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1
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Oelschläger L, Künstner A, Frey F, Leitner T, Leypoldt L, Reimer N, Gebauer N, Bastian L, Weisel K, Sailer VW, Röcken C, Klapper W, Konukiewitz B, Murga Penas EM, Forster M, Schub N, Ahmed HMM, Kirfel J, von Bubnoff NCC, Busch H, Khandanpour C. Whole-Exome Sequencing, Mutational Signature Analysis, and Outcome in Multiple Myeloma-A Pilot Study. Int J Mol Sci 2024; 25:13418. [PMID: 39769182 PMCID: PMC11680055 DOI: 10.3390/ijms252413418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/02/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
The complex and heterogeneous genomic landscape of multiple myeloma (MM) and many of its clinical and prognostic implications remains to be understood. In other cancers, such as breast cancer, using whole-exome sequencing (WES) and molecular signatures in clinical practice has revolutionized classification, prognostic prediction, and patient management. However, such integration is still in its early stages in MM. In this study, we analyzed WES data from 35 MM patients to identify potential mutational signatures and driver mutations correlated with clinical and cytogenetic characteristics. Our findings confirm the complex mutational spectrum and its impact on previously described ontogenetic and epigenetic pathways. They show TYW1 as a possible new potential driver gene and find no significant associations of mutational signatures with clinical findings. Further studies are needed to strengthen the role of mutational signatures in the clinical context of patients with MM to improve patient management.
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Affiliation(s)
- Lorenz Oelschläger
- Department of Hematology and Oncology, University Medical Center Schleswig-Holstein (UKSH), University Cancer Center Schleswig-Holstein (UCCSH), Campus Lübeck, 23538 Lübeck, Germany
| | - Axel Künstner
- Medical Systems Biology Group, Lübeck Institute of Experimental Dermatology, University of Lübeck, 23538 Lübeck, Germany
- University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany
| | - Friederike Frey
- Department of Hematology and Oncology, University Medical Center Schleswig-Holstein (UKSH), University Cancer Center Schleswig-Holstein (UCCSH), Campus Lübeck, 23538 Lübeck, Germany
| | - Theo Leitner
- Department of Hematology and Oncology, University Medical Center Schleswig-Holstein (UKSH), University Cancer Center Schleswig-Holstein (UCCSH), Campus Lübeck, 23538 Lübeck, Germany
| | - Lisa Leypoldt
- Department of Hematology, Oncology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, 20521 Hamburg, Germany
| | - Niklas Reimer
- Medical Systems Biology Group, Lübeck Institute of Experimental Dermatology, University of Lübeck, 23538 Lübeck, Germany
- University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany
| | - Niklas Gebauer
- Department of Hematology and Oncology, University Medical Center Schleswig-Holstein (UKSH), University Cancer Center Schleswig-Holstein (UCCSH), Campus Lübeck, 23538 Lübeck, Germany
| | - Lorenz Bastian
- University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany
- Division for Stem Cell Transplantation and Immunotherapy, University Hospital of Schleswig-Holstein, 24105 Kiel, Germany
| | - Katja Weisel
- Department of Hematology, Oncology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, 20521 Hamburg, Germany
| | - Verena-Wilbeth Sailer
- University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany
- Department of Pathology, University of Lübeck, 23538 Lübeck, Germany
| | - Christoph Röcken
- Department of Pathology, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, 24105 Kiel, Germany
| | - Wolfram Klapper
- Department of Pathology, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, 24105 Kiel, Germany
| | - Björn Konukiewitz
- Department of Pathology, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, 24105 Kiel, Germany
| | - Eva Maria Murga Penas
- Institute of Human Genetics, University Hospital Schleswig-Holstein (UKSH)/Christian-Albrechts University Kiel (CAU), 24105 Kiel, Germany
| | - Michael Forster
- Institute of Clinical Molecular Biology, Christian-Albrechts University, 24105 Kiel, Germany
| | - Natalie Schub
- Division for Stem Cell Transplantation and Immunotherapy, University Hospital of Schleswig-Holstein, 24105 Kiel, Germany
| | - Helal M. M. Ahmed
- Department of Hematology and Oncology, University Medical Center Schleswig-Holstein (UKSH), University Cancer Center Schleswig-Holstein (UCCSH), Campus Lübeck, 23538 Lübeck, Germany
| | - Jutta Kirfel
- University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany
- Department of Pathology, University of Lübeck, 23538 Lübeck, Germany
| | - Nikolas Christian Cornelius von Bubnoff
- Department of Hematology and Oncology, University Medical Center Schleswig-Holstein (UKSH), University Cancer Center Schleswig-Holstein (UCCSH), Campus Lübeck, 23538 Lübeck, Germany
| | - Hauke Busch
- Medical Systems Biology Group, Lübeck Institute of Experimental Dermatology, University of Lübeck, 23538 Lübeck, Germany
- University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany
| | - Cyrus Khandanpour
- Department of Hematology and Oncology, University Medical Center Schleswig-Holstein (UKSH), University Cancer Center Schleswig-Holstein (UCCSH), Campus Lübeck, 23538 Lübeck, Germany
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Wang Y, Zhang Y, Luo H, Wei W, Liu W, Wang W, Wu Y, Peng C, Ji Y, Zhang J, Zhu C, Bai W, Xia L, Lei H, Xu H, Yin L, Weng W, Yang L, Liu L, Zhou A, Wei Y, Zhu Q, Zhu W, Yang Y, Xu Z, Wu Y. Identification of USP2 as a novel target to induce degradation of KRAS in myeloma cells. Acta Pharm Sin B 2024; 14:5235-5248. [PMID: 39807309 PMCID: PMC11725127 DOI: 10.1016/j.apsb.2024.08.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 06/12/2024] [Accepted: 07/25/2024] [Indexed: 01/16/2025] Open
Abstract
Inducing the degradation of KRAS represents a novel strategy to combat cancers with KRAS mutation. In this study, we identify ubiquitin-specific protease 2 (USP2) as a novel deubiquitinating enzyme of KRAS in multiple myeloma (MM). Specifically, we demonstrate that gambogic acid (GA) forms a covalent bond with the cysteine 284 residue of USP2 through an allosteric pocket, inhibiting its deubiquitinating activity. Inactivation or knockdown of USP2 leads to the degradation of KRAS, resulting in the suppression of MM cell proliferation in vitro and in vivo. Conversely, overexpressing USP2 stabilizes KRAS and partially abrogates GA-induced apoptosis in MM cells. Furthermore, elevated USP2 levels may be associated with poorer prognoses in MM patients. These findings highlight the potential of the USP2/KRAS axis as a therapeutic target in MM, suggesting that strategically inducing KRAS degradation via USP2 inhibition could be a promising approach for treating cancers with KRAS mutations.
