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Targeted Cancer Therapy: Targeting Tyrosine/Serine Kinases by Small Molecule Inhibitors, Immune Modulators, and Monoclonal Antibodies

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

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 31119

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Special Issue Editors

Dr. Mohammad Hojjat-Farsangi

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Guest Editor

Department of Oncology-Pathology, Karolinska Institute and Karolinska University Hospital Solna, BioClinicum, 17164, Solnavagen 30, Solna, Stockholm, Sweden
Interests: targeted cancer therapy; tyrosine kinase inhibitors; small molecule inhibitors; apoptosis; monoclonal antibodies; immunomodulators; leukemia; lymphoma; acquired drug resistance; intracellular signaling
Special Issues, Collections and Topics in MDPI journals

Dr. Afshin Namdar

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Cross Cancer Institute, Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada

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Dear Colleagues,

Cancer is still an incurable disease and remains one of the main reasons of death. Several conventional methods as chemotherapy, surgery, and radiotherapy have been the main common anti-cancer therapeutic approaches for decades. However, these methods are non-specific, with a range of side effects. Targeted cancer therapy (TCT) agents and methods have revolutionized cancer treatment. Monoclonal antibodies (mAbs) and small molecule inhibitors (SMIs) are among the most effective agents of TCT. These natural or synthetic chemicals have improved the survival of cancer patients with fewer side effects than conventional methods; however, resistance has subdued the effects. Several mechanisms induce cancer drug resistance such as the resistance of cancer stem cells to different drugs, mutations in the drug targets, and the activation of compensatory intracellular pathways. Preventing drug resistance is important to increase the efficiency of cancer treatment. Therefore, new drugs or optimized treatment regimens are necessary. The success of new and efficient TCT agents such as mAbs, SMIs, and immunomodulatory agents has sparked further therapeutic modalities with new targets to inhibit.

This Special Issue of Cancers therefore encompasses new research articles and timely reviews on small molecule inhibitors, immune modulators, and monoclonal antibodies in human cancer.

Dr. Mohammad Hojjat-Farsangi
Dr. Afshin Namdar
Guest Editors

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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 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

tyrosine/serine kinases
receptor tyrosine kinases
cancer
targeted cancer therapy
kinase inhibitors
tyrosine kinase inhibitors
small molecule inhibitors
apoptosis
monoclonal antibodies
leukemia
lymphoma
acquired drug resistance

Published Papers (9 papers)

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Research

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19 pages, 5951 KiB

Open AccessArticle

Midostaurin Modulates Tumor Microenvironment and Enhances Efficacy of Anti-PD-1 against Colon Cancer

by Cheng-Ta Lai, Chih-Wen Chi, Shu-Hua Wu, Hui-Ru Shieh, Jiin-Cherng Yen and Yu-Jen Chen

Cancers 2022, 14(19), 4847; https://doi.org/10.3390/cancers14194847 - 4 Oct 2022

Cited by 9 | Viewed by 2435

Abstract

Immunotherapy modulating the tumor microenvironment (TME) immune function has a promising effect on various types of cancers, but it remains as a limited efficacy in colon cancer. Midostaurin (PKC412) has been used in the clinical treatment of fms-like tyrosine kinase 3 (FLT3)-mutant acute myeloid leukemia and has demonstrated immunomodulatory activity. We aimed to evaluate the effect of midostaurin on the modulation of TME and the efficacy of anti-programmed cell death protein 1 (PD-1) against colon cancer. Midostaurin inhibited the growth of murine CT26 and human HCT116 and SW480 cells with multinucleation and micronuclei formation in morphology examination. The cell cycle arrested in the G2/M phase and the formation of the polyploid phase was noted. The formation of cytosolic DNA, including double-strand and single-strand DNA, was increased. Midostaurin increased mRNA expressions of cGAS, IRF3, and IFNAR1 in colorectal adenocarcinoma cells and mouse spleen macrophages. The protein expressions of Trex-1, c-KIT, and Flt3, but not PKCα/β/γ and VEGFR1, were down-regulated in midostaurin-treated colorectal adenocarcinoma cells and macrophages. Trex-1 protein expression was abrogated after FLT3L activation. In vivo, the combination of midostaurin and anti-PD-1 exhibited the greatest growth inhibition on a CT26-implanted tumor without major toxicity. TME analysis demonstrated that midostaurin alone decreased Treg cells and increased neutrophils and inflammatory monocytes. NKG2D⁺ and PD-1 were suppressed and M1 macrophage was increased after combination therapy. When combined with anti-PD-1, STING and INFβ protein expression was elevated in the tumor. The oral administration of midostaurin may have the potential to enhance anti-PD-1 efficacy, accompanied by the modulation of cytosolic DNA-sensing signaling and tumor microenvironment. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy: Targeting Tyrosine/Serine Kinases by Small Molecule Inhibitors, Immune Modulators, and Monoclonal Antibodies)

