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Cancers
Special Issues
Novel Drug Targets and Advances in Treatment of CLL
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Novel Drug Targets and Advances in Treatment of CLL

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 31167

Special Issue Editors

Dr. Martina Seiffert

E-Mail Website
Guest Editor
Division of Molecular Genetics, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Interests: chronic lymphocytic leukemia; tumor microenvironment; immunotherapy; tumor immune escape; T cell exhaustion; myeloid-derived suppressor cells; extracellular vesicles
Dr. Sascha Dietrich

E-Mail Website
Guest Editor
University of Heidelberg, Medizinische Klinik V, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
Interests: B-cell lymphoma; systems medicine; drug testing; multi-omic profiling; bioinformatic analysis; mathematical modeling; clinical studies

Special Issue Information

Chronic lymphocytic leukemia (CLL) is a very common malignancy of the mature B lymphocytes and its incidence and burden will continue to increase in our aging society. In recent years, novel treatment options with targeted drugs like the Bruton Tyrosine Kinase (BTK) inhibitor ibrutinib or the B-cell lymphoma BCL-2 inhibitor venetoclax have improved outcomes for CLL patients considerably. However, the continuous dosing strategy of these drugs carries a high risk of developing resistance to therapy, frequently associated with a transformation to an aggressive disease that is hard to treat. The current strategy to overcome this risk and to achieve a cure for CLL patients is the development of combination treatments, including state-of-the-art and novel drugs, to target CLL from different angles. As the tumor microenvironment is a known driver of CLL, considering this additional layer in disease pathology and drug development is of high relevance. Consequently, the efficacies of drugs need to be evaluated not only in relation to malignant cells, but also the microenvironment and its crosstalk with CLL cells, and the inclusion of drugs that specifically target the microenvironment, including immunotherapeutic regimens, will be important.

This Special Issue of Cancers encompasses new research articles, case reports and timely reviews on all aspects of novel drug targets and advances in the treatment of CLL. This includes explorative and mechanistic studies to identify novel potential targets for treatment, preclinical drug testing in vitro and in animal models, as well as results of clinical trials for the treatment of CLL.

Dr. Martina Seiffert
Dr. Sascha Dietrich
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • chronic lymphocytic leukemia
  • targeted therapy
  • therapy resistance
  • combination treatment
  • microenvironment
  • immunotherapy
  • drug target

Published Papers (10 papers)

