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Cancers
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ALK: A Tyrosine Kinase Target for Cancer Therapy
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ALK: A Tyrosine Kinase Target for Cancer Therapy

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

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 16487

Special Issue Editors

Dr. Sunitha Nagrath

E-Mail Website
Guest Editor
Department of Chemical Engineering, University of Michigan, 3074 H.H. Dow, 2300 Hayward Street Ann Arbor, MI 48109, USA
Interests: circulating tumor cells; extracellular vesicles; microfluidic technologies; lung cancer; single-cell technologies
Prof. Dr. Nithya Ramnath

E-Mail Website
Guest Editor
Department of Internal Medicine, University of Michigan, 1500 E Medical Center Dr. SPC 5912, Ann Arbor, MI 48109, USA
Interests: lung cancer, circulating biomarkers, circulating tumor cells, immunotherapies

Special Issue Information

Dear Colleagues,

The anaplastic lymphoma kinase (ALK) gene located on chromosome 2 encodes for a protein that is crucial for neuronal development. The ALK gene has been found to be rearranged, mutated, or amplified in cancers, including anaplastic large-cell lymphomas, neuroblastomas, and lung adenocarcinomas.

Despite tremendous progress in the clinical development of tyrosine kinase inhibitors that target oncogenic ALK, the responses are temporary, with the development of resistance within 1–2 years. There is much work to be done to understand the early events that underpin the transformation of ALK-rearranged or -mutated cancers, the clonal evolution of these cancers, and the development of resistance, as well as identifying newer therapies including those that target the removal of proteins (e.g., proteolysis targeting chimera, PROTAC) rather than targeting the receptor itself. Additionally, these cancers are seldom responsive to the usual immunotherapeutic strategies that involve immune checkpoint inhibition, and more work is needed to identify and target specific mechanisms of immune evasion of these cancers. These studies may allow earlier intervention and allow more durable responses and eventually cures for this subgroup of patients with aggressive cancers.

In this Special Issue, we explore the current understanding of the pathobiology of these unique cancers, therapy options, and blood-based modalities for diagnosis and monitoring, as well as how they complement initial tumor biopsies and offer potential solutions to unanswered questions in the field. We hope to generate enthusiasm within the cancer community to hasten progress in the approach to these rare but aggressive cancers.

Dr. Sunitha Nagrath
Dr. Nithya Ramnath
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
  • ALK rearrangement
  • lung cancer
  • tyrosine kinase inhibitors
  • resistance

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Published Papers (4 papers)

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Research

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17 pages, 1261 KiB  
Article
Inconsistent Intersample ALK FISH Results in Patients with Lung Cancer: Analysis of Potential Causes
by Zhenya Tang, Hui Chen, Lingzhi Hong, Guilin Tang, Gokce A. Toruner, Wei Wang, Sinchita Roy Chowdhuri, Wei Yin, Hai Suk Jung, Jun Gu, Mark J. Routbort, Jianjun Zhang, Joseph D. Khoury and L. Jeffrey Medeiros
Cancers 2020, 12(7), 1903; https://doi.org/10.3390/cancers12071903 - 14 Jul 2020
Viewed by 2111
Abstract
ALK FISH analyses of multiple specimens occasionally yield inconsistent intersample results in lung cancer patients, posing clinical challenges requiring intensive analysis of all potential causative pre- and post- analytic factors. In this study, 19 patients (8M/11F) with inconsistent intersample ALK FISH results were [...] Read more.
ALK FISH analyses of multiple specimens occasionally yield inconsistent intersample results in lung cancer patients, posing clinical challenges requiring intensive analysis of all potential causative pre- and post- analytic factors. In this study, 19 patients (8M/11F) with inconsistent intersample ALK FISH results were analyzed, representing 4.9% of patients assessed ≥ twice in our institution. Fifteen patients received ALK tyrosine kinase inhibitor(s) (TKIs). Nine patients died, and ten were alive for 8 to 74-month follow-ups (median, 40 months). Through strict and stringent laboratory and case-review policies, all postanalytic factors were excluded. Correlating clinical information, ALK results obtained by RNA sequencing (RNA-seq) and other concurrent tests, several pre-analytic factors were determined. A suboptimal specimen was likely the cause in three patients, supported by the failure of one or more concurrent tests or discrepant results between FISH and RNA-seq. ALK inhibition by TKIs might have been responsible for the change of ALK status from positive to negative in eight patients. Other potential explanations include the existence of multiple primary lung cancer lesions, tumor heterogeneity, and the clonal evolution of tumor cells, related or not to ALK TKI therapy. This study is helpful for both pathologists and clinicians encountering inconsistent and/or discrepant intersample results. Full article
(This article belongs to the Special Issue ALK: A Tyrosine Kinase Target for Cancer Therapy)
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Review

