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ALK in Cancer: Lessons from the Future
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ALK in Cancer: Lessons from the Future

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

Deadline for manuscript submissions: closed (15 December 2023) | Viewed by 8907

Special Issue Editors

Dr. Petros Christopoulos

E-Mail Website
Guest Editor
1. Department of Oncology, Thoraxklinik at Heidelberg University Hospital, 69126 Heidelberg, Germany
2. National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany
3. Translational Lung Research Center, German Center for Lung Research (DZL) at Heidelberg University Hospital, 69120 Heidelberg, Germany
Interests: targeted therapies; molecular stratification of NSCLC; lung cancer immunology; liquid biopsies; experimental immunotherapies
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Richard Bayliss

E-Mail Website
Guest Editor
Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK
Interests: protein kinases; cell cycle; oncogenic gene fusions; structural biology; Myc
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Within the exciting and rapidly evolving field of thoracic oncology, the ALK+ disease has a model role for several important and interrelated reasons: it has the most favourable biology, with a tumor mutational burden uniquely below 3 mut/MB on average; the largest number and highest efficacy of targeted drugs; the most complex management; and the longest survival, currently exceeding a median of 5 years. Consequently, ALK+ NSCLC has also become a premium testing ground for novel concepts and cutting-edge tools destined to shape the future of cancer medicine: baseline molecular risk stratification, disease monitoring using serial liquid biopsies, availability of targeted next-line therapies for all patients, genetic profiling and tailored treatment of acquired resistance in the majority of cases. The purpose of this Special Issue is to recapitulate recent achievements, outline current challenges, and highlight prospects for the future. Its scope includes all aspects with instrumental importance for a better understanding and management of the ALK+ malignancies. While its focus is on ALK+ lung cancer, preclinical studies on ALK+ biology and insights from other ALK+ diseases are very welcome to broaden our horizons and carry the field further. The ongoing advancement of third-generation ALK inhibitors in the first line, the commencing of clinical trials for fourth-generation inhibitors, accumulating evidence about the clinical importance of fusion variants and comutations, and the ongoing development of next-generation immunotherapeutics to overcome the inherently immunosuppresive ALK+ tumor microenvironment are only a few examples of topics where contributions to this Special Issue can meet and enrich current literature on this less common but most impressive lung cancer subtype.

Dr. Petros Christopoulos
Prof. Dr. Richard Bayliss
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 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

  • ALK inhibitors
  • ALK fusion variants
  • TP53 mutations
  • immunotherapy
  • liquid biopsies
  • disease monitoring
  • therapeutic sequencing

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Published Papers (3 papers)

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Research

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13 pages, 2026 KiB  
Article
Early Development of Ubiquitous Acanthocytosis and Extravascular Hemolysis in Lung Cancer Patients Receiving Alectinib
by Julia Kunz, Christiane Wiedemann, Heidrun Grosch, Katharina Kriegsmann, Stefanie Gryzik, Julia Felden, Michael Hundemer, Huriye Seker-Cin, Miriam Stenzinger, Albrecht Leo, Albrecht Stenzinger, Michael Thomas and Petros Christopoulos
Cancers 2022, 14(11), 2720; https://doi.org/10.3390/cancers14112720 - 31 May 2022
Cited by 9 | Viewed by 2493
Abstract
Alectinib is a standard initial treatment for patients with advanced anaplastic lymphoma kinase (ALK) rearranged non-small-cell lung cancer (NSCLC). The current study analyzed a prospective cohort of 24 consecutive alectinib-treated patients and controls in order to comprehensively characterize longitudinal erythrocyte changes under treatment [...] Read more.
Alectinib is a standard initial treatment for patients with advanced anaplastic lymphoma kinase (ALK) rearranged non-small-cell lung cancer (NSCLC). The current study analyzed a prospective cohort of 24 consecutive alectinib-treated patients and controls in order to comprehensively characterize longitudinal erythrocyte changes under treatment with ALK inhibitors. Upon starting alectinib, all examined patients developed reticulocytosis and abnormal erythrocyte morphology with anisocytosis and a predominance of acanthocytes (64% of red blood cells on average, range 36–100%) in the peripheral blood smear within approximately 2 weeks. Changes were accompanied by a gradual reduction in Eosin-5-maleimide (EMA) binding, which became pathologic (<80% of cells) within 1–2 months in all cases, mimicking an abortive form of hereditary spherocytosis. The latter could be ruled out in 3/3 of analyzed cases by normal sequencing results for the ANK1, EPB42, SLC4A1, SPTA1, or SBTB genes. The direct Coombs test was also negative in 11/11 tested cases. Besides, anemia, increased LDH, and increased bilirubin were noted in a fraction of patients only, ranging between 42 and 68%. Furthermore, haptoglobin decreases were infrequent, occurring in approximately 1/3 of cases only, and mild, with an average value of 0.93 g/L within the normal range of 0.3–2 g/dL, suggesting that hemolysis occurred predominantly in the extravascular compartment, likely due to splenic trapping of the deformed erythrocytes. These changes showed no association with progression-free survival under alectinib or molecular features, i.e., ALK fusion variant or TP53 status of the disease, and resolved upon a switch to an alternative ALK inhibitor. Thus, alectinib induces mild, reversible erythrocyte changes in practically all treated patients, whose most sensitive signs are aberrant red cell morphology in the peripheral smear, a pathologic EMA test, and reactive reticulocytosis. Frank hemolytic anemia is rare, but mild subclinical hemolysis is very frequent and poses differential-diagnostic problems. Alectinib can be continued under the regular control of hemolysis parameters, but the risk of long-term complications, such as cholelithiasis due to increased serum bilirubin in most patients, remains unclear at present. Full article
(This article belongs to the Special Issue ALK in Cancer: Lessons from the Future)
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Review

