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Emerging Targets and Therapeutic Strategies in Cancer

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell and Gene Therapy".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 20693

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Special Issue Editors

Prof. Dr. Shams Tabrez

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Guest Editor

1. King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia 2. Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
Interests: cancer chemoprevention; nanomedicine; metabolomics

Dr. Mohammad Imran Khan

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Guest Editor

Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
Interests: epigenetics; metabolomics; cellular Signaling

Dr. Aamir Ahmad

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Guest Editor

Interim Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
Interests: cancer; metastasis; drug resistance; miRNA
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The emergence of information related to cancer genomes have extended our knowledge towards the altered genes patterns across different cancer types, and enabled a wide array of opportunities to develop new therapeutic strategies. However, the function of these mutated or altered alleles still remain mysterious. Therefore, genomic characterization of cancer fails to provide a comprehensive remission for most patients. Putting this forward, the current research efforts to understand the function and circuitry of cancer associated genes and their patterns provide an alternative approach for elucidating both oncogene and non-oncogene dependencies of cancer. Also, the scientific approach for therapeutic targets engendered by non-oncogene dependencies is much larger than the list of recurrently mutated genes.

Owing this in mind, we propose to have a special issue which encompasses a wide range of articles related to emerging targets and therapeutics in cancer. The issue will entertain articles that will help in identification of new targets and emerging therapeutics relevant to these fields:

Emerging Targets

Metabolic vulnerabilities
Cancer cell plasticity
Tumor Microenvironment

Emerging Therapeutics

Nanomedicine
Epigenetics and Epitranscriptomics

The articles of the proposed special issue will provide a clear understanding about the targets and therapeutics, are needed for successful management of various cancer types and holds promise to provide robust and durable outcomes.

Prof. Dr. Shams Tabrez
Dr. Mohammad Imran Khan
Dr. Aamir Ahmad
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. Cells 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 2700 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

cancer chemoprevention
nanomedicine
epigenetics
natural compounds
interleukins

Published Papers (6 papers)

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Research

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19 pages, 3359 KiB

Open AccessArticle

Mediating EGFR-TKI Resistance by VEGF/VEGFR Autocrine Pathway in Non-Small Cell Lung Cancer

by Chike Osude, Leo Lin, Meet Patel, Adam Eckburg, Joseph Berei, Adijan Kuckovic, Namrata Dube, Aayush Rastogi, Shruti Gautam, Thomas J. Smith, Shylendra B. Sreenivassappa and Neelu Puri

Cells 2022, 11(10), 1694; https://doi.org/10.3390/cells11101694 - 19 May 2022

Cited by 18 | Viewed by 2833

Abstract

NSCLC treatment includes targeting of EGFR with tyrosine kinase inhibitors (TKIs) such as Erlotinib; however, resistance to TKIs is commonly acquired through T790M EGFR mutations or overexpression of vascular endothelial growth factor receptor-2 (VEGFR-2). We investigated the mechanisms of EGFR-TKI resistance in NSCLC cell lines with EGFR mutations or acquired resistance to Erlotinib. These studies showed upregulated gene and protein expression of VEGF, VEGFR-2, and a VEGF co-receptor neuropilin-1 (NP-1) in Erlotinib-resistant (1.4–5.3-fold) and EGFR double-mutant (L858R and T790M; 4.1–8.3-fold) NSCLC cells compared to parental and EGFR single-mutant (L858R) NSCLC cell lines, respectively. Immunofluorescence and FACS analysis revealed increased expression of VEGFR-2 and NP-1 in EGFR-TKI-resistant cell lines compared to TKI-sensitive cell lines. Cell proliferation assays showed that treatment with a VEGFR-2 inhibitor combined with Erlotinib lowered cell survival in EGFR double-mutant NSCLC cells to 9% compared to 72% after treatment with Erlotinib alone. Furthermore, Kaplan–Meier analysis revealed shorter median survival in late-stage NSCLC patients with high vs. low VEGFR-2 expression (14 mos vs. 21 mos). The results indicate that VEGFR-2 may play a key role in EGFR-TKI resistance and that combined treatment of Erlotinib with a VEGFR-2 inhibitor may serve as an effective therapy in NSCLC patients with EGFR mutations. Full article

(This article belongs to the Special Issue Emerging Targets and Therapeutic Strategies in Cancer)

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19 pages, 5283 KiB

Open AccessArticle

Quantification of EGFR-HER2 Heterodimers in HER2-Overexpressing Breast Cancer Cells Using Liquid-Phase Electron Microscopy