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12 pages, 2405 KiB

Open AccessFeature PaperArticle

Centralised RECIST Assessment and Clinical Outcomes with Lenvatinib Monotherapy in Recurrent and Metastatic Adenoid Cystic Carcinoma

by Laura Feeney, Yatin Jain, Matthew Beasley, Oliver Donnelly, Anthony Kong, Rafael Moleron, Chandran Nallathambi, Martin Rolles, Paul Sanghera, Aung Tin, Danny Ulahannan, Harriet S. Walter, Richard Webster and Robert Metcalf

Cancers 2021, 13(17), 4336; https://doi.org/10.3390/cancers13174336 - 27 Aug 2021

Cited by 9 | Viewed by 2936

Abstract

Adenoid cystic carcinoma (ACC) is a rare cancer of secretory glands. Recurrent or metastatic (R/M) ACC is generally considered resistant to cytotoxic chemotherapy. Recent phase II studies have reported improved objective response rates (ORR) with the use of the multi-kinase inhibitor lenvatinib. We sought to evaluate real-world experience of R/M ACC patients treated with lenvatinib monotherapy within the UK National Health Service (NHS) to determine the response rates by Response Evaluation Criteria of Solid Tumour (RECIST) and clinical outcomes. Twenty-three R/M ACC patients from eleven cancer centres were included. All treatment assessments for clinical decision making related to drug therapy were undertaken at the local oncology centre. Central radiology review was performed by an independent clinical trial radiologist and blinded to the clinical decision making. In contrast to previously reported ORR of 12–15%, complete or partial response was not observed in any patients. Eleven patients (52.4%) had stable disease and 5 patients (23.8%) had progression of disease as the best overall response. The median time on treatment was 4 months and the median survival from discontinuation was 1 month. The median PFS and OS from treatment initiation were 4.5 months and 12 months respectively. Multicentre collaborative studies such as this are required to evaluate rare cancers with no recommended standard of care therapy and variable disease courses. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy: Targeting Tyrosine/Serine Kinases by Small Molecule Inhibitors, Immune Modulators, and Monoclonal Antibodies)

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20 pages, 2945 KiB

Open AccessArticle

HER2-Targeted Immunotherapy and Combined Protocols Showed Promising Antiproliferative Effects in Feline Mammary Carcinoma Cell-Based Models