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Research

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19 pages, 3573 KiB  
Article
The Tumor Microenvironment-Dependent Transcription Factors AHR and HIF-1α Are Dispensable for Leukemogenesis in the Eµ-TCL1 Mouse Model of Chronic Lymphocytic Leukemia
by Susanne Gonder, Anne Largeot, Ernesto Gargiulo, Sandrine Pierson, Iria Fernandez Botana, Giulia Pagano, Jerome Paggetti and Etienne Moussay
Cancers 2021, 13(18), 4518; https://doi.org/10.3390/cancers13184518 - 08 Sep 2021
Cited by 5 | Viewed by 2321
Abstract
Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in the elderly and is characterized by the accumulation of mature B lymphocytes in peripheral blood and primary lymphoid organs. In order to proliferate, leukemic cells are highly dependent on complex interactions with their [...] Read more.
Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in the elderly and is characterized by the accumulation of mature B lymphocytes in peripheral blood and primary lymphoid organs. In order to proliferate, leukemic cells are highly dependent on complex interactions with their microenvironment in proliferative niches. Not only soluble factors and BCR stimulation are important for their survival and proliferation, but also the activation of transcription factors through different signaling pathways. The aryl hydrocarbon receptor (AHR) and hypoxia-inducible factor (HIF)-1α are two transcription factors crucial for cancer development, whose activities are dependent on tumor microenvironment conditions, such as the presence of metabolites from the tryptophan pathway and hypoxia, respectively. In this study, we addressed the potential role of AHR and HIF-1α in chronic lymphocytic leukemia (CLL) development in vivo. To this end, we crossed the CLL mouse model Eµ-TCL1 with the corresponding transcription factor-conditional knock-out mice to delete one or both transcription factors in CD19+ B cells only. Despite AHR and HIF-1α being activated in CLL cells, deletion of either or both of them had no impact on CLL progression or survival in vivo, suggesting that these transcription factors are not crucial for leukemogenesis in CLL. Full article
(This article belongs to the Special Issue Novel Drug Targets and Advances in Treatment of CLL)
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16 pages, 5039 KiB  
Article
Targeting HIF-1α Regulatory Pathways as a Strategy to Hamper Tumor-Microenvironment Interactions in CLL
by Candida Vitale, Valentina Griggio, Chiara Riganti, Maria Todaro, Joanna Kopecka, Rebecca Jones, Chiara Salvetti, Elia Boccellato, Francesca Perutelli, Claudia Voena, Laura Godio, Mario Boccadoro and Marta Coscia
Cancers 2021, 13(12), 2883; https://doi.org/10.3390/cancers13122883 - 09 Jun 2021
Cited by 12 | Viewed by 1913
Abstract
The hypoxia-inducible factor 1 (HIF-1) and the CXCL12/CXCR4 axis regulate the interaction of chronic lymphocytic leukemia cells and the tumor microenvironment. However, the interconnections occurring between HIF-1 and the CXCL12/CXCR4 axis are not fully elucidated. Here, we demonstrate that the CXCL12/CXCR4 axis plays [...] Read more.
The hypoxia-inducible factor 1 (HIF-1) and the CXCL12/CXCR4 axis regulate the interaction of chronic lymphocytic leukemia cells and the tumor microenvironment. However, the interconnections occurring between HIF-1 and the CXCL12/CXCR4 axis are not fully elucidated. Here, we demonstrate that the CXCL12/CXCR4 axis plays a pivotal role in the positive regulation of the α subunit of HIF-1 (HIF-1α) that occurs in CLL cells co-cultured with stromal cells (SC). Inhibitors acting at different levels on CXCR4 downstream signalling counteract the SC-induced HIF-1α upregulation in CLL cells, also hindering the SC-mediated pro-survival effect. HIF-1α inhibition also exerts off-tumor effects on the SC component, inducing the downregulation of target genes, including CXCL12. Consistently, our data show that pretreatment of leukemic cells and/or SC with idelalisib effectively abrogates the SC-mediated survival support. A combined on-tumor and off-tumor inhibition of HIF-1α was also observed in idelalisib-treated patients, who showed, along with a downregulation of HIF-1α target genes in leukemic cells, a significant decrease in CXCL12 serum concentration and changes in the bone marrow microenvironment. Our data demonstrate that the targeting of HIF-1α or its regulatory pathways acts at the tumor- and SC-level, and may be an appealing strategy to overcome the microenvironment-mediated protection of CLL cells. Full article
(This article belongs to the Special Issue Novel Drug Targets and Advances in Treatment of CLL)