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14 pages, 690 KiB  
Review
Anaplastic Lymphoma Kinase Inhibitor-Induced Neutropenia: A Systematic Review
by Fabien Moinard-Butot, Simon Nannini, Cathie Fischbach, Safa Abdallahoui, Martin Demarchi, Thierry Petit, Laura Bender and Roland Schott
Cancers 2023, 15(20), 4940; https://doi.org/10.3390/cancers15204940 - 11 Oct 2023
Viewed by 1649
Abstract
Lung cancers with ALK rearrangement represent less than 5% of all lung cancers. ALK inhibitors are currently used to treat first-line metastatic non-small cell lung cancer with ALK rearrangement. Compared to chemotherapy, ALK inhibitors have improved progression-free survival, overall survival, and quality of [...] Read more.
Lung cancers with ALK rearrangement represent less than 5% of all lung cancers. ALK inhibitors are currently used to treat first-line metastatic non-small cell lung cancer with ALK rearrangement. Compared to chemotherapy, ALK inhibitors have improved progression-free survival, overall survival, and quality of life for patients. The results of several phase 3 studies with a follow-up of over 6 years suggest that the life expectancy of these patients treated with targeted therapies is significantly higher than 5 years and could approach 10 years. Nevertheless, these treatments induce haematological toxicities, including neutropenia. Few data are available on neutropenia induced by ALK inhibitors and on the pathophysiological mechanism and therapeutic adaptations necessary to continue the treatment. Given the high efficacy of these treatments, managing side effects to avoid treatment interruptions is essential. Here, we have reviewed the data from published clinical studies and case reports to provide an overview of neutropenia induced by ALK inhibitors. Full article
(This article belongs to the Special Issue ALK in Cancer: Lessons from the Future)
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19 pages, 10650 KiB  
Review
Alternative Treatment Options to ALK Inhibitor Monotherapy for EML4-ALK-Driven Lung Cancer
by Savvas Papageorgiou, Sarah L. Pashley, Laura O’Regan, Sam Khan, Richard Bayliss and Andrew M. Fry
Cancers 2022, 14(14), 3452; https://doi.org/10.3390/cancers14143452 - 15 Jul 2022
Cited by 13 | Viewed by 4069
Abstract
EML4-ALK is an oncogenic fusion protein that accounts for approximately 5% of NSCLC cases. Targeted inhibitors of ALK are the standard of care treatment, often leading to a good initial response. Sadly, some patients do not respond well, and most will develop resistance [...] Read more.
EML4-ALK is an oncogenic fusion protein that accounts for approximately 5% of NSCLC cases. Targeted inhibitors of ALK are the standard of care treatment, often leading to a good initial response. Sadly, some patients do not respond well, and most will develop resistance over time, emphasizing the need for alternative treatments. This review discusses recent advances in our understanding of the mechanisms behind EML4-ALK-driven NSCLC progression and the opportunities they present for alternative treatment options to ALK inhibitor monotherapy. Targeting ALK-dependent signalling pathways can overcome resistance that has developed due to mutations in the ALK catalytic domain, as well as through activation of bypass mechanisms that utilise the same pathways. We also consider evidence for polytherapy approaches that combine targeted inhibition of these pathways with ALK inhibitors. Lastly, we review combination approaches that use targeted inhibitors of ALK together with chemotherapy, radiotherapy or immunotherapy. Throughout this article, we highlight the importance of alternative breakpoints in the EML4 gene that result in the generation of distinct EML4-ALK variants with different biological and pathological properties and consider monotherapy and polytherapy approaches that may be selective to particular variants. Full article
(This article belongs to the Special Issue ALK in Cancer: Lessons from the Future)
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