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Affiliation(s)
- Yingying Wang
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Youping Zhang
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hao Luo
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- School of Basic Medical Sciences, Shandong Second Medical University, Weifang 261053, China
| | - Wei Wei
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Wanting Liu
- Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Weiwei Wang
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yunzhao Wu
- Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK
| | - Cheng Peng
- State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yanjie Ji
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jianfang Zhang
- State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Chujiao Zhu
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Wenhui Bai
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Li Xia
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hu Lei
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Hanzhang Xu
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Leimiao Yin
- Shanghai Research Institute of Acupuncture and Meridian, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wei Weng
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Li Yang
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Ligen Liu
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Aiwu Zhou
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yueyue Wei
- State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Qi Zhu
- Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Weiliang Zhu
- State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yongqing Yang
- Shanghai Research Institute of Acupuncture and Meridian, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhijian Xu
- State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yingli Wu
- Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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3
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Lu Q, Yang D, Li H, Niu T, Tong A. Multiple myeloma: signaling pathways and targeted therapy. MOLECULAR BIOMEDICINE 2024; 5:25. [PMID: 38961036 PMCID: PMC11222366 DOI: 10.1186/s43556-024-00188-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 05/21/2024] [Indexed: 07/05/2024] Open
Abstract
Multiple myeloma (MM) is the second most common hematological malignancy of plasma cells, characterized by osteolytic bone lesions, anemia, hypercalcemia, renal failure, and the accumulation of malignant plasma cells. The pathogenesis of MM involves the interaction between MM cells and the bone marrow microenvironment through soluble cytokines and cell adhesion molecules, which activate various signaling pathways such as PI3K/AKT/mTOR, RAS/MAPK, JAK/STAT, Wnt/β-catenin, and NF-κB pathways. Aberrant activation of these pathways contributes to the proliferation, survival, migration, and drug resistance of myeloma cells, making them attractive targets for therapeutic intervention. Currently, approved drugs targeting these signaling pathways in MM are limited, with many inhibitors and inducers still in preclinical or clinical research stages. Therapeutic options for MM include non-targeted drugs like alkylating agents, corticosteroids, immunomodulatory drugs, proteasome inhibitors, and histone deacetylase inhibitors. Additionally, targeted drugs such as monoclonal antibodies, chimeric antigen receptor T cells, bispecific T-cell engagers, and bispecific antibodies are being used in MM treatment. Despite significant advancements in MM treatment, the disease remains incurable, emphasizing the need for the development of novel or combined targeted therapies based on emerging theoretical knowledge, technologies, and platforms. In this review, we highlight the key role of signaling pathways in the malignant progression and treatment of MM, exploring advances in targeted therapy and potential treatments to offer further insights for improving MM management and outcomes.
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Affiliation(s)
- Qizhong Lu
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Donghui Yang
- College of Veterinary Medicine, Shaanxi Center of Stem Cells Engineering and Technology, Northwest A&F University, Yangling, 712100, China
| | - Hexian Li
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ting Niu
- Department of Hematology, State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Aiping Tong
- State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610212, China.
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4
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Haertle L, Munawar U, Hernández HNC, Arroyo-Barea A, Heckel T, Cuenca I, Martin L, Höschle C, Müller N, Vogt C, Bischler T, Del Campo PL, Han S, Buenache N, Zhou X, Bassermann F, Waldschmidt J, Steinbrunn T, Rasche L, Stühmer T, Martinez-Lopez J, Martin Kortüm K, Barrio S. Clonal competition assays identify fitness signatures in cancer progression and resistance in multiple myeloma. Hemasphere 2024; 8:e110. [PMID: 38993727 PMCID: PMC11237348 DOI: 10.1002/hem3.110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 04/15/2024] [Accepted: 05/09/2024] [Indexed: 07/13/2024] Open
Abstract
Multiple myeloma (MM) is a genetically heterogeneous disease and the management of relapses is one of the biggest clinical challenges. TP53 alterations are established high-risk markers and are included in the current disease staging criteria. KRAS is the most frequently mutated gene affecting around 20% of MM patients. Applying Clonal Competition Assays (CCA) by co-culturing color-labeled genetically modified cell models, we recently showed that mono- and biallelic alterations in TP53 transmit a fitness advantage to the cells. Here, we report a similar dynamic for two mutations in KRAS (G12A and A146T), providing a biological rationale for the high frequency of KRAS and TP53 alterations at MM relapse. Resistance mutations, on the other hand, did not endow MM cells with a general fitness advantage but rather presented a disadvantage compared to the wild-type. CUL4B KO and IKZF1 A152T transmit resistance against immunomodulatory agents, PSMB5 A20T to proteasome inhibition. However, MM cells harboring such lesions only outcompete the culture in the presence of the respective drug. To better prevent the selection of clones with the potential of inducing relapse, these results argue in favor of treatment-free breaks or a switch of the drug class given as maintenance therapy. In summary, the fitness benefit of TP53 and KRAS mutations was not treatment-related, unlike patient-derived drug resistance alterations that may only induce an advantage under treatment. CCAs are suitable models for the study of clonal evolution and competitive (dis)advantages conveyed by a specific genetic lesion of interest, and their dependence on external factors such as the treatment.
