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John M Timmerman - One of the best experts on this subject based on the ideXlab platform.
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an hk2 antisense oligonucleotide induces synthetic lethality in hk1 hk2 Multiple Myeloma
Cancer Research, 2019Co-Authors: Shili Xu, Arthur Catapang, Nicholas A Bayley, Reiko E Yamada, Alex Vasuthasawat, Joshua Sasine, Tianyuan Zhou, Daniel Braas, Ryan K. Trinh, John M TimmermanAbstract:Although the majority of adult tissues express only hexokinase 1 (HK1) for glycolysis, most cancers express hexokinase 2 (HK2) and many coexpress HK1 and HK2. In contrast to HK1+HK2+ cancers, HK1−HK2+ cancer subsets are sensitive to cytostasis induced by HK2shRNA knockdown and are also sensitive to synthetic lethality in response to the combination of HK2shRNA knockdown, an oxidative phosphorylation (OXPHOS) inhibitor diphenyleneiodonium (DPI), and a fatty acid oxidation (FAO) inhibitor perhexiline (PER). The majority of human Multiple Myeloma cell lines are HK1−HK2+. Here we describe an antisense oligonucleotide (ASO) directed against human HK2 (HK2-ASO1), which suppressed HK2 expression in human Multiple Myeloma cell cultures and human Multiple Myeloma mouse xenograft models. The HK2-ASO1/DPI/PER triple-combination achieved synthetic lethality in Multiple Myeloma cells in culture and prevented HK1−HK2+ Multiple Myeloma tumor xenograft progression. DPI was replaceable by the FDA-approved OXPHOS inhibitor metformin (MET), both for synthetic lethality in culture and for inhibition of tumor xenograft progression. In addition, we used an ASO targeting murine HK2 (mHK2-ASO1) to validate the safety of mHK2-ASO1/MET/PER combination therapy in mice bearing murine Multiple Myeloma tumors. HK2-ASO1 is the first agent that shows selective HK2 inhibition and therapeutic efficacy in cell culture and in animal models, supporting clinical development of this synthetically lethal combination as a therapy for HK1−HK2+ Multiple Myeloma. Significance: A first-in-class HK2 antisense oligonucleotide suppresses HK2 expression in cell culture and in in vivo, presenting an effective, tolerated combination therapy for preventing progression of HK1−HK2+ Multiple Myeloma tumors. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/10/2748/F1.large.jpg.
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an hk2 antisense oligonucleotide induces synthetic lethality in hk1 hk2 Multiple Myeloma
Cancer Research, 2019Co-Authors: Shili Xu, Arthur Catapang, Nicholas A Bayley, Reiko E Yamada, Alex Vasuthasawat, Joshua Sasine, Tianyuan Zhou, Daniel Braas, Ryan K. Trinh, John M TimmermanAbstract:Although the majority of adult tissues express only hexokinase 1 (HK1) for glycolysis, most cancers express hexokinase 2 (HK2) and many coexpress HK1 and HK2. In contrast to HK1+HK2+ cancers, HK1−HK2+ cancer subsets are sensitive to cytostasis induced by HK2shRNA knockdown and are also sensitive to synthetic lethality in response to the combination of HK2shRNA knockdown, an oxidative phosphorylation (OXPHOS) inhibitor diphenyleneiodonium (DPI), and a fatty acid oxidation (FAO) inhibitor perhexiline (PER). The majority of human Multiple Myeloma cell lines are HK1−HK2+. Here we describe an antisense oligonucleotide (ASO) directed against human HK2 (HK2-ASO1), which suppressed HK2 expression in human Multiple Myeloma cell cultures and human Multiple Myeloma mouse xenograft models. The HK2-ASO1/DPI/PER triple-combination achieved synthetic lethality in Multiple Myeloma cells in culture and prevented HK1−HK2+ Multiple Myeloma tumor xenograft progression. DPI was replaceable by the FDA-approved OXPHOS inhibitor metformin (MET), both for synthetic lethality in culture and for inhibition of tumor xenograft progression. In addition, we used an ASO targeting murine HK2 (mHK2-ASO1) to validate the safety of mHK2-ASO1/MET/PER combination therapy in mice bearing murine Multiple Myeloma tumors. HK2-ASO1 is the first agent that shows selective HK2 inhibition and therapeutic efficacy in cell culture and in animal models, supporting clinical development of this synthetically lethal combination as a therapy for HK1−HK2+ Multiple Myeloma. Significance: A first-in-class HK2 antisense oligonucleotide suppresses HK2 expression in cell culture and in in vivo, presenting an effective, tolerated combination therapy for preventing progression of HK1−HK2+ Multiple Myeloma tumors. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/10/2748/F1.large.jpg.