by Andreia Gameiro, Catarina Nascimento, Jorge Correia and Fernando Ferreira

Cancers 2021, 13(9), 2007; https://doi.org/10.3390/cancers13092007 - 21 Apr 2021

Cited by 11 | Viewed by 3389

Abstract

Feline mammary carcinoma (FMC) is a highly prevalent tumor, showing aggressive clinicopathological features, with HER2-positive being the most frequent subtype. While, in human breast cancer, the use of anti-HER2 monoclonal antibodies (mAbs) is common, acting by blocking the extracellular domain (ECD) of the HER2 protein and by inducing cell apoptosis, scarce information is available on use these immunoagents in FMC. Thus, the antiproliferative effects of two mAbs (trastuzumab and pertuzumab), of an antibody–drug conjugate compound (T-DM1) and of combined treatments with a tyrosine kinase inhibitor (lapatinib) were evaluated on three FMC cell lines (CAT-MT, FMCm and FMCp). In parallel, the DNA sequence of the her2 ECD (subdomains II and IV) was analyzed in 40 clinical samples of FMC, in order to identify mutations, which can lead to antibody resistance or be used as prognostic biomarkers. Results obtained revealed a strong antiproliferative effect in all feline cell lines, and a synergistic response was observed when combined therapies were performed. Additionally, the mutations found were not described as inducing resistance to therapy in breast cancer patients. Altogether, our results suggested that anti-HER2 mAbs could become useful in the treatment of FMC, particularly, if combined with lapatinib, since drug-resistance seems to be rare. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy: Targeting Tyrosine/Serine Kinases by Small Molecule Inhibitors, Immune Modulators, and Monoclonal Antibodies)

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20 pages, 9475 KiB

Open AccessArticle

Inhibiting FAK–Paxillin Interaction Reduces Migration and Invadopodia-Mediated Matrix Degradation in Metastatic Melanoma Cells

by Antoine Mousson, Marlène Legrand, Tania Steffan, Romain Vauchelles, Philippe Carl, Jean-Pierre Gies, Maxime Lehmann, Guy Zuber, Jan De Mey, Denis Dujardin, Emilie Sick and Philippe Rondé

Cancers 2021, 13(8), 1871; https://doi.org/10.3390/cancers13081871 - 14 Apr 2021

Cited by 19 | Viewed by 3502

Abstract

The nonreceptor tyrosine kinase FAK is a promising target for solid tumor treatment because it promotes invasion, tumor progression, and drug resistance when overexpressed. Investigating the role of FAK in human melanoma cells, we found that both in situ and metastatic melanoma cells strongly express FAK, where it controls tumor cells’ invasiveness by regulating focal adhesion-mediated cell motility. Inhibiting FAK in human metastatic melanoma cells with either siRNA or a small inhibitor targeting the kinase domain impaired migration but led to increased invadopodia formation and extracellular matrix degradation. Using FAK mutated at Y397, we found that this unexpected increase in invadopodia activity is due to the lack of phosphorylation at this residue. To preserve FAK–Src interaction while inhibiting pro-migratory functions of FAK, we found that altering FAK–paxillin interaction, with either FAK mutation in the focal adhesion targeting (FAT) domain or a competitive inhibitor peptide mimicking paxillin LD domains drastically reduces cell migration and matrix degradation by preserving FAK activity in the cytoplasm. In conclusion, our data show that targeting FAK–paxillin interactions could be a potential therapeutic strategy to prevent metastasis formation, and molecules targeting this interface could be alternative to inhibitors of FAK kinase activity which display unexpected effects. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy: Targeting Tyrosine/Serine Kinases by Small Molecule Inhibitors, Immune Modulators, and Monoclonal Antibodies)

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15 pages, 1815 KiB

Open AccessArticle

Clinical Response to the CD95-Ligand Inhibitor Asunercept Is Defined by a Pro-Inflammatory Serum Cytokine Profile

by Aleksandar Radujkovic, Tobias Boch, Florian Nolte, Daniel Nowak, Claudia Kunz, Alexandra Gieffers, Carsten Müller-Tidow, Peter Dreger, Wolf-Karsten Hofmann and Thomas Luft