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Affiliation(s)
- Larissa Haertle
- Department of Internal Medicine II University Hospital Würzburg Würzburg Germany
- Department of Hematology Hospital Universitario 12 de Octubre, Spanish National Cancer Research Center (CNIO), Complutense University Madrid Madrid Spain
- Department of Medicine III, Klinikum rechts der Isar Technical University of Munich Munich Germany
| | - Umair Munawar
- Department of Internal Medicine II University Hospital Würzburg Würzburg Germany
| | - Hipólito N C Hernández
- Department of Hematology Hospital Universitario 12 de Octubre, Spanish National Cancer Research Center (CNIO), Complutense University Madrid Madrid Spain
| | - Andres Arroyo-Barea
- Department of Hematology Hospital Universitario 12 de Octubre, Spanish National Cancer Research Center (CNIO), Complutense University Madrid Madrid Spain
- Department of Biochemistry and Molecular Biology, Pharmacy School Complutense University Madrid Madrid Spain
| | - Tobias Heckel
- Core Unit Systems Medicine University of Würzburg Würzburg Germany
| | - Isabel Cuenca
- Department of Hematology Hospital Universitario 12 de Octubre, Spanish National Cancer Research Center (CNIO), Complutense University Madrid Madrid Spain
| | - Lucia Martin
- Department of Hematology Hospital Universitario 12 de Octubre, Spanish National Cancer Research Center (CNIO), Complutense University Madrid Madrid Spain
| | - Carlotta Höschle
- TranslaTUM, Center for Translational Cancer Research Technical University of Munich Munich Germany
| | - Nicole Müller
- Department of Internal Medicine II University Hospital Würzburg Würzburg Germany
| | - Cornelia Vogt
- Department of Internal Medicine II University Hospital Würzburg Würzburg Germany
| | | | - Paula L Del Campo
- Department of Hematology Hospital Universitario 12 de Octubre, Spanish National Cancer Research Center (CNIO), Complutense University Madrid Madrid Spain
| | - Seungbin Han
- Department of Internal Medicine II University Hospital Würzburg Würzburg Germany
| | - Natalia Buenache
- Department of Hematology Hospital Universitario 12 de Octubre, Spanish National Cancer Research Center (CNIO), Complutense University Madrid Madrid Spain
| | - Xiang Zhou
- Department of Internal Medicine II University Hospital Würzburg Würzburg Germany
| | - Florian Bassermann
- Department of Medicine III, Klinikum rechts der Isar Technical University of Munich Munich Germany
- TranslaTUM, Center for Translational Cancer Research Technical University of Munich Munich Germany
| | - Johannes Waldschmidt
- Department of Internal Medicine II University Hospital Würzburg Würzburg Germany
| | - Torsten Steinbrunn
- Department of Internal Medicine II University Hospital Würzburg Würzburg Germany
- Department of Medical Oncology Dana-Farber Cancer Institute, Harvard Medical School Boston Massachusetts USA
| | - Leo Rasche
- Department of Internal Medicine II University Hospital Würzburg Würzburg Germany
| | - Thorsten Stühmer
- Comprehensive Cancer Center Mainfranken University Hospital Würzburg Würzburg Germany
| | - Joaquin Martinez-Lopez
- Department of Hematology Hospital Universitario 12 de Octubre, Spanish National Cancer Research Center (CNIO), Complutense University Madrid Madrid Spain
| | - K Martin Kortüm
- Department of Internal Medicine II University Hospital Würzburg Würzburg Germany
| | - Santiago Barrio
- Department of Hematology Hospital Universitario 12 de Octubre, Spanish National Cancer Research Center (CNIO), Complutense University Madrid Madrid Spain
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Li Y, Mondaza-Hernandez JL, Moura DS, Revenko AS, Tolentino A, Nguyen JT, Tran N, Meyer CA, Merino-Garcia J, Ramos R, Di Lernia D, Martin-Broto J, Hayenga HN, Bleris L. STAT6-targeting antisense oligonucleotides against solitary fibrous tumor. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102154. [PMID: 38511173 PMCID: PMC10950871 DOI: 10.1016/j.omtn.2024.102154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 02/13/2024] [Indexed: 03/22/2024]
Abstract
Solitary fibrous tumor (SFT) is a rare, non-hereditary soft tissue sarcoma thought to originate from fibroblastic mesenchymal stem cells. The etiology of SFT is thought to be due to an environmental intrachromosomal gene fusion between NGFI-A-binding protein 2 (NAB2) and signal transducer and activator protein 6 (STAT6) genes on chromosome 12, wherein the activation domain of STAT6 is fused with the DNA-binding domain of NAB2 resulting in the oncogenesis of SFT. All NAB2-STAT6 fusion variations discovered in SFTs contain the C-terminal of STAT6 transcript, and thus can serve as target site for antisense oligonucleotides (ASOs)-based therapies. Indeed, our in vitro studies show the STAT6 3' untranslated region (UTR)-targeting ASO (ASO 993523) was able to reduce expression of NAB2-STAT6 fusion transcripts in multiple SFT cell models with high efficiency (half-maximal inhibitory concentration: 116-300 nM). Encouragingly, in vivo treatment of SFT patient-derived xenograft mouse models with ASO 993523 resulted in acceptable tolerability profiles, reduced expression of NAB2-STAT6 fusion transcripts in xenograft tissues (21.9%), and, importantly, reduced tumor growth (32.4% decrease in tumor volume compared with the untreated control). Taken together, our study established ASO 993523 as a potential agent for the treatment of SFTs.