Paul G. Richardson - One of the best experts on this subject based on the ideXlab platform.
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ixazomib for the treatment of Multiple Myeloma
Expert Opinion on Pharmacotherapy, 2018Co-Authors: Paul G. Richardson, Noopur Raje, Jacob P Laubach, Shaji Kumar, Sonja Zweegman, Elizabeth Odonnell, Peter M Voorhees, Renda H Ferrari, Tomas Skacel, Sagar LonialAbstract:Introduction: Proteasome inhibitors (PIs) are among the backbones of Multiple Myeloma (MM) treatment; however, their long-term use can be limited by parenteral administration and treatment-related ...
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Multiple Myeloma masquerading as ovarian carcinosarcoma metastases a case report and review of the approach to Multiple Myeloma screening and diagnosis
Case reports in hematology, 2018Co-Authors: Robert Stuver, Thomas Guerrerogarcia, Alec Petersen, Ursula A Matulonis, Paul G. Richardson, Prabhsimranjot SinghAbstract:Multiple Myeloma is the most common plasma cell dyscrasia and causes 2% of all cancer deaths in Western countries. Ovarian carcinosarcomas are very rare gynecological malignancies and account for only 1–2% of all ovarian tumors. In this case, we report a 67-year-old woman with known relapsed ovarian carcinosarcoma who presented with headache and neck pain. She was found to have new lytic lesions in the cranial and thoracic regions. While these lesions were assumed to be metastases, a diligent approach detected an M-spike on serum protein electrophoresis and a monoclonal gammopathy with immunoglobulin G lambda monoclonal immunoglobulin on immunofixation. A bone marrow biopsy confirmed the diagnosis of Multiple Myeloma. To our knowledge, this is the first ever reported case of concomitant Multiple Myeloma and ovarian carcinosarcoma. Our case highlights the utmost importance of a systematic approach to lytic lesions and emphasizes the need to consider secondary malignancies in the evaluation of possible metastases. We used the International Myeloma Working Group guidelines for screening and diagnosing Multiple Myeloma, and we provide a thorough review of this updated approach.
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cd38 targeted immunochemotherapy in refractory Multiple Myeloma a new horizon
Clinical Cancer Research, 2015Co-Authors: Jacob P Laubach, Paul G. RichardsonAbstract:CD38 is a type II transmembrane glycoprotein that is highly expressed in Multiple Myeloma and is a promising target for immunotherapy. Daratumumab is a human monoclonal antibody that has potent anti-Multiple Myeloma activity both as monotherapy and in combination with other Multiple Myeloma treatments, and has breakthrough designation on this basis.
