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Cancers
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Targeted Therapy for Small Cell Lung Cancer
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Targeted Therapy for Small Cell Lung Cancer

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

Deadline for manuscript submissions: closed (28 September 2019) | Viewed by 39924

Special Issue Editors

Dr. Klaas Kok

E-Mail Website
Guest Editor
Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
Interests: ccRCC; NGS; TSGs; LUAD driver mutations; microRNAs; intratumor heterogeneity
Dr. Birgitta I Hiddinga

E-Mail Website
Guest Editor
Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

Special Issue Information

Dear Colleagues,

The therapy of non-small cell lung cancer (NSCLC) has seen major advances in therapeutic modalities involving the targeting of a range of driver kinases and the activation of the immune system by checkpoint inhibitors. In contrast, small cell lung cancer (SCLC), which constitutes approximately 15% of lung cancers, poses a much tougher problem, and its treatment has lacked significant advances for the past decades, with the possible exception of the recent successes of immunotherapy. However, the response rates to immunotherapy are rather low and linked to a modest prolongation of survival, and, therefore, there is much room for improvement in the targeted therapy of SCLC. The genomic characterization of SCLC has revealed the universal impairment of p53 and pRb tumor suppressor proteins and the presence of multiple interchangeable drivers which are difficult to target. A host of targeted therapies aimed at reversing resistance to apoptosis and inhibiting developmental signaling pathways and growth factor receptors failed to show clinical progress. Investigations on inhibitors of DNA repair, global modifiers of gene transcription, or cytotoxic drug conjugates directed to constituents of growth stimulatory circuits are ongoing. In the past, SCLC was preferentially studied by two-dimensional tumor models or poorly representative xenografts. The three-dimensional nature and organization of SCLC tumors has been largely neglected, although vigorously proliferating tumors may outgrow vessel supply and may show avascular tumor areas comprising hypoxic regions with resulting chemo- and radioresistance. Likewise, the importance of the growth of circulating tumor cells (CTC) as three-dimensional aggregates in metastasis and drug resistance has not been considered in the treatment of SCLC so far. Therefore, for this Special Issue on targeted therapy for SCLC, all kinds of new concepts, alternative druggable targets and, especially, means to reverse drug resistance at the multicellular level are invited.

Dr. Klaas Kok
Dr. Birgitta I Hiddinga
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

  • small cell lung cancer
  • targeted therapy
  • cell signaling inhibitors
  • kinase inhibitors
  • transcription modifiers
  • drug conjugates
  • biomarkers
  • spheroid
  • hypoxia

Published Papers (8 papers)

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Editorial

Jump to: Research, Review

5 pages, 204 KiB  
Editorial
Small-Cell Lung Cancer: Is the Black Box Finally Opening Up?
by Birgitta I. Hiddinga and Klaas Kok
Cancers 2021, 13(2), 236; https://doi.org/10.3390/cancers13020236 - 11 Jan 2021
Viewed by 1598
Abstract
Small-cell lung cancer (SCLC) is an aggressive cancer that originates from the neuroendocrine crest [...] Full article
(This article belongs to the Special Issue Targeted Therapy for Small Cell Lung Cancer)