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Affiliation(s)
- Yi Li
- Department of Bioengineering, University of Texas at Dallas, Richardson, TX 75080, USA
- Center for Systems Biology, University of Texas at Dallas, Richardson, TX 75080, USA
| | - Jose L. Mondaza-Hernandez
- Health Research Institute Fundacion Jimenez Diaz, Universidad Autonoma de Madrid (IIS/FJD-UAM), 28049 Madrid, Spain
- University Hospital General de Villalba, 28400 Madrid, Spain
| | - David S. Moura
- Health Research Institute Fundacion Jimenez Diaz, Universidad Autonoma de Madrid (IIS/FJD-UAM), 28049 Madrid, Spain
| | - Alexey S. Revenko
- Department of Antisense Drug Discovery, Ionis Pharmaceuticals, Inc, Carlsbad, CA 92010, USA
| | - Angelica Tolentino
- Department of Antisense Drug Discovery, Ionis Pharmaceuticals, Inc, Carlsbad, CA 92010, USA
| | - John T. Nguyen
- Department of Bioengineering, University of Texas at Dallas, Richardson, TX 75080, USA
- Center for Systems Biology, University of Texas at Dallas, Richardson, TX 75080, USA
| | - Nam Tran
- Neurosurgical Oncology, Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Clark A. Meyer
- Department of Bioengineering, University of Texas at Dallas, Richardson, TX 75080, USA
| | - Jose Merino-Garcia
- Pathology Department, University Hospital Fundacion Jimenez Diaz, Universidad Autonoma, Av. Reyes Catolicos 2, 28040 Madrid, Spain
| | - Rafael Ramos
- Pathology Department, University Hospital Son Espases, 07120 Palma de Mallorca, Spain
| | - Davide Di Lernia
- Health Research Institute Fundacion Jimenez Diaz, Universidad Autonoma de Madrid (IIS/FJD-UAM), 28049 Madrid, Spain
| | - Javier Martin-Broto
- Health Research Institute Fundacion Jimenez Diaz, Universidad Autonoma de Madrid (IIS/FJD-UAM), 28049 Madrid, Spain
- University Hospital General de Villalba, 28400 Madrid, Spain
- Medical Oncology Department, University Hospital Fundacion Jimenez Diaz, 28040 Madrid, Spain
| | - Heather N. Hayenga
- Department of Bioengineering, University of Texas at Dallas, Richardson, TX 75080, USA
| | - Leonidas Bleris
- Department of Bioengineering, University of Texas at Dallas, Richardson, TX 75080, USA
- Center for Systems Biology, University of Texas at Dallas, Richardson, TX 75080, USA
- Department of Biological Sciences, University of Texas at Dallas, Richardson, TX 75080, USA
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6
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Heestermans R, Schots R, De Becker A, Van Riet I. Liquid Biopsies as Non-Invasive Tools for Mutation Profiling in Multiple Myeloma: Application Potential, Challenges, and Opportunities. Int J Mol Sci 2024; 25:5208. [PMID: 38791247 PMCID: PMC11121516 DOI: 10.3390/ijms25105208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 05/06/2024] [Accepted: 05/07/2024] [Indexed: 05/26/2024] Open
Abstract
Over the last decades, the survival of multiple myeloma (MM) patients has considerably improved. However, despite the availability of new treatments, most patients still relapse and become therapy-resistant at some point in the disease evolution. The mutation profile has an impact on MM patients' outcome, while typically evolving over time. Because of the patchy bone marrow (BM) infiltration pattern, the analysis of a single bone marrow sample can lead to an underestimation of the known genetic heterogeneity in MM. As a result, interest is shifting towards blood-derived liquid biopsies, which allow for a more comprehensive and non-invasive genetic interrogation without the discomfort of repeated BM aspirations. In this review, we compare the application potential for mutation profiling in MM of circulating-tumor-cell-derived DNA, cell-free DNA and extracellular-vesicle-derived DNA, while also addressing the challenges associated with their use.
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Affiliation(s)
- Robbe Heestermans
- Department of Clinical Biology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium
- Department of Hematology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium
- Translational Oncology Research Center (Team Hematology and Immunology), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Rik Schots
- Department of Hematology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium
- Translational Oncology Research Center (Team Hematology and Immunology), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Ann De Becker
- Department of Hematology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium
- Translational Oncology Research Center (Team Hematology and Immunology), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Ivan Van Riet
- Department of Hematology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan 101, 1090 Brussels, Belgium
- Translational Oncology Research Center (Team Hematology and Immunology), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium
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7
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Tonon G. Myeloma and DNA damage. Blood 2024; 143:488-495. [PMID: 37992215 DOI: 10.1182/blood.2023021384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 10/27/2023] [Accepted: 10/28/2023] [Indexed: 11/24/2023] Open
Abstract
ABSTRACT DNA-damaging agents have represented the first effective treatment for the blood cancer multiple myeloma, and after 65 years since their introduction to the clinic, they remain one of the mainstay therapies for this disease. Myeloma is a cancer of plasma cells. Despite exceedingly slow proliferation, myeloma cells present extended genomic rearrangements and intense genomic instability, starting at the premalignant stage of the disease. Where does such DNA damage stem from? A reliable model argues that the powerful oncogenes activated in myeloma as well the phenotypic peculiarities of cancer plasma cells, including the dependency on the proteasome for survival and the constant presence of oxidative stress, all converge on modulating DNA damage and repair. Beleaguered by these contraposing forces, myeloma cells survive in a precarious balance, in which the robust engagement of DNA repair mechanisms to guarantee cell survival is continuously challenged by rampant genomic instability, essential for cancer cells to withstand hostile selective pressures. Shattering this delicate equilibrium has been the goal of the extensive use of DNA-damaging agents since their introduction in the clinic, now enriched by novel approaches that leverage upon synthetic lethality paradigms. Exploiting the impairment of homologous recombination caused by myeloma genetic lesions or treatments, it is now possible to design therapeutic combinations that could target myeloma cells more effectively. Furthermore, DNA-damaging agents, as demonstrated in solid tumors, may sensitize cells to immune therapies. In all, targeting DNA damage and repair remains as central as ever in myeloma, even for the foreseeable future.
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Affiliation(s)
- Giovanni Tonon
- Università Vita-Salute San Raffaele, Milan, Italy
- Division of Experimental Oncology and Center for Omics Sciences, Functional Genomics of Cancer Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
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8
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Chhichholiya Y, Singh HV, Vashistha R, Singh S, Munshi A. Deciphering the role of KRAS gene in oncogenesis: Focus on signaling pathways, genetic alterations in 3'UTR, KRAS specific miRNAs and therapeutic interventions. Crit Rev Oncol Hematol 2024; 194:104250. [PMID: 38143047 DOI: 10.1016/j.critrevonc.2023.104250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 12/05/2023] [Accepted: 12/20/2023] [Indexed: 12/26/2023] Open
Abstract
Cancer is a significant cause of death after cardiovascular disease. The genomic, epigenetic and environmental factors have been found to be the risk factor for the disease. The most important genes that develop cancer are oncogenes and tumor suppressor genes. Among oncogenes, KRAS has emerged as a significant player in the development of many cancers. Dysregulation of the RAS signaling pathway either on account of mutation in significant genes involved in the pathway or aberrant expression of different miRNAs targeting these genes including KRAS. The focus is also on the alterations in 3'UTR of the KRAS gene sequence as well as the changes in the miRNA encoding genes especially the one targeting the KRAS gene. Efforts are also being put in to target the dysregulated KRAS gene as a therapeutic approach to treat different cancers. However, there are some challenges like resistance to KRAS inhibitors that need to be addressed.