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in vitro and in vivo antitumor activity of a novel alkylating agent melphalan flufenamide against Multiple Myeloma cells
Clinical Cancer Research, 2013Co-Authors: Dharminder Chauhan, Paul G. Richardson, Nikhil C Munshi, Arghya Ray, Kristina Viktorsson, Jack Spira, Claudia Pabaprada, Rolf Lewensohn, Kenneth C AndersonAbstract:Purpose: The alkylating agent melphalan prolongs survival in patients with Multiple Myeloma; however, it is associated with toxicities and development of drug-resistance. Here, we evaluated the efficacy of melphalan-flufenamide (mel-flufen), a novel dipeptide prodrug of melphalan in Multiple Myeloma. Experimental Design: Multiple Myeloma cell lines, primary patient cells, and the human Multiple Myeloma xenograft animal model were used to study the antitumor activity of mel-flufen. Results: Low doses of mel-flufen trigger more rapid and higher intracellular concentrations of melphalan in Multiple Myeloma cells than are achievable by free melphalan. Cytotoxicity analysis showed significantly lower IC 50 of mel-flufen than melphalan in Multiple Myeloma cells. Importantly, mel-flufen induces apoptosis even in melphalan- and bortezomib-resistant Multiple Myeloma cells. Mechanistic studies show that siRNA knockdown of aminopeptidase N, a key enzyme mediating intracellular conversion of mel-flufen to melphalan, attenuates anti–Multiple Myeloma activity of mel-flufen. Furthermore, mel-flufen–induced apoptosis was associated with: (i) activation of caspases and PARP cleavage; (ii) reactive oxygen species generation; (iii) mitochondrial dysfunction and release of cytochrome c; and (iv) induction of DNA damage. Moreover, mel-flufen inhibits Multiple Myeloma cell migration and tumor-associated angiogenesis. Human Multiple Myeloma xenograft studies showed a more potent inhibition of tumor growth in mice treated with mel-flufen than mice receiving equimolar doses of melphalan. Finally, combining mel-flufen with lenalidomide, bortezomib, or dexamethasone triggers synergistic anti–Multiple Myeloma activity. Conclusion: Our preclinical study supports clinical evaluation of mel-flufen to enhance therapeutic potential of melphalan, overcome drug-resistance, and improve Multiple Myeloma patient outcome. Clin Cancer Res; 19(11); 3019–31. ©2013 AACR .
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understanding Multiple Myeloma pathogenesis in the bone marrow to identify new therapeutic targets
Nature Reviews Cancer, 2007Co-Authors: Teru Hideshima, Paul G. Richardson, Constantine S Mitsiades, Giovanni Tonon, Kenneth C AndersonAbstract:Multiple Myeloma is a plasma cell malignancy characterized by complex heterogeneous cytogenetic abnormalities. The bone marrow microenvironment promotes Multiple Myeloma cell growth and resistance to conventional therapies. Although Multiple Myeloma remains incurable, novel targeted agents, used alone or in combination, have shown great promise to overcome conventional drug resistance and improve patient outcome. Recent oncogenomic studies have further advanced our understanding of the molecular pathogenesis of Multiple Myeloma, providing the framework for new prognostic classification and identifying new therapeutic targets.
Shili Xu - One of the best experts on this subject based on the ideXlab platform.
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an hk2 antisense oligonucleotide induces synthetic lethality in hk1 hk2 Multiple Myeloma
Cancer Research, 2019Co-Authors: Shili Xu, Arthur Catapang, Nicholas A Bayley, Reiko E Yamada, Alex Vasuthasawat, Joshua Sasine, Tianyuan Zhou, Daniel Braas, Ryan K. Trinh, John M TimmermanAbstract:Although the majority of adult tissues express only hexokinase 1 (HK1) for glycolysis, most cancers express hexokinase 2 (HK2) and many coexpress HK1 and HK2. In contrast to HK1+HK2+ cancers, HK1−HK2+ cancer subsets are sensitive to cytostasis induced by HK2shRNA knockdown and are also sensitive to synthetic lethality in response to the combination of HK2shRNA knockdown, an oxidative phosphorylation (OXPHOS) inhibitor diphenyleneiodonium (DPI), and a fatty acid oxidation (FAO) inhibitor perhexiline (PER). The majority of human Multiple Myeloma cell lines are HK1−HK2+. Here we describe an antisense oligonucleotide (ASO) directed against human HK2 (HK2-ASO1), which suppressed HK2 expression in human Multiple Myeloma cell cultures and human Multiple Myeloma mouse xenograft models. The HK2-ASO1/DPI/PER triple-combination achieved synthetic lethality in Multiple Myeloma cells in culture and prevented HK1−HK2+ Multiple Myeloma tumor xenograft progression. DPI was replaceable by the FDA-approved OXPHOS inhibitor metformin (MET), both for synthetic lethality in culture and for inhibition of tumor xenograft progression. In addition, we used an ASO targeting murine HK2 (mHK2-ASO1) to validate the safety of mHK2-ASO1/MET/PER combination therapy in mice bearing murine Multiple Myeloma tumors. HK2-ASO1 is the first agent that shows selective HK2 inhibition and therapeutic efficacy in cell culture and in animal models, supporting clinical development of this synthetically lethal combination as a therapy for HK1−HK2+ Multiple Myeloma. Significance: A first-in-class HK2 antisense oligonucleotide suppresses HK2 expression in cell culture and in in vivo, presenting an effective, tolerated combination therapy for preventing progression of HK1−HK2+ Multiple Myeloma tumors. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/10/2748/F1.large.jpg.