Research

Jump to: Editorial, Review

18 pages, 3194 KiB  
Article
Increased Expression and Activation of FAK in Small-Cell Lung Cancer Compared to Non-Small-Cell Lung Cancer
by Frank Aboubakar Nana, Delphine Hoton, Jérôme Ambroise, Marylène Lecocq, Marie Vanderputten, Yves Sibille, Bart Vanaudenaerde, Charles Pilette, Caroline Bouzin and Sebahat Ocak
Cancers 2019, 11(10), 1526; https://doi.org/10.3390/cancers11101526 - 10 Oct 2019
Cited by 27 | Viewed by 3149
Abstract
Introduction: Focal adhesion kinase (FAK) plays a crucial role in cancer development and progression. FAK is overexpressed and/or activated and associated with poor prognosis in various malignancies. However, in lung cancer, activated FAK expression and its prognostic value are unknown. Methods: FAK and [...] Read more.
Introduction: Focal adhesion kinase (FAK) plays a crucial role in cancer development and progression. FAK is overexpressed and/or activated and associated with poor prognosis in various malignancies. However, in lung cancer, activated FAK expression and its prognostic value are unknown. Methods: FAK and activated FAK (phospho-FAK Y397) expressions were analyzed by multiplex immunofluorescence staining in formalin-fixed paraffin-embedded tissues from 95 non-small-cell lung cancer (NSCLC) and 105 small-cell lung cancer (SCLC) patients, and 37 healthy donors. The FAK staining score was defined as the percentage (%) of FAK-stained tumor area multiplied by (×) FAK mean intensity and phospho-FAK staining score as the (% of phospho-FAK-stained area of low intensity × 1) + (% of phospho-FAK-stained area of medium intensity × 2) + (% of the phospho-FAK-stained area of high intensity × 3). FAK and phospho-FAK staining scores were compared between normal, NSCLC, and SCLC tissues. They were also tested for correlations with patient characteristics and clinical outcomes. Results: The median follow-up time after the first treatment was 42.5 months and 6.4 months for NSCLC and SCLC patients, respectively. FAK and phospho-FAK staining scores were significantly higher in lung cancer than in normal lung and significantly higher in SCLC compared to NSCLC tissues (p < 0.01). Moreover, the ratio between phospho-FAK and FAK staining scores was significantly higher in SCLC than in NSCLC tissues (p < 0.01). However, FAK and activated FAK expression in lung cancer did not correlate with recurrence-free and overall survival in NSCLC and SCLC patients. Conclusions: Total FAK and activated FAK expressions are significantly higher in lung cancer than in normal lung, and significantly higher in SCLC compared to NSCLC, but are not prognostic biomarkers in this study. Full article
(This article belongs to the Special Issue Targeted Therapy for Small Cell Lung Cancer)
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Review