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Affiliation(s)
- Yogita Chhichholiya
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, Punjab, India
| | - Harsh Vikram Singh
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, Punjab, India
| | | | - Sandeep Singh
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, Punjab, India
| | - Anjana Munshi
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, Punjab, India.
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9
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Dragomir M, Călugăru OT, Popescu B, Jardan C, Jardan D, Popescu M, Aposteanu S, Bădeliță S, Nedelcu G, Șerban C, Popa C, Vassu-Dimov T, Coriu D. DNA Sequencing of CD138 Cell Population Reveals TP53 and RAS-MAPK Mutations in Multiple Myeloma at Diagnosis. Cancers (Basel) 2024; 16:358. [PMID: 38254847 PMCID: PMC10813921 DOI: 10.3390/cancers16020358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/11/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
Multiple myeloma is a hematologic neoplasm caused by abnormal proliferation of plasma cells. Sequencing studies suggest that plasma cell disorders are caused by both cytogenetic abnormalities and oncogene mutations. Therefore, it is necessary to detect molecular abnormalities to improve the diagnosis and management of MM. The main purpose of this study is to determine whether NGS, in addition to cytogenetics, can influence risk stratification and management. Additionally, we aim to establish whether mutational analysis of the CD138 cell population is a suitable option for the characterization of MM compared to the bulk population. Following the separation of the plasma cells harvested from 35 patients newly diagnosed with MM, we performed a FISH analysis to detect the most common chromosomal abnormalities. Consecutively, we used NGS to evaluate NRAS, KRAS, BRAF, and TP53 mutations in plasma cell populations and in bone marrow samples. NGS data showed that sequencing CD138 cells provides a more sensitive approach. We identified several variants in BRAF, KRAS, and TP53 that were not previously associated with MM. Considering that the presence of somatic mutations could influence risk stratification and therapeutic approaches of patients with MM, sensitive detection of these mutations at diagnosis is essential for optimal management of MM.
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Affiliation(s)
- Mihaela Dragomir
- Faculty of Biology, University of Bucharest, 030018 Bucharest, Romania; (M.D.); (T.V.-D.)
- Fundeni Clinical Institute, 022328 Bucharest, Romania; (C.J.); (M.P.); (S.A.); (S.B.); (G.N.); (C.Ș.); (C.P.); (D.C.)
| | - Onda-Tabita Călugăru
- Fundeni Clinical Institute, 022328 Bucharest, Romania; (C.J.); (M.P.); (S.A.); (S.B.); (G.N.); (C.Ș.); (C.P.); (D.C.)
| | - Bogdan Popescu
- Hematology Department, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Cerasela Jardan
- Fundeni Clinical Institute, 022328 Bucharest, Romania; (C.J.); (M.P.); (S.A.); (S.B.); (G.N.); (C.Ș.); (C.P.); (D.C.)
- Hematology Department, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Dumitru Jardan
- Molecular Biology Laboratory, Medlife Bucharest, 010093 Bucharest, Romania;
| | - Monica Popescu
- Fundeni Clinical Institute, 022328 Bucharest, Romania; (C.J.); (M.P.); (S.A.); (S.B.); (G.N.); (C.Ș.); (C.P.); (D.C.)
| | - Silvia Aposteanu
- Fundeni Clinical Institute, 022328 Bucharest, Romania; (C.J.); (M.P.); (S.A.); (S.B.); (G.N.); (C.Ș.); (C.P.); (D.C.)
| | - Sorina Bădeliță
- Fundeni Clinical Institute, 022328 Bucharest, Romania; (C.J.); (M.P.); (S.A.); (S.B.); (G.N.); (C.Ș.); (C.P.); (D.C.)
| | - Gabriela Nedelcu
- Fundeni Clinical Institute, 022328 Bucharest, Romania; (C.J.); (M.P.); (S.A.); (S.B.); (G.N.); (C.Ș.); (C.P.); (D.C.)
| | - Cătălin Șerban
- Fundeni Clinical Institute, 022328 Bucharest, Romania; (C.J.); (M.P.); (S.A.); (S.B.); (G.N.); (C.Ș.); (C.P.); (D.C.)
| | - Codruța Popa
- Fundeni Clinical Institute, 022328 Bucharest, Romania; (C.J.); (M.P.); (S.A.); (S.B.); (G.N.); (C.Ș.); (C.P.); (D.C.)
- Hematology Department, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Tatiana Vassu-Dimov
- Faculty of Biology, University of Bucharest, 030018 Bucharest, Romania; (M.D.); (T.V.-D.)
| | - Daniel Coriu
- Fundeni Clinical Institute, 022328 Bucharest, Romania; (C.J.); (M.P.); (S.A.); (S.B.); (G.N.); (C.Ș.); (C.P.); (D.C.)