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20 pages, 2835 KiB  
Article
Prognostic Value of Tie2-Expressing Monocytes in Chronic Lymphocytic Leukemia Patients
by Justyna Woś, Sylwia Chocholska, Wioleta Kowalska, Waldemar Tomczak, Agata Szymańska, Agnieszka Karczmarczyk, Agnieszka Szuster-Ciesielska, Agnieszka Wojciechowska and Agnieszka Bojarska-Junak
Cancers 2021, 13(11), 2817; https://doi.org/10.3390/cancers13112817 - 05 Jun 2021
Cited by 4 | Viewed by 2547
Abstract
Tie2-expressing monocytes (TEMs) are associated with tumor progression and metastasis. This unique subset of monocytes has been identified as a potential prognostic marker in several solid tumors. However, TEMs remain poorly characterized in hematological cancers, including chronic lymphocytic leukemia (CLL). This study analyzed, [...] Read more.
Tie2-expressing monocytes (TEMs) are associated with tumor progression and metastasis. This unique subset of monocytes has been identified as a potential prognostic marker in several solid tumors. However, TEMs remain poorly characterized in hematological cancers, including chronic lymphocytic leukemia (CLL). This study analyzed, for the first time, the clinical significance of TEM population in CLL patients. Flow cytometry analysis of TEMs (defined as CD14+CD16+Tie2+ cells) was performed at the time of diagnosis on peripheral blood mononuclear cells from 104 untreated CLL patients. Our results revealed an expansion of circulating TEM in CLL patients. These monocytes express high levels of VEGF and suppressive IL-10. A high percentage of TEM was associated closely with unfavorable prognostic markers (ZAP-70, CD38, 17p and 11q deletion, and IGHV mutational status). Moreover, increased percentages of circulating TEMs were significantly higher in patients not responding to the first-line therapy as compared to responding patients, suggesting its potential predictive value. High TEM percentage was also correlated with shorter overall survival (OS) and shorter time to treatment (TTT). Importantly, based on multivariate Cox regression analysis, TEM percentage was an independent predictor for TTT. Thus, we can suggest the adverse role of TEMs in CLL. Full article
(This article belongs to the Special Issue Novel Drug Targets and Advances in Treatment of CLL)
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12 pages, 1267 KiB  
Article
IDO1-Targeted Therapy Does Not Control Disease Development in the Eµ-TCL1 Mouse Model of Chronic Lymphocytic Leukemia
by Selcen Öztürk, Verena Kalter, Philipp M. Roessner, Murat Sunbul and Martina Seiffert
Cancers 2021, 13(8), 1899; https://doi.org/10.3390/cancers13081899 - 15 Apr 2021
Cited by 9 | Viewed by 2267
Abstract
Indoleamine-2,3-dioxygenase 1 (IDO1), a tryptophan (Trp)-catabolizing enzyme producing metabolites such as kynurenine (Kyn), is expressed by myeloid-derived suppressor cells (MDSCs) and associated with cancer immune escape. IDO1-expressing monocytic MDSCs were shown to accumulate in patients with chronic lymphocytic leukemia (CLL) and to suppress [...] Read more.
Indoleamine-2,3-dioxygenase 1 (IDO1), a tryptophan (Trp)-catabolizing enzyme producing metabolites such as kynurenine (Kyn), is expressed by myeloid-derived suppressor cells (MDSCs) and associated with cancer immune escape. IDO1-expressing monocytic MDSCs were shown to accumulate in patients with chronic lymphocytic leukemia (CLL) and to suppress T cell activity and induce suppressive regulatory T cells (Tregs) in vitro. In the Eµ-TCL1 mouse model of CLL, we observed a strong upregulation of IDO1 in monocytic and granulocytic MDSCs, and a significantly increased Kyn to Trp serum ratio. To explore the potential of IDO1 as a therapeutic target for CLL, we treated mice after adoptive transfer of Eµ-TCL1 leukemia cells with the IDO1 modulator 1-methyl-D-tryptophan (1-MT) which resulted in a minor reduction in leukemia development which disappeared over time. 1-MT treatment further led to a partial rescue of the immune cell changes that are induced with CLL development. Similarly, treatment of leukemic mice with the clinically investigated IDO1 inhibitor epacadostat reduced the frequency of Tregs and initially delayed CLL development slightly, an effect that was, however, lost at later time points. In sum, despite the observed upregulation of IDO1 in CLL, its inhibition is not sufficient to control leukemia development in the Eµ-TCL1 adoptive transfer model. Full article
(This article belongs to the Special Issue Novel Drug Targets and Advances in Treatment of CLL)
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Review