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32 pages, 1851 KiB  
Review
Role of Focal Adhesion Kinase in Small-Cell Lung Cancer and Its Potential as a Therapeutic Target
by Frank Aboubakar Nana, Marie Vanderputten and Sebahat Ocak
Cancers 2019, 11(11), 1683; https://doi.org/10.3390/cancers11111683 - 29 Oct 2019
Cited by 35 | Viewed by 5333
Abstract
Small-cell lung cancer (SCLC) represents 15% of all lung cancers and it is clinically the most aggressive type, being characterized by a tendency for early metastasis, with two-thirds of the patients diagnosed with an extensive stage (ES) disease and a five-year overall survival [...] Read more.
Small-cell lung cancer (SCLC) represents 15% of all lung cancers and it is clinically the most aggressive type, being characterized by a tendency for early metastasis, with two-thirds of the patients diagnosed with an extensive stage (ES) disease and a five-year overall survival (OS) as low as 5%. There are still no effective targeted therapies in SCLC despite improved understanding of the molecular steps leading to SCLC development and progression these last years. After four decades, the only modest improvement in OS of patients suffering from ES-SCLC has recently been shown in a trial combining atezolizumab, an anti-PD-L1 immune checkpoint inhibitor, with carboplatin and etoposide, chemotherapy agents. This highlights the need to pursue research efforts in this field. Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that is overexpressed and activated in several cancers, including SCLC, and contributing to cancer progression and metastasis through its important role in cell proliferation, survival, adhesion, spreading, migration, and invasion. FAK also plays a role in tumor immune evasion, epithelial-mesenchymal transition, DNA damage repair, radioresistance, and regulation of cancer stem cells. FAK is of particular interest in SCLC, being known for its aggressiveness. The inhibition of FAK in SCLC cell lines demonstrated significative decrease in cell proliferation, invasion, and migration, and induced cell cycle arrest and apoptosis. In this review, we will focus on the role of FAK in cancer cells and their microenvironment, and its potential as a therapeutic target in SCLC. Full article
(This article belongs to the Special Issue Targeted Therapy for Small Cell Lung Cancer)
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21 pages, 458 KiB  
Review
Technological and Therapeutic Advances in Advanced Small Cell Lung Cancer
by Caroline Lum and Muhammad Alamgeer
Cancers 2019, 11(10), 1570; https://doi.org/10.3390/cancers11101570 - 15 Oct 2019
Cited by 17 | Viewed by 5007
Abstract
Small cell lung cancer (SCLC) accounts for approximately 10–15% of all lung cancers. The prognosis is poor with median survival in the advanced stage remaining at around 12 months. Despite applying every known therapeutic approach, no major breakthrough has improved the overall survival [...] Read more.
Small cell lung cancer (SCLC) accounts for approximately 10–15% of all lung cancers. The prognosis is poor with median survival in the advanced stage remaining at around 12 months. Despite applying every known therapeutic approach, no major breakthrough has improved the overall survival in the last 30 years. Historically, experiments performed on conventional cell lines may have limitations of not accurately reflecting the complex biological and genomic heterogeneity of this disease. However, additional knowledge gained from recently developed genetically engineered mouse models (GEMMs) and patient derived xenografts (PDXs) have made encouraging inroads. Whole genome sequencing (WGS) data reveals a high mutational burden and a number of genetic alterations but low frequency of targetable mutations. Despite several failures, considerable therapeutic opportunities have recently emerged. Potentially promising therapies include those targeting DNA damage repair, stem cell/renewal and drug resistant mechanisms. Modest success has also been achieved with immune checkpoint inhibitors while therapeutic exploration of various other components of the immune system is underway. However, the complex heterogeneities reflect the need for accurate bio-markers to translate novel discoveries into clinical benefit. Additionally, the molecular mechanisms that differentiate chemo-sensitive from chemo-refractory disease remain unknown. Obtaining reliable tumour samples by utilising novel techniques such as endobronchial ultrasound guided needle aspiration or adopting to liquid biopsies are becoming popular. This review will focus on recent technological and therapeutic advancements to surmount this recalcitrant disease. Full article
(This article belongs to the Special Issue Targeted Therapy for Small Cell Lung Cancer)
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14 pages, 656 KiB  
Review
MET Inhibitors in Small Cell Lung Cancer: From the Bench to the Bedside
by Max Hardy-Werbin, Raúl del Rey-Vergara, Miguel Alejandro Galindo-Campos, Laura Moliner and Edurne Arriola
Cancers 2019, 11(10), 1404; https://doi.org/10.3390/cancers11101404 - 20 Sep 2019
Cited by 9 | Viewed by 3528
Abstract
Small cell lung cancer (SCLC) is the most aggressive type of lung cancer. The different systemic treatment approaches attempted in the last 35 years have not improved overall survival in the advanced stage. Targeted therapies assessed in clinical trials have failed to show [...] Read more.
Small cell lung cancer (SCLC) is the most aggressive type of lung cancer. The different systemic treatment approaches attempted in the last 35 years have not improved overall survival in the advanced stage. Targeted therapies assessed in clinical trials have failed to show efficacy against SCLC. Within the potentially interesting targets, the hepatocyte growth factor (HGF)/mesenchymal-epithelial transition (MET) pathway activation is associated with worse survival and chemoresistance in SCLC. Preclinical data suggest that the inhibition of the MET pathway can revert chemoresistance and prevent tumor growth. Recently, immunotherapy has shown modest but relevant activity in SCLC. Interestingly, MET modulation seems to be involved in increasing the efficacy of standard checkpoint inhibitors. Here, we review the preclinical and clinical data of MET inhibition in SCLC, and the role of this pathway in the immune response. Full article
(This article belongs to the Special Issue Targeted Therapy for Small Cell Lung Cancer)