- Hematology Department, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
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10
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Rosa-Rosa JM, Cuenca I, Medina A, Vázquez I, Sánchez-delaCruz A, Buenache N, Sánchez R, Jiménez C, Rosiñol L, Gutiérrez NC, Ruiz-Heredia Y, Barrio S, Oriol A, Martin-Ramos ML, Blanchard MJ, Ayala R, Ríos-Tamayo R, Sureda A, Hernández MT, de la Rubia J, Alkorta-Aranburu G, Agirre X, Bladé J, Mateos MV, Lahuerta JJ, San-Miguel JF, Calasanz MJ, Garcia-Sanz R, Martínez-Lopez J. NGS-Based Molecular Karyotyping of Multiple Myeloma: Results from the GEM12 Clinical Trial. Cancers (Basel) 2022; 14:cancers14205169. [PMID: 36291952 PMCID: PMC9601262 DOI: 10.3390/cancers14205169] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/07/2022] [Accepted: 10/12/2022] [Indexed: 12/01/2022] Open
Abstract
Simple Summary Multiple Myeloma (MM) is considered an incurable chronic disease, which prognosis depends on the presence of different genomic alterations. To accomplish a complete molecular diagnosis in a single essay, we have designed and validated a capture-based NGS approach to reliably identify pathogenic mutations (SNVs and indels), genomic alterations (CNVs and chromosomic translocations), and IGH rearrangements. We have observed a good correlation of the results obtained using our capture panel with data obtained by both FISH and WES techniques. In this study, the molecular classification performed using our approach was significantly associated with the stratification and outcome of MM patients. Additionally, this panel has been proven to detect specific IGH rearrangements that could be used as biomarkers in patient follow-ups through minimal residual disease (MRD) assays. In conclusion, we think that MM patients could benefit from the use of this capture-based NGS approach with a more accurate, single-essay molecular diagnosis. Abstract Next-generation sequencing (NGS) has greatly improved our ability to detect the genomic aberrations occurring in multiple myeloma (MM); however, its transfer to routine clinical labs and its validation in clinical trials remains to be established. We designed a capture-based NGS targeted panel to identify, in a single assay, known genetic alterations for the prognostic stratification of MM. The NGS panel was designed for the simultaneous study of single nucleotide and copy number variations, insertions and deletions, chromosomal translocations and V(D)J rearrangements. The panel was validated using a cohort of 149 MM patients enrolled in the GEM2012MENOS65 clinical trial. The results showed great global accuracy, with positive and negative predictive values close to 90% when compared with available data from fluorescence in situ hybridization and whole-exome sequencing. While the treatments used in the clinical trial showed high efficacy, patients defined as high-risk by the panel had shorter progression-free survival (p = 0.0015). As expected, the mutational status of TP53 was significant in predicting patient outcomes (p = 0.021). The NGS panel also efficiently detected clonal IGH rearrangements in 81% of patients. In conclusion, molecular karyotyping using a targeted NGS panel can identify relevant prognostic chromosomal abnormalities and translocations for the clinical management of MM patients.
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Affiliation(s)
- Juan Manuel Rosa-Rosa
- Hematology Department, Hospital 12 de Octubre, 28041 Madrid, Spain
- H12O–CNIO Hematological Malignancies Clinical Research Unit, Spanish National Cancer Research (CNIO), 29029 Madrid, Spain
- Correspondence: (J.M.R.-R.); (J.M.-L.)
| | - Isabel Cuenca
- Hematology Department, Hospital 12 de Octubre, 28041 Madrid, Spain
- H12O–CNIO Hematological Malignancies Clinical Research Unit, Spanish National Cancer Research (CNIO), 29029 Madrid, Spain
| | - Alejandro Medina
- Unidad de Biología Molecular-HLA, Laboratorio de Hematología, Hospital Universitario de Salamanca, 37007 Salamanca, Spain
| | - Iria Vázquez
- Center for Applied Medical Research (CIMA) LAB Diagnostics, Universidad de Navarra, 31008 Pamplona, Spain
| | - Andrea Sánchez-delaCruz
- H12O–CNIO Hematological Malignancies Clinical Research Unit, Spanish National Cancer Research (CNIO), 29029 Madrid, Spain
| | - Natalia Buenache
- Hematology Department, Hospital 12 de Octubre, 28041 Madrid, Spain
- H12O–CNIO Hematological Malignancies Clinical Research Unit, Spanish National Cancer Research (CNIO), 29029 Madrid, Spain
| | - Ricardo Sánchez
- Hematology Department, Hospital 12 de Octubre, 28041 Madrid, Spain
- H12O–CNIO Hematological Malignancies Clinical Research Unit, Spanish National Cancer Research (CNIO), 29029 Madrid, Spain
| | - Cristina Jiménez
- Unidad de Biología Molecular-HLA, Laboratorio de Hematología, Hospital Universitario de Salamanca, 37007 Salamanca, Spain
- Cancer Research Institute of Salamanca-IBMCC (USAL-CSIC), 37007 Salamanca, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Laura Rosiñol
- Hospital Clinic de Barcelona, 08036 Barcelona, Spain
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain
| | - Norma C. Gutiérrez
- Unidad de Biología Molecular-HLA, Laboratorio de Hematología, Hospital Universitario de Salamanca, 37007 Salamanca, Spain
- Cancer Research Institute of Salamanca-IBMCC (USAL-CSIC), 37007 Salamanca, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Yanira Ruiz-Heredia
- Hematology Department, Hospital 12 de Octubre, 28041 Madrid, Spain
- H12O–CNIO Hematological Malignancies Clinical Research Unit, Spanish National Cancer Research (CNIO), 29029 Madrid, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Santiago Barrio
- Hematology Department, Hospital 12 de Octubre, 28041 Madrid, Spain
- H12O–CNIO Hematological Malignancies Clinical Research Unit, Spanish National Cancer Research (CNIO), 29029 Madrid, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Albert Oriol
- Clinical Research Support Unit, Institut Català d’Oncologia, 08036 Barcelona, Spain
| | | | | | - Rosa Ayala
- Hematology Department, Hospital 12 de Octubre, 28041 Madrid, Spain
| | | | - Anna Sureda
- Institut Catalá d’Oncologia-l’Hospitalet, Institut de Investigació Biomèdica de Bellvitge (IDIBELL), Universitat de Barcelona, 08908 Barcelona, Spain
| | | | | | - Gorka Alkorta-Aranburu
- Center for Applied Medical Research (CIMA) LAB Diagnostics, Universidad de Navarra, 31008 Pamplona, Spain
| | - Xabier Agirre
- Center for Applied Medical Research (CIMA) LAB Diagnostics, Universidad de Navarra, 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain
- Instituto de Investigaciones Sanitarias de Navarra (IdiSNA), Universidad de Navarra, 31008 Pamplona, Spain
| | - Joan Bladé
- Hospital Clinic de Barcelona, 08036 Barcelona, Spain
- August Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain
| | - María-Victoria Mateos
- Unidad de Biología Molecular-HLA, Laboratorio de Hematología, Hospital Universitario de Salamanca, 37007 Salamanca, Spain
- Cancer Research Institute of Salamanca-IBMCC (USAL-CSIC), 37007 Salamanca, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Juan-José Lahuerta
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Jesús F. San-Miguel
- Center for Applied Medical Research (CIMA) LAB Diagnostics, Universidad de Navarra, 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain
- Instituto de Investigaciones Sanitarias de Navarra (IdiSNA), Universidad de Navarra, 31008 Pamplona, Spain
| | - María-José Calasanz
- Center for Applied Medical Research (CIMA) LAB Diagnostics, Universidad de Navarra, 31008 Pamplona, Spain
| | - Ramón Garcia-Sanz
- Unidad de Biología Molecular-HLA, Laboratorio de Hematología, Hospital Universitario de Salamanca, 37007 Salamanca, Spain
- Cancer Research Institute of Salamanca-IBMCC (USAL-CSIC), 37007 Salamanca, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Joaquín Martínez-Lopez
- Hematology Department, Hospital 12 de Octubre, 28041 Madrid, Spain
- H12O–CNIO Hematological Malignancies Clinical Research Unit, Spanish National Cancer Research (CNIO), 29029 Madrid, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain
- Correspondence: (J.M.R.-R.); (J.M.-L.)