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27 pages, 2429 KiB  
Review
Proteomics and Drug Repurposing in CLL towards Precision Medicine
by Dimitra Mavridou, Konstantina Psatha and Michalis Aivaliotis
Cancers 2021, 13(14), 3391; https://doi.org/10.3390/cancers13143391 - 06 Jul 2021
Cited by 3 | Viewed by 3065
Abstract
CLL is a hematological malignancy considered as the most frequent lymphoproliferative disease in the western world. It is characterized by high molecular heterogeneity and despite the available therapeutic options, there are many patient subgroups showing the insufficient effectiveness of disease treatment. The challenge [...] Read more.
CLL is a hematological malignancy considered as the most frequent lymphoproliferative disease in the western world. It is characterized by high molecular heterogeneity and despite the available therapeutic options, there are many patient subgroups showing the insufficient effectiveness of disease treatment. The challenge is to investigate the individual molecular characteristics and heterogeneity of these patients. Proteomics analysis is a powerful approach that monitors the constant state of flux operators of genetic information and can unravel the proteome heterogeneity and rewiring into protein pathways in CLL patients. This review essences all the available proteomics studies in CLL and suggests the way these studies can be exploited to find effective therapeutic options combined with drug repurposing approaches. Drug repurposing utilizes all the existing knowledge of the safety and efficacy of FDA-approved or investigational drugs and anticipates drug alignment to crucial CLL therapeutic targets, leading to a better disease outcome. The drug repurposing studies in CLL are also discussed in this review. The next goal involves the integration of proteomics-based drug repurposing in precision medicine, as well as the application of this procedure into clinical practice to predict the most appropriate drugs combination that could ensure therapy and the long-term survival of each CLL patient. Full article
(This article belongs to the Special Issue Novel Drug Targets and Advances in Treatment of CLL)
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22 pages, 2209 KiB  
Review
Challenges with Approved Targeted Therapies against Recurrent Mutations in CLL: A Place for New Actionable Targets
by Irene López-Oreja, Heribert Playa-Albinyana, Fabián Arenas, Mónica López-Guerra and Dolors Colomer
Cancers 2021, 13(13), 3150; https://doi.org/10.3390/cancers13133150 - 24 Jun 2021
Cited by 2 | Viewed by 2848
Abstract
Chronic lymphocytic leukemia (CLL) is characterized by a high degree of genetic variability and interpatient heterogeneity. In the last decade, novel alterations have been described. Some of them impact on the prognosis and evolution of patients. The approval of BTK inhibitors, PI3K inhibitors [...] Read more.
Chronic lymphocytic leukemia (CLL) is characterized by a high degree of genetic variability and interpatient heterogeneity. In the last decade, novel alterations have been described. Some of them impact on the prognosis and evolution of patients. The approval of BTK inhibitors, PI3K inhibitors and Bcl-2 inhibitors has drastically changed the treatment of patients with CLL. The effect of these new targeted therapies has been widely analyzed in TP53-mutated cases, but few data exist about the response of patients carrying other recurrent mutations. In this review, we describe the biological pathways recurrently altered in CLL that might have an impact on the response to these new therapies together with the possibility to use new actionable targets to optimize treatment responses. Full article
(This article belongs to the Special Issue Novel Drug Targets and Advances in Treatment of CLL)
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15 pages, 471 KiB  
Review
Chemoimmunotherapy in the First-Line Treatment of Chronic Lymphocytic Leukaemia: Dead Yet, or Alive and Kicking?
by Lukáš Smolej, Pavel Vodárek, Dominika Écsiová and Martin Šimkovič
Cancers 2021, 13(13), 3134; https://doi.org/10.3390/cancers13133134 - 23 Jun 2021
Cited by 9 | Viewed by 2906
Abstract
The paradigm of first-line treatment of chronic lymphocytic leukaemia (CLL) is currently undergoing a radical change. On the basis of several randomised phase III trials showing prolongation of progression-free survival, chemoimmunotherapy is being replaced by treatment based on novel, orally available targeted inhibitors [...] Read more.
The paradigm of first-line treatment of chronic lymphocytic leukaemia (CLL) is currently undergoing a radical change. On the basis of several randomised phase III trials showing prolongation of progression-free survival, chemoimmunotherapy is being replaced by treatment based on novel, orally available targeted inhibitors such as Bruton tyrosine kinase inhibitors ibrutinib and acalabrutinib or bcl-2 inhibitor venetoclax. However, the use of these agents may be associated with other disadvantages. First, with the exception of one trial in younger/fit patients, no studies have so far demonstrated benefit regarding the ultimate endpoint of overall survival. Second, oral inhibitors are extremely expensive and thus currently unavailable due to the absence of reimbursement in some countries. Third, treatment with ibrutinib and acalabrutinib necessitates long-term administration until progression; this may be associated with accumulation of late side effects, problems with patient compliance, and selection of resistant clones. Therefore, the identification of a subset of patients who could benefit from chemoimmunotherapy would be ideal. Current data suggest that patients with the mutated variable region of the immunoglobulin heavy chain (IGHV) achieve fairly durable remissions, especially when treated with fludarabine, cyclophosphamide, and rituximab (FCR) regimen. This review discusses current options for treatment-naïve patients with CLL. Full article
