inositol-requiring enzyme 1 (IRE-1), and protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK) arms of the ER stress response pathway, as well as oxidative stress. UAE inhibition showed comparable activity against otherwise isogenic cell lines with wild-type (WT) or deleted p53 despite induction of TP53 signaling in WT cells. Notably, TAK-243 overcame resistance to conventional drugs and novel agents in cell-line models, including bortezomib and carfilzomib resistance, and showed activity against primary cells from relapsed/refractory myeloma patients. In addition, TAK-243 showed strong synergy with a number of antimyeloma agents, including doxorubicin, melphalan, and panobinostat as measured by low combination indices. Finally, TAK-243 was active against a number of in vivo myeloma models in association with activation of ER stress. Taken together, the data support the conclusion that UAE inhibition could be an attractive strategy to move forward to the clinic for patients with relapsed and/or refractory multiple myeloma.
MeSH term(s)	Antineoplastic Agents/therapeutic use ; Cell Line, Tumor ; Drug Resistance, Neoplasm/drug effects ; Drug Synergism ; Endoplasmic Reticulum Stress/drug effects ; Humans ; Multiple Myeloma/drug therapy ; Oxidative Stress/drug effects ; Proteasome Inhibitors/pharmacology ; Salvage Therapy/methods ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/drug effects ; Tumor Suppressor Protein p53/metabolism ; Ubiquitin-Activating Enzymes/antagonists & inhibitors ; Unfolded Protein Response/drug effects
Chemical Substances	Antineoplastic Agents ; Proteasome Inhibitors ; TP53 protein, human ; Tumor Suppressor Protein p53 ; Ubiquitin-Activating Enzymes (EC 6.2.1.45)
Language	English
Publishing date	2019-02-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2018-06-859686
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Article ; Online: The novel protein homeostatic modulator BTX306 is active in myeloma and overcomes bortezomib and lenalidomide resistance.

Journal of molecular medicine (Berlin, Germany)

2020 Volume 98, Issue 8, Page(s) 1161–1173

Abstract: Small molecules targeting the cereblon-containing E3 ubiquitin ligase including thalidomide, lenalidomide, and pomalidomide modulate turnover of downstream client proteins and demonstrate pre-clinical and clinical anti-myeloma activity. Different drugs ... ...

Abstract	Small molecules targeting the cereblon-containing E3 ubiquitin ligase including thalidomide, lenalidomide, and pomalidomide modulate turnover of downstream client proteins and demonstrate pre-clinical and clinical anti-myeloma activity. Different drugs that engage with cereblon hold the potential of unique phenotypic effects, and we therefore studied the novel protein homeostatic modulator (PHM™) BTX306 with a unique thiophene-fused scaffold bearing a substituted phenylurea and glutarimide. This agent much more potently reduced human-derived myeloma cell line viability, with median inhibitory concentrations in the single nanomolar range versus micromolar values for lenalidomide or pomalidomide, and more potently activated caspases 3/8/9. While lenalidomide and pomalidomide induced greater degradation of Ikaros and Aiolos in myeloma cells, BTX306 more potently reduced levels of GSPT1, eRF1, CK1α, MCL-1, and c-MYC. Suppression of cereblon or overexpression of Aiolos or Ikaros induced relative resistance to BTX306, and this agent did not impact viability of murine hematopoietic cells in an in vivo model, demonstrating its specificity for human cereblon. Interestingly, BTX306 did show some reduced activity in lenalidomide-resistant cell line models but nonetheless retained its nanomolar potency in vitro, overcame bortezomib resistance, and was equipotent against otherwise isogenic cell line models with either wild-type or knockout TP53. Finally, BTX306 demonstrated strong activity against primary CD138-positive plasma cells, showed enhanced anti-proliferative activity in combination with bortezomib and dexamethasone, and was effective in an in vivo systemic model of multiple myeloma. Taken together, the data support further translational studies of BTX306 and its derivatives to the clinic for patients with relapsed and/or refractory myeloma. KEY MESSAGES: BTX306 has a unique thiophene-fused scaffold bearing phenylurea and glutarimide. BTX306 is more potent against myeloma cells than lenalidomide or pomalidomide. BTX306 overcomes myeloma cell resistance to lenalidomide or bortezomib in vitro. BTX306 is active against primary myeloma cells, and shows efficacy in vivo.
MeSH term(s)	Animals ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Biomarkers, Tumor ; Bortezomib/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Disease Models, Animal ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/genetics ; Humans ; Lenalidomide/pharmacology ; Mice ; Multiple Myeloma ; Proteostasis/drug effects ; Ubiquitin-Protein Ligases/antagonists & inhibitors
Chemical Substances	Antineoplastic Agents ; Biomarkers, Tumor ; Bortezomib (69G8BD63PP) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Lenalidomide (F0P408N6V4)
Language	English
Publishing date	2020-07-06
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1223802-8
ISSN	1432-1440 ; 0946-2716
ISSN (online)	1432-1440
ISSN	0946-2716
DOI	10.1007/s00109-020-01943-6
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Article ; Online: Dynamic balance of multiple myeloma clonogenic side population cell percentages controlled by environmental conditions.