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11
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Barresi V, Musmeci C, Rinaldi A, Condorelli DF. Transcript-Targeted Therapy Based on RNA Interference and Antisense Oligonucleotides: Current Applications and Novel Molecular Targets. Int J Mol Sci 2022; 23:ijms23168875. [PMID: 36012138 PMCID: PMC9408055 DOI: 10.3390/ijms23168875] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 08/03/2022] [Accepted: 08/07/2022] [Indexed: 12/28/2022] Open
Abstract
The development of novel target therapies based on the use of RNA interference (RNAi) and antisense oligonucleotides (ASOs) is growing in an exponential way, challenging the chance for the treatment of the genetic diseases and cancer by hitting selectively targeted RNA in a sequence-dependent manner. Multiple opportunities are taking shape, able to remove defective protein by silencing RNA (e.g., Inclisiran targets mRNA of protein PCSK9, permitting a longer half-life of LDL receptors in heterozygous familial hypercholesteremia), by arresting mRNA translation (i.e., Fomivirsen that binds to UL123-RNA and blocks the translation into IE2 protein in CMV-retinitis), or by reactivating modified functional protein (e.g., Eteplirsen able to restore a functional shorter dystrophin by skipping the exon 51 in Duchenne muscular dystrophy) or a not very functional protein. In this last case, the use of ASOs permits modifying the expression of specific proteins by modulating splicing of specific pre-RNAs (e.g., Nusinersen acts on the splicing of exon 7 in SMN2 mRNA normally not expressed; it is used for spinal muscular atrophy) or by downregulation of transcript levels (e.g., Inotersen acts on the transthryretin mRNA to reduce its expression; it is prescribed for the treatment of hereditary transthyretin amyloidosis) in order to restore the biochemical/physiological condition and ameliorate quality of life. In the era of precision medicine, recently, an experimental splice-modulating antisense oligonucleotide, Milasen, was designed and used to treat an 8-year-old girl affected by a rare, fatal, progressive form of neurodegenerative disease leading to death during adolescence. In this review, we summarize the main transcriptional therapeutic drugs approved to date for the treatment of genetic diseases by principal regulatory government agencies and recent clinical trials aimed at the treatment of cancer. Their mechanism of action, chemical structure, administration, and biomedical performance are predominantly discussed.
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12
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Offidani M, Corvatta L, Morè S, Manieri MV, Olivieri A. An update on novel multiple myeloma targets. Expert Rev Hematol 2022; 15:519-537. [PMID: 35640130 DOI: 10.1080/17474086.2022.2085088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Introduction: despite therapeutic progress, leading to a significant improvement of outcome, multiple myeloma (MM) remains a difficult to treat hematologic disease due to its biological heterogeneity and clinical complexity. Areas covered: Treatment of patients refractory and resistant to all classes of agents used in newly diagnosed MM, is becoming a relevant problem for every hematologist. New generation immunotherapies, such as conjugated mAb, bispecific mAbs and CAR-T cells, targeting novel molecules as BCMA, have showed relevant results in very advanced MM. In the same setting, small molecules, such as selinexor and melflufen, also proved to be effective. We are currently waiting for the results of under evaluation personalized therapy, directed against specific gene mutations or signaling pathways, responsible for disease progression. Expert Opinion: In the near future, many therapeutic strategies will become available for MM and the challenge will be to position each approach in order to cure, maintaining a good quality of life in these patients.
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Affiliation(s)
- Massimo Offidani
- Clinica di Ematologia Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona
| | | | - Sonia Morè
- Clinica di Ematologia Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona
| | | | - Attilio Olivieri
- Clinica di Ematologia Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona
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13
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Vendramini E, Bomben R, Pozzo F, Bittolo T, Tissino E, Gattei V, Zucchetto A. KRAS and RAS-MAPK Pathway Deregulation in Mature B Cell Lymphoproliferative Disorders. Cancers (Basel) 2022; 14:666. [PMID: 35158933 PMCID: PMC8833570 DOI: 10.3390/cancers14030666] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/24/2022] [Accepted: 01/26/2022] [Indexed: 02/04/2023] Open
Abstract
KRAS mutations account for the most frequent mutations in human cancers, and are generally correlated with disease aggressiveness, poor prognosis, and poor response to therapies. KRAS is required for adult hematopoiesis and plays a key role in B cell development and mature B cell proliferation and survival, proved to be critical for B cell receptor-induced ERK pathway activation. In mature B cell neoplasms, commonly seen in adults, KRAS and RAS-MAPK pathway aberrations occur in a relevant fraction of patients, reaching high recurrence in some specific subtypes like multiple myeloma and hairy cell leukemia. As inhibitors targeting the RAS-MAPK pathway are being developed and improved, it is of outmost importance to precisely identify all subgroups of patients that could potentially benefit from their use. Herein, we review the role of KRAS and RAS-MAPK signaling in malignant hematopoiesis, focusing on mature B cell lymphoproliferative disorders. We discuss KRAS and RAS-MAPK pathway aberrations describing type, incidence, mutual exclusion with other genetic abnormalities, and association with prognosis. We review the current therapeutic strategies applied in mature B cell neoplasms to counteract RAS-MAPK signaling in pre-clinical and clinical studies, including most promising combination therapies. We finally present an overview of genetically engineered mouse models bearing KRAS and RAS-MAPK pathway aberrations in the hematopoietic compartment, which are valuable tools in the understanding of cancer biology and etiology.
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Affiliation(s)
- Elena Vendramini
- Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (R.B.); (F.P.); (T.B.); (E.T.); (V.G.); (A.Z.)