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25 pages, 4511 KiB  
Review
Recent Advances in Device Engineering and Computational Analysis for Characterization of Cell-Released Cancer Biomarkers
by Hesam Abouali, Seied Ali Hosseini, Emma Purcell, Sunitha Nagrath and Mahla Poudineh
Cancers 2022, 14(2), 288; https://doi.org/10.3390/cancers14020288 - 7 Jan 2022
Cited by 10 | Viewed by 3352
Abstract
During cancer progression, tumors shed different biomarkers into the bloodstream, including circulating tumor cells (CTCs), extracellular vesicles (EVs), circulating cell-free DNA (cfDNA), and circulating tumor DNA (ctDNA). The analysis of these biomarkers in the blood, known as ‘liquid biopsy’ (LB), is a promising [...] Read more.
During cancer progression, tumors shed different biomarkers into the bloodstream, including circulating tumor cells (CTCs), extracellular vesicles (EVs), circulating cell-free DNA (cfDNA), and circulating tumor DNA (ctDNA). The analysis of these biomarkers in the blood, known as ‘liquid biopsy’ (LB), is a promising approach for early cancer detection and treatment monitoring, and more recently, as a means for cancer therapy. Previous reviews have discussed the role of CTCs and ctDNA in cancer progression; however, ctDNA and EVs are rapidly evolving with technological advancements and computational analysis and are the subject of enormous recent studies in cancer biomarkers. In this review, first, we introduce these cell-released cancer biomarkers and briefly discuss their clinical significance in cancer diagnosis and treatment monitoring. Second, we present conventional and novel approaches for the isolation, profiling, and characterization of these markers. We then investigate the mathematical and in silico models that are developed to investigate the function of ctDNA and EVs in cancer progression. We convey our views on what is needed to pave the way to translate the emerging technologies and models into the clinic and make the case that optimized next-generation techniques and models are needed to precisely evaluate the clinical relevance of these LB markers. Full article
(This article belongs to the Special Issue ALK: A Tyrosine Kinase Target for Cancer Therapy)
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13 pages, 922 KiB  
Review
Immunotherapy for ALK-Rearranged Non-Small Cell Lung Cancer: Challenges Inform Promising Approaches
by Kamya Sankar, Sunitha Nagrath and Nithya Ramnath
Cancers 2021, 13(6), 1476; https://doi.org/10.3390/cancers13061476 - 23 Mar 2021
Cited by 20 | Viewed by 5125
Abstract
Rearrangements in the Anaplastic Lymphoma Kinase (ALK) gene have been implicated in 5–6% of all non-small cell lung cancers. ALK-rearranged non-small cell lung cancers are sensitive to ALK-directed tyrosine kinase inhibitors, but generally resistant to single-agent immune checkpoint inhibitors. [...] Read more.
Rearrangements in the Anaplastic Lymphoma Kinase (ALK) gene have been implicated in 5–6% of all non-small cell lung cancers. ALK-rearranged non-small cell lung cancers are sensitive to ALK-directed tyrosine kinase inhibitors, but generally resistant to single-agent immune checkpoint inhibitors. Here, we aim to describe the mechanisms of ALK aberrations in non-small cell lung cancer by which an immunosuppressed tumor microenvironment is created, leading to host immune evasion. We report pre-clinical and clinical studies evaluating novel immunotherapeutic approaches and describe the promises and challenges of incorporating immune-based treatments for ALK-rearranged non-small cell lung cancer. Full article
(This article belongs to the Special Issue ALK: A Tyrosine Kinase Target for Cancer Therapy)
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15 pages, 1319 KiB  
Review
Emerging Roles of ALK in Immunity and Insights for Immunotherapy
by Lan Wang and Vivian Wai Yan Lui
Cancers 2020, 12(2), 426; https://doi.org/10.3390/cancers12020426 - 12 Feb 2020
Cited by 18 | Viewed by 4782
Abstract
Anaplastic lymphoma kinase (ALK) is mostly known for its oncogenic role in several human cancers. Recent evidences clearly indicate new roles of ALK and its genetic aberrations (e.g. gene rearrangements and mutations) in immune evasion, innate and cell-mediated immunity. New ALK-related immunotherapy approaches [...] Read more.
Anaplastic lymphoma kinase (ALK) is mostly known for its oncogenic role in several human cancers. Recent evidences clearly indicate new roles of ALK and its genetic aberrations (e.g. gene rearrangements and mutations) in immune evasion, innate and cell-mediated immunity. New ALK-related immunotherapy approaches are demonstrating both preclinical and clinical promises. Here, we provide a timely review on the most updated laboratory and patient-related findings on ALK and immunity, which would grant us important insights for the development of novel ALK immunotherapies for ALK-altered cancers. Full article
(This article belongs to the Special Issue ALK: A Tyrosine Kinase Target for Cancer Therapy)
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