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an hk2 antisense oligonucleotide induces synthetic lethality in hk1 hk2 Multiple Myeloma
Cancer Research, 2019Co-Authors: Shili Xu, Arthur Catapang, Nicholas A Bayley, Reiko E Yamada, Alex Vasuthasawat, Joshua Sasine, Tianyuan Zhou, Daniel Braas, Ryan K. Trinh, John M TimmermanAbstract:Although the majority of adult tissues express only hexokinase 1 (HK1) for glycolysis, most cancers express hexokinase 2 (HK2) and many coexpress HK1 and HK2. In contrast to HK1+HK2+ cancers, HK1−HK2+ cancer subsets are sensitive to cytostasis induced by HK2shRNA knockdown and are also sensitive to synthetic lethality in response to the combination of HK2shRNA knockdown, an oxidative phosphorylation (OXPHOS) inhibitor diphenyleneiodonium (DPI), and a fatty acid oxidation (FAO) inhibitor perhexiline (PER). The majority of human Multiple Myeloma cell lines are HK1−HK2+. Here we describe an antisense oligonucleotide (ASO) directed against human HK2 (HK2-ASO1), which suppressed HK2 expression in human Multiple Myeloma cell cultures and human Multiple Myeloma mouse xenograft models. The HK2-ASO1/DPI/PER triple-combination achieved synthetic lethality in Multiple Myeloma cells in culture and prevented HK1−HK2+ Multiple Myeloma tumor xenograft progression. DPI was replaceable by the FDA-approved OXPHOS inhibitor metformin (MET), both for synthetic lethality in culture and for inhibition of tumor xenograft progression. In addition, we used an ASO targeting murine HK2 (mHK2-ASO1) to validate the safety of mHK2-ASO1/MET/PER combination therapy in mice bearing murine Multiple Myeloma tumors. HK2-ASO1 is the first agent that shows selective HK2 inhibition and therapeutic efficacy in cell culture and in animal models, supporting clinical development of this synthetically lethal combination as a therapy for HK1−HK2+ Multiple Myeloma. Significance: A first-in-class HK2 antisense oligonucleotide suppresses HK2 expression in cell culture and in in vivo, presenting an effective, tolerated combination therapy for preventing progression of HK1−HK2+ Multiple Myeloma tumors. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/10/2748/F1.large.jpg.
Craig D Peacock - One of the best experts on this subject based on the ideXlab platform.