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14
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Chiarella E, Aloisio A, Scicchitano S, Todoerti K, Cosentino EG, Lico D, Neri A, Amodio N, Bond HM, Mesuraca M. ZNF521 Enhances MLL-AF9-Dependent Hematopoietic Stem Cell Transformation in Acute Myeloid Leukemias by Altering the Gene Expression Landscape. Int J Mol Sci 2021; 22:ijms221910814. [PMID: 34639154 PMCID: PMC8509509 DOI: 10.3390/ijms221910814] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/28/2021] [Accepted: 09/29/2021] [Indexed: 12/12/2022] Open
Abstract
Leukemias derived from the MLL-AF9 rearrangement rely on dysfunctional transcriptional networks. ZNF521, a transcription co-factor implicated in the control of hematopoiesis, has been proposed to sustain leukemic transformation in collaboration with other oncogenes. Here, we demonstrate that ZNF521 mRNA levels correlate with specific genetic aberrations: in particular, the highest expression is observed in AMLs bearing MLL rearrangements, while the lowest is detected in AMLs with FLT3-ITD, NPM1, or CEBPα double mutations. In cord blood-derived CD34+ cells, enforced expression of ZNF521 provides a significant proliferative advantage and enhances MLL-AF9 effects on the induction of proliferation and the expansion of leukemic progenitor cells. Transcriptome analysis of primary CD34+ cultures displayed subsets of genes up-regulated by MLL-AF9 or ZNF521 single transgene overexpression as well as in MLL-AF9/ZNF521 combinations, at either the early or late time points of an in vitro leukemogenesis model. The silencing of ZNF521 in the MLL-AF9 + THP-1 cell line coherently results in an impairment of growth and clonogenicity, recapitulating the effects observed in primary cells. Taken together, these results underscore a role for ZNF521 in sustaining the self-renewal of the immature AML compartment, most likely through the perturbation of the gene expression landscape, which ultimately favors the expansion of MLL-AF9-transformed leukemic clones.
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MESH Headings
- Apoptosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Cell Proliferation
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/metabolism
- Gene Expression Regulation, Neoplastic
- Hematopoietic Stem Cells/metabolism
- Hematopoietic Stem Cells/pathology
- Humans
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology
- Myeloid-Lymphoid Leukemia Protein/genetics
- Myeloid-Lymphoid Leukemia Protein/metabolism
- Nucleophosmin
- Oncogene Proteins, Fusion/genetics
- Oncogene Proteins, Fusion/metabolism
- Prognosis
- Survival Rate
- Tumor Cells, Cultured
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Affiliation(s)
- Emanuela Chiarella
- Department of Experimental and Clinical Medicine, University Magna Græcia, 88100 Catanzaro, Italy; (A.A.); (S.S.); (E.G.C.); (N.A.)
- Correspondence: (E.C.); (H.M.B.); (M.M.)
| | - Annamaria Aloisio
- Department of Experimental and Clinical Medicine, University Magna Græcia, 88100 Catanzaro, Italy; (A.A.); (S.S.); (E.G.C.); (N.A.)
| | - Stefania Scicchitano
- Department of Experimental and Clinical Medicine, University Magna Græcia, 88100 Catanzaro, Italy; (A.A.); (S.S.); (E.G.C.); (N.A.)
| | - Katia Todoerti
- Hematology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (K.T.); (A.N.)
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
| | - Emanuela G. Cosentino
- Department of Experimental and Clinical Medicine, University Magna Græcia, 88100 Catanzaro, Italy; (A.A.); (S.S.); (E.G.C.); (N.A.)
- Exiris S.r.l., 00128 Roma, Italy
- Department of Hematology, Cancer Research Centre Groningen, University Medical Centre Groningen, University of Groningen, 9712 CP Groningen, The Netherlands
| | - Daniela Lico
- Department of Obstetrics and Gynaecology, Pugliese-Ciaccio Hospital, University Magna Græcia, 88100 Catanzaro, Italy;
| | - Antonino Neri
- Hematology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (K.T.); (A.N.)
- Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy
| | - Nicola Amodio
- Department of Experimental and Clinical Medicine, University Magna Græcia, 88100 Catanzaro, Italy; (A.A.); (S.S.); (E.G.C.); (N.A.)
| | - Heather Mandy Bond
- Department of Experimental and Clinical Medicine, University Magna Græcia, 88100 Catanzaro, Italy; (A.A.); (S.S.); (E.G.C.); (N.A.)
- Correspondence: (E.C.); (H.M.B.); (M.M.)
| | - Maria Mesuraca
- Department of Experimental and Clinical Medicine, University Magna Græcia, 88100 Catanzaro, Italy; (A.A.); (S.S.); (E.G.C.); (N.A.)
- Correspondence: (E.C.); (H.M.B.); (M.M.)
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15
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Tang D, Kroemer G, Kang R. Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges. Mol Cancer 2021; 20:128. [PMID: 34607583 PMCID: PMC8489073 DOI: 10.1186/s12943-021-01422-7] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 09/08/2021] [Indexed: 02/08/2023] Open
Abstract
Across a broad range of human cancers, gain-of-function mutations in RAS genes (HRAS, NRAS, and KRAS) lead to constitutive activity of oncoproteins responsible for tumorigenesis and cancer progression. The targeting of RAS with drugs is challenging because RAS lacks classic and tractable drug binding sites. Over the past 30 years, this perception has led to the pursuit of indirect routes for targeting RAS expression, processing, upstream regulators, or downstream effectors. After the discovery that the KRAS-G12C variant contains a druggable pocket below the switch-II loop region, it has become possible to design irreversible covalent inhibitors for the variant with improved potency, selectivity and bioavailability. Two such inhibitors, sotorasib (AMG 510) and adagrasib (MRTX849), were recently evaluated in phase I-III trials for the treatment of non-small cell lung cancer with KRAS-G12C mutations, heralding a new era of precision oncology. In this review, we outline the mutations and functions of KRAS in human tumors and then analyze indirect and direct approaches to shut down the oncogenic KRAS network. Specifically, we discuss the mechanistic principles, clinical features, and strategies for overcoming primary or secondary resistance to KRAS-G12C blockade.
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Affiliation(s)
- Daolin Tang
- The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China. .,Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France. .,Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France. .,Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
| | - Rui Kang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
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