Special Issue "Advances in Our Understanding of ALK-Related Cancers: A Selection of Papers from the Joint Annual Meeting of the European Research Initiative for ALK-Related Malignancies (ERIA) and the European Union Marie Curie European Training Network ALKATRAS"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (15 November 2017)

Special Issue Editors

Guest Editor
Dr. Suzanne Turner

Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Lab Block Level 3, Box 231, Addenbrooke’s Hospital, Cambridge CB20QQ, UK
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Phone: +44 (0)1223 762655
Guest Editor
Prof. Dr. Lukas Kenner

Department of Experimental Pathology and Laboratory Animal Pathology, Medical University and University of Veterinary Medicine Vienna, Medizinische Universitat Wien, Vienna, Austria
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Phone: +43 1 40400 51760
Fax: +43 1 40400 51930
Interests: transgenic mouse research; analysis of tumour models; analysis of human patients tumor samples
Guest Editor
Dr. Olaf Merkel

Institute of Clinical Pathology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
Website | E-Mail
Phone: +43 1 40400 63900

Special Issue Information

Dear Colleagues,

This Special Issue of Cancers will consist of selected papers from the “Joint 8th Annual Meeting of the European Research Initiative for ALK Related Malignancies (ERIA) and the 2nd Annual meeting of the European Union Marie Curie European Training network, ALK as a target of translational science (ALKATRAS) (www.erialcl.net and www.alkatras.erialcl.net)”, taking place in Cambridge (UK), on 28–29 September 2017. ERIA was established in 2009 to bring together scientists and clinicians with a shared interest in ALK-related cancers and to provide a platform for the exchange of scientific data, reagents and informal peer review. Largely, this is mediated through annual meetings and whilst originally solely a European enterprise, now incorporates research groups from across the World. In 2016, 14 research groups, all members of ERIA were awarded an EU Marie Curie European training Network, ALKATRAS which has enabled further collaboration through a network of 15 PhD students recruited from around the world and representing the next generation of ERIA members. As such, this international conference represents the major event for the scientific community working on ALK-related cancers and promises to be an exciting and exhilarating meeting. Particular attention is given to trainees, whereby students are encouraged to present their early, unpublished data to facilitate collaboration and advancement in this important area of research. This Special Issue will cover new and novel areas of research pertaining to ALK-related malignancies presented at this conference and therefore will represent state-of-the-art and up-to-date coverage of progress.

Dr. Suzanne Turner
Prof. Lukas Kenner
Dr. Olaf Merkel
Guest Editors

Manuscript Submission Information

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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 monthly 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 1800 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.

Published Papers (8 papers)