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clonogenic Multiple Myeloma progenitors stem cell properties and drug resistance
Cancer Research, 2008Co-Authors: William Matsui, Qiuju Wang, James Barber, Sarah Brennan, Douglas B Smith, Ivan Borrello, Ian Mcniece, Richard F Ambinder, Craig D Peacock, Neil D WatkinsAbstract:Many agents are active in Multiple Myeloma, but the majority of patients relapse. This clinical pattern suggests most cancer cells are eliminated, but cells with the clonogenic potential to mediate tumor regrowth are relatively chemoresistant. Our previous data suggested that CD138 + Multiple Myeloma plasma cells cannot undergo long-term proliferation but rather arise from clonogenic CD138 neg B cells. We compared the relative sensitivity of these distinct cell types to clinical antiMyeloma agents and found that dexamethasone, lenadilomide, bortezomib, and 4-hydroxycyclophosphamide inhibited CD138 + Multiple Myeloma plasma cells but had little effect on CD138 neg precursors in vitro . We further characterized clonogenic Multiple Myeloma cells and stained cell lines using the Hoechst side population and Aldefluor assays. Each assay identified CD138 neg cells suggesting that they possess high drug efflux capacity and intracellular drug detoxification activity. We also found that Multiple Myeloma cells expressing the memory B-cell markers CD20 and CD27 could give rise to clonogenic Multiple Myeloma growth in vitro and engraft immunodeficient nonobese diabetes/severe combined immunodeficient mice during both primary and secondary transplantation. Furthermore, both the side population and Aldefluor assays were capable of identifying circulating clonotypic memory B-cell populations within the peripheral blood of Multiple Myeloma patients. Our results suggest that circulating clonotypic B-cell populations represent Multiple Myeloma stem cells, and the relative drug resistance of these cells is mediated by processes that protect normal stem cells from toxic injury. [Cancer Res 2008;68(1):190–7]
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clonogenic Multiple Myeloma progenitors stem cell properties and drug resistance
Cancer Research, 2008Co-Authors: William Matsui, Qiuju Wang, James Barber, Sarah Brennan, Douglas B Smith, Ivan Borrello, Ian Mcniece, Richard F Ambinder, Lan Lin, Craig D PeacockAbstract:Many agents are active in Multiple Myeloma, but the majority of patients relapse. This clinical pattern suggests most cancer cells are eliminated, but cells with the clonogenic potential to mediate tumor regrowth are relatively chemoresistant. Our previous data suggested that CD138(+) Multiple Myeloma plasma cells cannot undergo long-term proliferation but rather arise from clonogenic CD138(neg) B cells. We compared the relative sensitivity of these distinct cell types to clinical antiMyeloma agents and found that dexamethasone, lenadilomide, bortezomib, and 4-hydroxycyclophosphamide inhibited CD138(+) Multiple Myeloma plasma cells but had little effect on CD138(neg) precursors in vitro. We further characterized clonogenic Multiple Myeloma cells and stained cell lines using the Hoechst side population and Aldefluor assays. Each assay identified CD138(neg) cells suggesting that they possess high drug efflux capacity and intracellular drug detoxification activity. We also found that Multiple Myeloma cells expressing the memory B-cell markers CD20 and CD27 could give rise to clonogenic Multiple Myeloma growth in vitro and engraft immunodeficient nonobese diabetes/severe combined immunodeficient mice during both primary and secondary transplantation. Furthermore, both the side population and Aldefluor assays were capable of identifying circulating clonotypic memory B-cell populations within the peripheral blood of Multiple Myeloma patients. Our results suggest that circulating clonotypic B-cell populations represent Multiple Myeloma stem cells, and the relative drug resistance of these cells is mediated by processes that protect normal stem cells from toxic injury.
Daniel Braas - One of the best experts on this subject based on the ideXlab platform.