Cancers 2020, 12(12), 3683; https://doi.org/10.3390/cancers12123683 - 8 Dec 2020

Cited by 2 | Viewed by 1916

Abstract

Asunercept (APG101) is a well-tolerated CD95-ligand inhibitor that showed promising efficacy in a prospective, single-arm phase I study in anemic, transfusion-dependent patients with low and intermediate risk myelodysplastic syndrome (MDS). In this retrospective post hoc analysis, serum levels of biomarkers were measured in study patients focusing on cytokines associated with erythropoiesis, inflammation, apoptosis, bone marrow fibrosis, and inflammasome activity. Baseline serum biomarkers were correlated with treatment response, in order to propose a hypothetical responder serum profile. After an updated median follow-up of 54 months (range 7–65), response to asunercept was associated with improved overall survival (at 3-years: 67% [95%CI 36–97] versus 13% [95%CI 0–36] in responders versus non-responders, respectively). Higher baseline values of interleukin-18 (IL-18), S100 calcium-binding protein A9 (S100A9) and soluble p53 were predictive of non-response to asunercept (area under the receiver operating characteristic curve 0.79–0.82). Furthermore, non-responding patients showed a distinct, pro-inflammatory serum cytokine profile which was persistent throughout the first half of the treatment phase and appeared unaffected by asunercept. Although prospective validation is required, our post hoc analysis suggests that serum cytokine profiling based on IL-18, S100A9 and soluble p53 may represent an approach to identify and select low-risk MDS patients most likely to benefit from asunercept treatment. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy: Targeting Tyrosine/Serine Kinases by Small Molecule Inhibitors, Immune Modulators, and Monoclonal Antibodies)

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15 pages, 2059 KiB

Open AccessArticle

Exploiting GRK2 Inhibition as a Therapeutic Option in Experimental Cancer Treatment: Role of p53-Induced Mitochondrial Apoptosis

by Jessica Gambardella, Antonella Fiordelisi, Gaetano Santulli, Michele Ciccarelli, Federica Andrea Cerasuolo, Marina Sala, Eduardo Sommella, Pietro Campiglia, Maddalena Illario, Guido Iaccarino and Daniela Sorriento

Cancers 2020, 12(12), 3530; https://doi.org/10.3390/cancers12123530 - 26 Nov 2020

Cited by 5 | Viewed by 2262

Abstract

The involvement of GRK2 in cancer cell proliferation and its counter-regulation of p53 have been suggested in breast cancer even if the underlying mechanism has not yet been elucidated. Furthermore, the possibility to pharmacologically inhibit GRK2 to delay cancer cell proliferation has never been explored. We investigated this possibility by setting up a study that combined in vitro and in vivo models to underpin the crosstalk between GRK2 and p53. To reach this aim, we took advantage of the different expression of p53 in cell lines of thyroid cancer (BHT 101 expressing p53 and FRO cells, which are p53-null) in which we overexpressed or silenced GRK2. The pharmacological inhibition of GRK2 was achieved using the specific inhibitor KRX-C7. The in vivo study was performed in Balb/c nude mice, where we treated BHT-101 or FRO-derived tumors with KRX-C7. In our in vitro model, FRO cells were unaffected by GRK2 expression levels, whereas BHT-101 cells were sensitive, thus suggesting a role for p53. The regulation of p53 by GRK2 is due to phosphorylative events in Thr-55, which induce the degradation of p53. In BHT-101 cells, the pharmacologic inhibition of GRK2 by KRX-C7 increased p53 levels and activated apoptosis through the mitochondrial release of cytochrome c. These KRX-C7-mediated events were also confirmed in cancer allograft models in nude mice. In conclusion, our data showed that GRK2 counter-regulates p53 expression in cancer cells through a kinase-dependent activity. Our results further corroborate the anti-proliferative role of GRK2 inhibitors in p53-sensitive tumors and propose GRK2 as a therapeutic target in selected cancers. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy: Targeting Tyrosine/Serine Kinases by Small Molecule Inhibitors, Immune Modulators, and Monoclonal Antibodies)

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18 pages, 2937 KiB

Open AccessArticle

Dual Targeting of Endothelial and Cancer Cells Potentiates In Vitro Nanobody-Targeted Photodynamic Therapy

by Vida Mashayekhi, Katerina T. Xenaki, Paul M.P. van Bergen en Henegouwen and Sabrina Oliveira

Cancers 2020, 12(10), 2732; https://doi.org/10.3390/cancers12102732 - 23 Sep 2020