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Review

Open AccessFeature PaperReview Current Immunotherapeutic Approaches in T Cell Non-Hodgkin Lymphomas
Cancers 2018, 10(9), 339; https://doi.org/10.3390/cancers10090339
Received: 24 July 2018 / Revised: 31 August 2018 / Accepted: 14 September 2018 / Published: 18 September 2018
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Abstract
T cell non-Hodgkin lymphoma (T-NHL) is a rare and heterogeneous group of neoplasms of the lymphoid system. With the exception of a few relatively indolent entities, T-NHL is typically aggressive, treatment resistant, and associated with poor prognosis. Relatively few options with proven clinical [...] Read more.
T cell non-Hodgkin lymphoma (T-NHL) is a rare and heterogeneous group of neoplasms of the lymphoid system. With the exception of a few relatively indolent entities, T-NHL is typically aggressive, treatment resistant, and associated with poor prognosis. Relatively few options with proven clinical benefit are available for patients with relapsed or refractory disease. Immunotherapy has emerged as a promising treatment for the management of patients with hematological malignancies. The identification of tumor antigens has provided a large number of potential targets. Therefore, several monoclonal antibodies (alemtuzumab, SGN-30, brentuximab vedotin, and mogamulizumab), directed against tumor antigens, have been investigated in different subtypes of T-NHL. In addition to targeting antigens involved in cancer cell physiology, antibodies can stimulate immune effector functions or counteract immunosuppressive mechanisms. Chimeric antigen receptor (CAR)-T cells directed against CD30 and immune checkpoint inhibitors are currently being investigated in clinical trials. In this review, we summarize the currently available clinical evidence for immunotherapy in T-NHL, focusing on the results of clinical trials using first generation monoclonal antibodies, new immunotherapeutic agents, immune checkpoint inhibitors, and CAR-T cell therapies. Full article
Open AccessReview Immune Response against ALK in Children with ALK-Positive Anaplastic Large Cell Lymphoma
Cancers 2018, 10(4), 114; https://doi.org/10.3390/cancers10040114
Received: 28 February 2018 / Revised: 5 April 2018 / Accepted: 7 April 2018 / Published: 10 April 2018
Cited by 1 | PDF Full-text (4646 KB) | HTML Full-text | XML Full-text
Abstract
Patients with anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) mount a humoral and cellular immune response against ALK. More than 90% of children and adolescents with ALK-positive ALCL have detectable anti-ALK antibodies in serum or plasma, and the antibody titer inversely [...] Read more.
Patients with anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) mount a humoral and cellular immune response against ALK. More than 90% of children and adolescents with ALK-positive ALCL have detectable anti-ALK antibodies in serum or plasma, and the antibody titer inversely correlates with the risk of relapse. ALK-specific CD8 and CD4 T cell responses have been described in patients with ALK-positive ALCL. Vaccination with ALK DNA led to protection against lymphoma growth in a murine model. Collectively, these data suggest that the ALK-specific immune response is involved in the control of the disease. The characteristics of the humoral and cellular immune response against ALK as well as tumor immune escape mechanisms have been increasingly investigated. However, tumor and host factors contributing to the individual immune response against ALK are still largely unknown. Depending on the individual strength of the immune response and its determinants, individualized immunological approaches might be appropriate for the consolidation of ALCL patients. Strategies such as ALK vaccination could be effective for those with a pre-existing anti-tumor immunity, while an allogeneic blood stem cell transplantation or check-point inhibition could be effective for others. Full article
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Open AccessFeature PaperReview ALK in Neuroblastoma: Biological and Therapeutic Implications
Cancers 2018, 10(4), 113; https://doi.org/10.3390/cancers10040113
Received: 21 March 2018 / Revised: 5 April 2018 / Accepted: 6 April 2018 / Published: 10 April 2018
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Abstract
Neuroblastoma (NB) is the most common and deadly solid tumour in children. Despite the development of new treatment options for high-risk NB, over half of patients relapse and five-year survival remains at 40–50%. Therefore, novel treatment strategies aimed at providing long-term disease remission [...] Read more.