(This article belongs to the Special Issue Novel Drug Targets and Advances in Treatment of CLL)
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18 pages, 902 KiB  
Review
Current Treatment Options in CLL
by Moritz Bewarder, Stephan Stilgenbauer, Lorenz Thurner and Dominic Kaddu-Mulindwa
Cancers 2021, 13(10), 2468; https://doi.org/10.3390/cancers13102468 - 19 May 2021
Cited by 20 | Viewed by 4867
Abstract
After impressive developments in recent years with the rise of new targeted agents, chemoimmunotherapy (CIT) only plays a minor role in the treatment of patients with chronic lymphocytic leukemia (CLL). Inhibitors of the Bruton tyrosine kinase (BTK), such as ibrutinib or more recently [...] Read more.
After impressive developments in recent years with the rise of new targeted agents, chemoimmunotherapy (CIT) only plays a minor role in the treatment of patients with chronic lymphocytic leukemia (CLL). Inhibitors of the Bruton tyrosine kinase (BTK), such as ibrutinib or more recently acalabrutinib, are highly effective, even in poor-risk or chemo-refractory patients. Venetoclax, an inhibitor of the anti-apoptotic BCL2 protein and, to a lesser extent, phosphoinositide-3 kinase (PI3K) delta inhibitors, add to the armamentarium of targeted agents for the treatment of CLL. Furthermore, anti-CD20 monoclonal antibodies are used very successfully either alone or in combination with BTK, BCL2 or PI3K inhibitors. Despite these advances, there is still an ongoing pursuit for new therapeutic approaches in the treatment of CLL. An even bigger challenge poses the determination of the optimal combination and sequence of those drugs. Here, we give an overview of current treatment options in CLL, weighing the advantages and disadvantages of each approach in the light of different clinical settings. Full article
(This article belongs to the Special Issue Novel Drug Targets and Advances in Treatment of CLL)
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18 pages, 914 KiB  
Review
Novel Agents in Chronic Lymphocytic Leukemia: New Combination Therapies and Strategies to Overcome Resistance
by Moritz Fürstenau and Barbara Eichhorst
Cancers 2021, 13(6), 1336; https://doi.org/10.3390/cancers13061336 - 16 Mar 2021
Cited by 22 | Viewed by 4936
Abstract
The approval of Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib and acalabrutinib and the Bcl-2 inhibitor venetoclax have revolutionized the treatment of chronic lymphocytic leukemia (CLL). While these novel agents alone or in combination induce long lasting and deep remissions in most [...] Read more.
The approval of Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib and acalabrutinib and the Bcl-2 inhibitor venetoclax have revolutionized the treatment of chronic lymphocytic leukemia (CLL). While these novel agents alone or in combination induce long lasting and deep remissions in most patients with CLL, their use may be associated with the development of clinical resistance. In this review, we elucidate the genetic basis of acquired resistance to BTK and Bcl-2 inhibition and present evidence on resistance mechanisms that are not linked to single genomic alterations affecting these target proteins. Strategies to prevent resistance to novel agents are discussed in this review with a special focus on new combination therapies. Full article
(This article belongs to the Special Issue Novel Drug Targets and Advances in Treatment of CLL)
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8 pages, 570 KiB  
Brief Report
Ex Vivo Mitochondrial Respiration Parallels Biochemical Response to Ibrutinib in CLL Cells
by Subir Roy Chowdhury, Cheryl Peltier, Sen Hou, Amandeep Singh, James B. Johnston, Spencer B. Gibson, Aaron J. Marshall and Versha Banerji
Cancers 2021, 13(2), 354; https://doi.org/10.3390/cancers13020354 - 19 Jan 2021
Cited by 1 | Viewed by 2442
Abstract
Mitochondrial respiration is becoming more commonly used as a preclinical tool and potential biomarker for chronic lymphocytic leukemia (CLL) and activated B-cell receptor (BCR) signaling. However, respiration parameters have not been evaluated with respect to dose of ibrutinib given in clinical practice or [...] Read more.
Mitochondrial respiration is becoming more commonly used as a preclinical tool and potential biomarker for chronic lymphocytic leukemia (CLL) and activated B-cell receptor (BCR) signaling. However, respiration parameters have not been evaluated with respect to dose of ibrutinib given in clinical practice or the effect of progression on ibrutinib treatment on respiration of CLL cells. We evaluated the impact of low and standard dose ibrutinib on CLL cells from patients treated in vivo on mitochondrial respiration using Oroboros oxygraph. Cytokines CCL3 and CCL4 were evaluated using the Mesoscale. Western blot analysis was used to evaluate the BCR and apoptotic pathways. We observed no difference in the mitochondrial respiration rates or levels of plasma chemokine (C-C motif) ligands 3 and 4 (CCL3/CCL4), β-2 microglobulin (β-2 M) and lactate dehydrogenase (LDH) between low and standard doses of ibrutinib. This may confirm why clinical observations of the safety and efficacy of low dose ibrutinib are observed in practice. Of interest, we also observed that the mitochondrial respiration of CLL cells paralleled the increase in β-2 M and LDH at progression. Our study further supports mitochondrial respiration as a biomarker for response and progression on ibrutinib in CLL cells and a valuable pre-clinical tool. Full article
(This article belongs to the Special Issue Novel Drug Targets and Advances in Treatment of CLL)
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