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23 pages, 1182 KiB  
Review
Tumor-Targeted Drug Conjugates as an Emerging Novel Therapeutic Approach in Small Cell Lung Cancer (SCLC)
by Alexander Y. Deneka, Yanis Boumber, Tim Beck and Erica A. Golemis
Cancers 2019, 11(9), 1297; https://doi.org/10.3390/cancers11091297 - 3 Sep 2019
Cited by 19 | Viewed by 7302
Abstract
There are few effective therapies for small cell lung cancer (SCLC), a highly aggressive disease representing 15% of total lung cancers. With median survival <2 years, SCLC is one of the most lethal cancers. At present, chemotherapies and radiation therapy are commonly used [...] Read more.
There are few effective therapies for small cell lung cancer (SCLC), a highly aggressive disease representing 15% of total lung cancers. With median survival <2 years, SCLC is one of the most lethal cancers. At present, chemotherapies and radiation therapy are commonly used for SCLC management. Few protein-targeted therapies have shown efficacy in improving overall survival; immune checkpoint inhibitors (ICIs) are promising agents, but many SCLC tumors do not express ICI targets such as PD-L1. This article presents an alternative approach to the treatment of SCLC: the use of drug conjugates, where a targeting moiety concentrates otherwise toxic agents in the vicinity of tumors, maximizing the differential between tumor killing and the cytotoxicity of normal tissues. Several tumor-targeted drug conjugate delivery systems exist and are currently being actively tested in the setting of SCLC. These include antibody-drug conjugates (ADCs), radioimmunoconjugates (RICs), small molecule-drug conjugates (SMDCs), and polymer-drug conjugates (PDCs). We summarize the basis of action for these targeting compounds, discussing principles of construction and providing examples of effective versus ineffective compounds, as established by preclinical and clinical testing. Such agents may offer new therapeutic options for the clinical management of this challenging disease in the future. Full article
(This article belongs to the Special Issue Targeted Therapy for Small Cell Lung Cancer)
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15 pages, 1420 KiB  
Review
Targeting DNA Replication Stress and DNA Double-Strand Break Repair for Optimizing SCLC Treatment
by Xing Bian and Wenchu Lin
Cancers 2019, 11(9), 1289; https://doi.org/10.3390/cancers11091289 - 2 Sep 2019
Cited by 11 | Viewed by 3847
Abstract
Small cell lung cancer (SCLC), accounting for about 15% of all cases of lung cancer worldwide, is the most lethal form of lung cancer. Despite an initially high response rate of SCLC to standard treatment, almost all patients are invariably relapsed within one [...] Read more.
Small cell lung cancer (SCLC), accounting for about 15% of all cases of lung cancer worldwide, is the most lethal form of lung cancer. Despite an initially high response rate of SCLC to standard treatment, almost all patients are invariably relapsed within one year. Effective therapeutic strategies are urgently needed to improve clinical outcomes. Replication stress is a hallmark of SCLC due to several intrinsic factors. As a consequence, constitutive activation of the replication stress response (RSR) pathway and DNA damage repair system is involved in counteracting this genotoxic stress. Therefore, therapeutic targeting of such RSR and DNA damage repair pathways will be likely to kill SCLC cells preferentially and may be exploited in improving chemotherapeutic efficiency through interfering with DNA replication to exert their functions. Here, we summarize potentially valuable targets involved in the RSR and DNA damage repair pathways, rationales for targeting them in SCLC treatment and ongoing clinical trials, as well as possible predictive biomarkers for patient selection in the management of SCLC. Full article
(This article belongs to the Special Issue Targeted Therapy for Small Cell Lung Cancer)
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33 pages, 2447 KiB  
Review
Future Options of Molecular-Targeted Therapy in Small Cell Lung Cancer
by Arik Bernard Schulze, Georg Evers, Andrea Kerkhoff, Michael Mohr, Christoph Schliemann, Wolfgang E. Berdel and Lars Henning Schmidt
Cancers 2019, 11(5), 690; https://doi.org/10.3390/cancers11050690 - 17 May 2019
Cited by 54 | Viewed by 9217
Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. With a focus on histology, there are two major subtypes: Non-small cell lung cancer (NSCLC) (the more frequent subtype), and small cell lung cancer (SCLC) (the more aggressive one). Even though SCLC, in [...] Read more.
Lung cancer is the leading cause of cancer-related deaths worldwide. With a focus on histology, there are two major subtypes: Non-small cell lung cancer (NSCLC) (the more frequent subtype), and small cell lung cancer (SCLC) (the more aggressive one). Even though SCLC, in general, is a chemosensitive malignancy, relapses following induction therapy are frequent. The standard of care treatment of SCLC consists of platinum-based chemotherapy in combination with etoposide that is subsequently enhanced by PD-L1-inhibiting atezolizumab in the extensive-stage disease, as the addition of immune-checkpoint inhibition yielded improved overall survival. Although there are promising molecular pathways with potential therapeutic impacts, targeted therapies are still not an integral part of routine treatment. Against this background, we evaluated current literature for potential new molecular candidates such as surface markers (e.g., DLL3, TROP-2 or CD56), apoptotic factors (e.g., BCL-2, BET), genetic alterations (e.g., CREBBP, NOTCH or PTEN) or vascular markers (e.g., VEGF, FGFR1 or CD13). Apart from these factors, the application of so-called ‘poly-(ADP)-ribose polymerases’ (PARP) inhibitors can influence tumor repair mechanisms and thus offer new perspectives for future treatment. Another promising therapeutic concept is the inhibition of ‘enhancer of zeste homolog 2’ (EZH2) in the loss of function of tumor suppressors or amplification of (proto-) oncogenes. Considering the poor prognosis of SCLC patients, new molecular pathways require further investigation to augment our therapeutic armamentarium in the future. Full article
(This article belongs to the Special Issue Targeted Therapy for Small Cell Lung Cancer)
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