Neuroblastoma (NB) is the most common and deadly solid tumour in children. Despite the development of new treatment options for high-risk NB, over half of patients relapse and five-year survival remains at 40–50%. Therefore, novel treatment strategies aimed at providing long-term disease remission are urgently sought. ALK, encoding the anaplastic lymphoma kinase receptor, is altered by gain-of-function point mutations in around 14% of high-risk NB and represents an ideal therapeutic target given its low or absent expression in healthy tissue postnatally. Small-molecule inhibitors of Anaplastic Lymphoma Kinase (ALK) approved in ALK fusion-positive lung cancer are currently undergoing clinical assessment in patients with ALK-mutant NB. Parallel pre-clinical studies are demonstrating the efficacy of ALK inhibitors against common ALK variants in NB; however, a complex picture of therapeutic resistance is emerging. It is anticipated that long-term use of these compounds will require combinatorial targeting of pathways downstream of ALK, functionally-related ‘bypass’ mechanisms and concomitant oncogenic pathways. Full article
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Open AccessFeature PaperReview The Pathological Spectrum of Systemic Anaplastic Large Cell Lymphoma (ALCL)
Cancers 2018, 10(4), 107; https://doi.org/10.3390/cancers10040107
Received: 12 March 2018 / Revised: 30 March 2018 / Accepted: 2 April 2018 / Published: 4 April 2018
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Abstract
Anaplastic large cell lymphoma (ALCL) represents a group of malignant T-cell lymphoproliferations that share morphological and immunophenotypical features, namely strong CD30 expression and variable loss of T-cell markers, but differ in clinical presentation and prognosis. The recognition of anaplastic lymphoma kinase (ALK) fusion [...] Read more.
Anaplastic large cell lymphoma (ALCL) represents a group of malignant T-cell lymphoproliferations that share morphological and immunophenotypical features, namely strong CD30 expression and variable loss of T-cell markers, but differ in clinical presentation and prognosis. The recognition of anaplastic lymphoma kinase (ALK) fusion proteins as a result of chromosomal translocations or inversions was the starting point for the distinction of different subgroups of ALCL. According to their distinct clinical settings and molecular findings, the 2016 revised World Health Organization (WHO) classification recognizes four different entities: systemic ALK-positive ALCL (ALK+ ALCL), systemic ALK-negative ALCL (ALK− ALCL), primary cutaneous ALCL (pC-ALCL), and breast implant-associated ALCL (BI-ALCL), the latter included as a provisional entity. ALK is rearranged in approximately 80% of systemic ALCL cases with one of its partner genes, most commonly NPM1, and is associated with favorable prognosis, whereas systemic ALK− ALCL shows heterogeneous clinical, phenotypical, and genetic features, underlining the different oncogenesis between these two entities. Recognition of the pathological spectrum of ALCL is crucial to understand its pathogenesis and its boundaries with other entities. In this review, we will focus on the morphological, immunophenotypical, and molecular features of systemic ALK+ and ALK− ALCL. In addition, BI-ALCL will be discussed. Full article
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Open AccessFeature PaperReview Treatment Options for Paediatric Anaplastic Large Cell Lymphoma (ALCL): Current Standard and beyond
Received: 25 February 2018 / Revised: 26 March 2018 / Accepted: 29 March 2018 / Published: 30 March 2018
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Abstract
Anaplastic Lymphoma Kinase (ALK)-positive Anaplastic Large Cell Lymphoma (ALCL), remains one of the most curable cancers in the paediatric setting; multi-agent chemotherapy cures approximately 65–90% of patients. Over the last two decades, major efforts have focused on improving the survival rate by intensification [...] Read more.
Anaplastic Lymphoma Kinase (ALK)-positive Anaplastic Large Cell Lymphoma (ALCL), remains one of the most curable cancers in the paediatric setting; multi-agent chemotherapy cures approximately 65–90% of patients. Over the last two decades, major efforts have focused on improving the survival rate by intensification of combination chemotherapy regimens and employing stem cell transplantation for chemotherapy-resistant patients. More recently, several new and ‘renewed’ agents have offered the opportunity for a change in the paradigm for the management of both chemo-sensitive and chemo-resistant forms of ALCL. The development of ALK inhibitors following the identification of the EML4-ALK fusion gene in Non-Small Cell Lung Cancer (NSCLC) has opened new possibilities for ALK-positive ALCL. The uniform expression of CD30 on the cell surface of ALCL has given the opportunity for anti-CD30 antibody therapy. The re-evaluation of vinblastine, which has shown remarkable activity as a single agent even in the face of relapsed disease, has led to the consideration of a revised approach to frontline therapy. The advent of immune therapies such as checkpoint inhibition has provided another option for the treatment of ALCL. In fact, the number of potential new agents now presents a real challenge to the clinical community that must prioritise those thought to offer the most promise for the future. In this review, we will focus on the current status of paediatric ALCL therapy, explore how new and ‘renewed’ agents are re-shaping the therapeutic landscape for ALCL, and identify the strategies being employed in the next generation of clinical trials. Full article