Wen, Jianguo / Tao, Wenjing / Kuiatse, Isere / Lin, Pei / Feng, Yongdong / Jones, Richard J / Orlowski, Robert Z / Zu, Youli

International journal of cancer

2014 Volume 136, Issue 5, Page(s) 991–1002

Abstract: Cancer stem cells are key drivers of tumor progression and disease recurrence in multiple myeloma (MM). However, little is known about the regulation of MM stem cells. Here, we show that a population of MM cells, known as the side population (SP), ... ...

Abstract	Cancer stem cells are key drivers of tumor progression and disease recurrence in multiple myeloma (MM). However, little is known about the regulation of MM stem cells. Here, we show that a population of MM cells, known as the side population (SP), exhibits stem-like properties. Cells that constitute the SP in primary MM isolates are negative or seldom expressed for CD138 and CD20 markers. In addition, the SP population contains stem cells that belong to the same lineage as the mature neoplastic plasma cells. Importantly, our data indicate that the SP and nonside population (NSP) percentages in heterogeneous MM cells are balanced, and that this balance can be achieved through a prolonged in vitro culture. Furthermore, we show that SP cells, with confirmed molecular characteristics of MM stem cells, can be regenerated from purified NSP cell populations. We also show that the percentage of SP cells can be enhanced by the hypoxic stress, which is frequently observed within MM tumors. Finally, hypoxic stress enhanced the expression of transforming growth factor β1 (TGF-β1) and blocking the TGF-β1 signaling pathway inhibited the NSP dedifferentiation. Taken together, these findings indicate that the balance between MM SP and NSP is regulated by environmental factors and TGF-β1 pathway is involved in hypoxia-induced increase of SP population. Understanding the mechanisms that facilitate SP maintenance will accelerate the design of novel therapeutics aimed at controlling these cells in MM.
MeSH term(s)	Animals ; Cell Differentiation ; Environment ; Hypoxia/physiopathology ; Immunoenzyme Techniques ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Multiple Myeloma/metabolism ; Multiple Myeloma/pathology ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Phenotype ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Side-Population Cells/metabolism ; Side-Population Cells/pathology ; Signal Transduction ; Transforming Growth Factor beta1/genetics ; Transforming Growth Factor beta1/metabolism ; Tumor Cells, Cultured
Chemical Substances	RNA, Messenger ; Transforming Growth Factor beta1
Language	English
Publishing date	2014-07-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218257-9
ISSN	1097-0215 ; 0020-7136
ISSN (online)	1097-0215
ISSN	0020-7136
DOI	10.1002/ijc.29078
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Article ; Online: Targeting Myddosome Signaling in Waldenström's Macroglobulinemia with the Interleukin-1 Receptor-Associated Kinase 1/4 Inhibitor R191.

Ni, Haiwen / Shirazi, Fazal / Baladandayuthapani, Veerabhadran / Lin, Heather / Kuiatse, Isere / Wang, Hua / Jones, Richard J / Berkova, Zuzana / Hitoshi, Yasumichi / Ansell, Stephen M / Treon, Steven P / Thomas, Sheeba K / Lee, Hans C / Wang, Zhiqiang / Davis, R Eric / Orlowski, Robert Z

Clinical cancer research : an official journal of the American Association for Cancer Research

2018 Volume 24, Issue 24, Page(s) 6408–6420

Abstract: Purpose: Waldenström's macroglobulinemia is an incurable lymphoproliferative disorder driven by an L265P mutation in the myeloid differentiation primary response gene 88 (: Experimental design: Patient-derived cell lines and primary samples were used ...

Abstract	Purpose: Waldenström's macroglobulinemia is an incurable lymphoproliferative disorder driven by an L265P mutation in the myeloid differentiation primary response gene 88 ( Experimental design: Patient-derived cell lines and primary samples were used in both Results: R191 induced a dose- and time-dependent reduction in viability of BCWM.1 and MWCL-1 Waldenström's cell lines, and suppressed activation of IRAK1/4. This was associated with cell-cycle arrest at G Conclusions: Taken together, these data support the translation of R191 as an approach to target IRAK1/4 to the clinic for patients with Waldenström's macroglobulinemia.
MeSH term(s)	Animals ; Apoptosis/genetics ; Cell Cycle Checkpoints/genetics ; Cell Line ; Cell Survival ; Disease Models, Animal ; Drug Synergism ; Endoplasmic Reticulum/metabolism ; Gene Expression Profiling ; Gene Expression Regulation ; Humans ; Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors ; Interleukin-1 Receptor-Associated Kinases/metabolism ; Mice, Transgenic ; Myeloid Differentiation Factor 88/genetics ; Myeloid Differentiation Factor 88/metabolism ; NF-kappa B/metabolism ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/metabolism ; Waldenstrom Macroglobulinemia/drug therapy ; Waldenstrom Macroglobulinemia/etiology ; Waldenstrom Macroglobulinemia/metabolism
Chemical Substances	Myeloid Differentiation Factor 88 ; NF-kappa B ; Protein Kinase Inhibitors ; IRAK1 protein, human (EC 2.7.11.1) ; IRAK4 protein, human (EC 2.7.11.1) ; Interleukin-1 Receptor-Associated Kinases (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2018-08-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-17-3265
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Inter-library loan at ZB MED

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Inter-library loan at ZB MED

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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Full text online

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In stock of ZB MED Cologne/Königswinter

Order via subito

More links

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In stock of ZB MED Cologne/Königswinter

Order via subito