Cited by 13 | Viewed by 3053

Abstract

Photodynamic therapy (PDT) induces cell death through local light activation of a photosensitizer, although sub-optimal tumor specificity and side effects have hindered its clinical application. We introduced a new strategy named nanobody-targeted PDT in which photosensitizers are delivered to tumor cells by means of nanobodies. As efficacy of targeted PDT can be hampered by heterogeneity of target expression and/or moderate/low target expression levels, we explored the possibility of combined targeting of endothelial and cancer cells in vitro. We developed nanobodies binding to the mouse VEGFR2, which is overexpressed on tumor vasculature, and combined these with nanobodies specific for the cancer cell target EGFR. The nanobodies were conjugated to the photosensitizer IRDye700DX and specificity of the newly developed nanobodies was verified using several endothelial cell lines. The cytotoxicity of these conjugates was assessed in monocultures and in co-cultures with cancer cells, after illumination with an appropriate laser. The results show that the anti-VEGFR2 conjugates are specific and potent PDT agents. Nanobody-targeted PDT on co-culture of endothelial and cancer cells showed improved efficacy, when VEGFR2 and EGFR targeting nanobodies were applied simultaneously. Altogether, dual targeting of endothelial and cancer cells is a promising novel therapeutic strategy for more effective nanobody-targeted PDT. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy: Targeting Tyrosine/Serine Kinases by Small Molecule Inhibitors, Immune Modulators, and Monoclonal Antibodies)

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Review

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25 pages, 6772 KiB

Open AccessEditor’s ChoiceReview

Cancer-Associated Fibroblast Functions as a Road-Block in Cancer Therapy

by Pradip De, Jennifer Aske and Nandini Dey

Cancers 2021, 13(20), 5246; https://doi.org/10.3390/cancers13205246 - 19 Oct 2021

Cited by 23 | Viewed by 4382

Abstract

The journey of a normal resident fibroblast belonging to the tumor microenvironment (TME) from being a tumor pacifier to a tumor patron is fascinating. We introduce cancer-associated fibroblast (CAF) as a crucial component of the TME. Activated-CAF partners with tumor cells and all components of TME in an established solid tumor. We briefly overview the origin, activation, markers, and overall functions of CAF with a particular reference to how different functions of CAF in an established tumor are functionally connected to the development of resistance to cancer therapy in solid tumors. We interrogate the role of CAF in mediating resistance to different modes of therapies. Functional diversity of CAF in orchestrating treatment resistance in solid tumors portrays CAF as a common orchestrator of treatment resistance; a roadblock in cancer therapy Full article

(This article belongs to the Special Issue Targeted Cancer Therapy: Targeting Tyrosine/Serine Kinases by Small Molecule Inhibitors, Immune Modulators, and Monoclonal Antibodies)

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24 pages, 1682 KiB

Open AccessReview

Untwining Anti-Tumor and Immunosuppressive Effects of JAK Inhibitors—A Strategy for Hematological Malignancies?

by Klara Klein, Dagmar Stoiber, Veronika Sexl and Agnieszka Witalisz-Siepracka

Cancers 2021, 13(11), 2611; https://doi.org/10.3390/cancers13112611 - 26 May 2021

Cited by 14 | Viewed by 6060

Abstract

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway propagates signals from a variety of cytokines, contributing to cellular responses in health and disease. Gain of function mutations in JAKs or STATs are associated with malignancies, with JAK2^V617F being the main driver mutation in myeloproliferative neoplasms (MPN). Therefore, inhibition of this pathway is an attractive therapeutic strategy for different types of cancer. Numerous JAK inhibitors (JAKinibs) have entered clinical trials, including the JAK1/2 inhibitor Ruxolitinib approved for the treatment of MPN. Importantly, loss of function mutations in JAK-STAT members are a cause of immune suppression or deficiencies. MPN patients undergoing Ruxolitinib treatment are more susceptible to infections and secondary malignancies. This highlights the suppressive effects of JAKinibs on immune responses, which renders them successful in the treatment of autoimmune diseases but potentially detrimental for cancer patients. Here, we review the current knowledge on the effects of JAKinibs on immune cells in the context of hematological malignancies. Furthermore, we discuss the potential use of JAKinibs for the treatment of diseases in which lymphocytes are the source of malignancies. In summary, this review underlines the necessity of a robust immune profiling to provide the best benefit for JAKinib-treated patients. Full article

(This article belongs to the Special Issue Targeted Cancer Therapy: Targeting Tyrosine/Serine Kinases by Small Molecule Inhibitors, Immune Modulators, and Monoclonal Antibodies)

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