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Open AccessFeature PaperReview The Role of Activator Protein-1 (AP-1) Family Members in CD30-Positive Lymphomas
Received: 22 February 2018 / Revised: 21 March 2018 / Accepted: 25 March 2018 / Published: 28 March 2018
Cited by 7 | PDF Full-text (5147 KB) | HTML Full-text | XML Full-text
Abstract
The Activator Protein-1 (AP-1) transcription factor (TF) family, composed of a variety of members including c-JUN, c-FOS and ATF, is involved in mediating many biological processes such as proliferation, differentiation and cell death. Since their discovery, the role of AP-1 TFs in cancer [...] Read more.
The Activator Protein-1 (AP-1) transcription factor (TF) family, composed of a variety of members including c-JUN, c-FOS and ATF, is involved in mediating many biological processes such as proliferation, differentiation and cell death. Since their discovery, the role of AP-1 TFs in cancer development has been extensively analysed. Multiple in vitro and in vivo studies have highlighted the complexity of these TFs, mainly due to their cell-type specific homo- or hetero-dimerization resulting in diverse transcriptional response profiles. However, as a result of the increasing knowledge of the role of AP-1 TFs in disease, these TFs are being recognized as promising therapeutic targets for various malignancies. In this review, we focus on the impact of deregulated expression of AP-1 TFs in CD30-positive lymphomas including Classical Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma. Full article
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Open AccessReview The Role of Oncogenic Tyrosine Kinase NPM-ALK in Genomic Instability
Received: 26 January 2018 / Revised: 20 February 2018 / Accepted: 27 February 2018 / Published: 5 March 2018
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Abstract
Genomic stability is crucial for cell life and transmitting genetic material is one of the primary tasks of the cell. The cell needs to be able to recognize any possible error and quickly repair it, and thus, cells have developed several mechanisms to [...] Read more.
Genomic stability is crucial for cell life and transmitting genetic material is one of the primary tasks of the cell. The cell needs to be able to recognize any possible error and quickly repair it, and thus, cells have developed several mechanisms to detect DNA damage and promote repair during evolution. The DNA damage response (DDR) and DNA repair pathways ensure the control of possible errors that could impair the duplication of genetic information and introduce variants in the DNA. Endogenous and exogenous factors compromise genomic stability and cause dysregulation in the DDR and DNA repair pathways. Cancer cells often impair these mechanisms to overcome cellular barriers (cellular senescence and/or apoptosis), leading to malignancy. NPM (nucleophosmin)-ALK (anaplastic lymphoma kinase) is an oncogenic tyrosine kinase that is involved in the development of anaplastic large cell lymphoma (ALCL). NPM-ALK is known to be involved in the activation of proliferative and anti-apoptotic signaling pathways. New evidence reveals that NPM-ALK translocation also impairs the ability of cells to maintain the genomic stability through both DDR and DNA repair pathways. This review aims to highlight the role of the oncogenic tyrosine kinase NPM-ALK in the cell, and pointing to new possible therapeutic strategies. Full article
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Open AccessReview Tumor Resistance against ALK Targeted Therapy-Where It Comes From and Where It Goes
Received: 1 February 2018 / Revised: 25 February 2018 / Accepted: 26 February 2018 / Published: 28 February 2018
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Abstract
Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval [...] Read more.
Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval for ALK-positive NSCLC patients treatment. However, the clinical benefit observed in targeting ALK in NSCLC is almost universally limited by the emergence of drug resistance with a median of occurrence of approximately 10 months after the initiation of therapy. Thus, to overcome crizotinib resistance, second/third-generation ALK inhibitors have been developed and received, or are close to receiving, FDA approval. However, even when treated with these new inhibitors tumors became resistant, both in vitro and in clinical settings. The elucidation of the diverse mechanisms through which resistance to ALK TKI emerges, has informed the design of novel therapeutic strategies to improve patients disease outcome. This review summarizes the currently available knowledge regarding ALK physiologic function/structure and neoplastic transforming role, as well as an update on ALK inhibitors and resistance mechanisms along with possible therapeutic strategies that may overcome the development of resistance. Full article
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