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an hk2 antisense oligonucleotide induces synthetic lethality in hk1 hk2 Multiple Myeloma
Cancer Research, 2019Co-Authors: Shili Xu, Arthur Catapang, Nicholas A Bayley, Reiko E Yamada, Alex Vasuthasawat, Joshua Sasine, Tianyuan Zhou, Daniel Braas, Ryan K. Trinh, John M TimmermanAbstract:Although the majority of adult tissues express only hexokinase 1 (HK1) for glycolysis, most cancers express hexokinase 2 (HK2) and many coexpress HK1 and HK2. In contrast to HK1+HK2+ cancers, HK1−HK2+ cancer subsets are sensitive to cytostasis induced by HK2shRNA knockdown and are also sensitive to synthetic lethality in response to the combination of HK2shRNA knockdown, an oxidative phosphorylation (OXPHOS) inhibitor diphenyleneiodonium (DPI), and a fatty acid oxidation (FAO) inhibitor perhexiline (PER). The majority of human Multiple Myeloma cell lines are HK1−HK2+. Here we describe an antisense oligonucleotide (ASO) directed against human HK2 (HK2-ASO1), which suppressed HK2 expression in human Multiple Myeloma cell cultures and human Multiple Myeloma mouse xenograft models. The HK2-ASO1/DPI/PER triple-combination achieved synthetic lethality in Multiple Myeloma cells in culture and prevented HK1−HK2+ Multiple Myeloma tumor xenograft progression. DPI was replaceable by the FDA-approved OXPHOS inhibitor metformin (MET), both for synthetic lethality in culture and for inhibition of tumor xenograft progression. In addition, we used an ASO targeting murine HK2 (mHK2-ASO1) to validate the safety of mHK2-ASO1/MET/PER combination therapy in mice bearing murine Multiple Myeloma tumors. HK2-ASO1 is the first agent that shows selective HK2 inhibition and therapeutic efficacy in cell culture and in animal models, supporting clinical development of this synthetically lethal combination as a therapy for HK1−HK2+ Multiple Myeloma. Significance: A first-in-class HK2 antisense oligonucleotide suppresses HK2 expression in cell culture and in in vivo, presenting an effective, tolerated combination therapy for preventing progression of HK1−HK2+ Multiple Myeloma tumors. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/10/2748/F1.large.jpg.
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an hk2 antisense oligonucleotide induces synthetic lethality in hk1 hk2 Multiple Myeloma
Cancer Research, 2019Co-Authors: Shili Xu, Arthur Catapang, Nicholas A Bayley, Reiko E Yamada, Alex Vasuthasawat, Joshua Sasine, Tianyuan Zhou, Daniel Braas, Ryan K. Trinh, John M TimmermanAbstract:Although the majority of adult tissues express only hexokinase 1 (HK1) for glycolysis, most cancers express hexokinase 2 (HK2) and many coexpress HK1 and HK2. In contrast to HK1+HK2+ cancers, HK1−HK2+ cancer subsets are sensitive to cytostasis induced by HK2shRNA knockdown and are also sensitive to synthetic lethality in response to the combination of HK2shRNA knockdown, an oxidative phosphorylation (OXPHOS) inhibitor diphenyleneiodonium (DPI), and a fatty acid oxidation (FAO) inhibitor perhexiline (PER). The majority of human Multiple Myeloma cell lines are HK1−HK2+. Here we describe an antisense oligonucleotide (ASO) directed against human HK2 (HK2-ASO1), which suppressed HK2 expression in human Multiple Myeloma cell cultures and human Multiple Myeloma mouse xenograft models. The HK2-ASO1/DPI/PER triple-combination achieved synthetic lethality in Multiple Myeloma cells in culture and prevented HK1−HK2+ Multiple Myeloma tumor xenograft progression. DPI was replaceable by the FDA-approved OXPHOS inhibitor metformin (MET), both for synthetic lethality in culture and for inhibition of tumor xenograft progression. In addition, we used an ASO targeting murine HK2 (mHK2-ASO1) to validate the safety of mHK2-ASO1/MET/PER combination therapy in mice bearing murine Multiple Myeloma tumors. HK2-ASO1 is the first agent that shows selective HK2 inhibition and therapeutic efficacy in cell culture and in animal models, supporting clinical development of this synthetically lethal combination as a therapy for HK1−HK2+ Multiple Myeloma. Significance: A first-in-class HK2 antisense oligonucleotide suppresses HK2 expression in cell culture and in in vivo, presenting an effective, tolerated combination therapy for preventing progression of HK1−HK2+ Multiple Myeloma tumors. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/10/2748/F1.large.jpg.