by Diana B. Peckys, Daniel Gaa and Niels de Jonge

Cells 2021, 10(11), 3244; https://doi.org/10.3390/cells10113244 - 19 Nov 2021

Cited by 4 | Viewed by 2923

Abstract

Currently, breast cancer patients are classified uniquely according to the expression level of hormone receptors, and human epidermal growth factor receptor 2 (HER2). This coarse classification is insufficient to capture the phenotypic complexity and heterogeneity of the disease. A methodology was developed for absolute quantification of receptor surface density ρ_R, and molecular interaction (dimerization), as well as the associated heterogeneities, of HER2 and its family member, the epidermal growth factor receptor (EGFR) in the plasma membrane of HER2 overexpressing breast cancer cells. Quantitative, correlative light microscopy (LM) and liquid-phase electron microscopy (LPEM) were combined with quantum dot (QD) labeling. Single-molecule position data of receptors were obtained from scanning transmission electron microscopy (STEM) images of intact cancer cells. Over 280,000 receptor positions were detected and statistically analyzed. An important finding was the subcellular heterogeneity in heterodimer shares with respect to plasma membrane regions with different dynamic properties. Deriving quantitative information about EGFR and HER2 ρ_R, as well as their dimer percentages, and the heterogeneities thereof, in single cancer cells, is potentially relevant for early identification of patients with HER2 overexpressing tumors comprising an enhanced share of EGFR dimers, likely increasing the risk for drug resistance, and thus requiring additional targeted therapeutic strategies. Full article

(This article belongs to the Special Issue Emerging Targets and Therapeutic Strategies in Cancer)

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Graphical abstract

14 pages, 22230 KiB

Open AccessArticle

The Platelet-Activating Factor Receptor’s Association with the Outcome of Ovarian Cancer Patients and Its Experimental Inhibition by Rupatadine

by Eileen Deuster, Ivi Hysenaj, Maja Kahaly, Elisa Schmoeckel, Doris Mayr, Susanne Beyer, Thomas Kolben, Anna Hester, Fabian Kraus, Anca Chelariu-Raicu, Alexander Burges, Sven Mahner, Udo Jeschke, Fabian Trillsch and Bastian Czogalla

Cells 2021, 10(9), 2337; https://doi.org/10.3390/cells10092337 - 7 Sep 2021

Cited by 4 | Viewed by 2154

Abstract

The platelet-activating factor receptor (PAFR) and its ligand (PAF) are important inflammatory mediators that are overexpressed in ovarian cancer. The receptor is an important player in ovarian cancer development. In this study, we aimed to evaluate the prognostic value of PAFR in epithelial ovarian cancer (EOC) and the potential use of its antagonist, rupatadine, as an experimental treatment. Tissue microarrays of ovarian cancer patients, most markedly those with a non-mucinous subtype, immunohistochemically overexpressed PAFR. Elevated cytoplasmic PAFR expression was found to significantly and independently impair patients’ overall and recurrence-free survival (OS: median 83.48 vs. 155.03 months; p = 0.022; RFS: median 164.46 vs. 78.03 months; p = 0.015). In vitro, the serous ovarian cancer subtypes especially displayed an elevated PAFR gene and protein expression. siRNA knockdown of PAFR decreased cell proliferation significantly, thus confirming the receptor’s protumorigenic effect on ovarian cancer cells. The clinically approved PAFR antagonist rupatadine effectively inhibited in vitro cell proliferation and migration of ovarian cancer cells. PAFR is a prognostic marker in ovarian cancer patients and its inhibition through rupatadine may have important therapeutic implications in the therapy of ovarian cancer patients. Full article

(This article belongs to the Special Issue Emerging Targets and Therapeutic Strategies in Cancer)

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20 pages, 5729 KiB

Open AccessArticle

Omega-3 Fatty Acids DHA and EPA Reduce Bortezomib Resistance in Multiple Myeloma Cells by Promoting Glutathione Degradation

by Jing Chen, Esther A. Zaal, Celia R. Berkers, Rob Ruijtenbeek, Johan Garssen and Frank A. Redegeld

Cells 2021, 10(9), 2287; https://doi.org/10.3390/cells10092287 - 2 Sep 2021

Cited by 20 | Viewed by 5586

Abstract

Multiple myeloma (MM) is a hematological malignancy that exhibits aberrantly high levels of proteasome activity. While treatment with the proteasome inhibitor bortezomib substantially increases overall survival of MM patients, acquired drug resistance remains the main challenge for MM treatment. Using a combination treatment of docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) and bortezomib, it was demonstrated previously that pretreatment with DHA/EPA significantly increased bortezomib chemosensitivity in MM cells. In the current study, both transcriptome and metabolome analysis were performed to comprehensively evaluate the underlying mechanism. It was demonstrated that pretreating MM cells with DHA/EPA before bortezomib potently decreased the cellular glutathione (GSH) level and altered the expression of the related metabolites and key enzymes in GSH metabolism, whereas simultaneous treatment only showed minor effects on these factors, thereby suggesting the critical role of GSH degradation in overcoming bortezomib resistance in MM cells. Moreover, RNA-seq results revealed that the nuclear factor erythroid 2-related factor 2 (NRF2)-activating transcription factor 3/4 (ATF3/4)-ChaC glutathione specific gamma-glutamylcyclotransferase 1 (CHAC1) signaling pathway may be implicated as the central player in the GSH degradation. Pathways of necroptosis, ferroptosis, p53, NRF2, ATF4, WNT, MAPK, NF-κB, EGFR, and ERK may be connected to the tumor suppressive effect caused by pretreatment of DHA/EPA prior to bortezomib. Collectively, this work implicates GSH degradation as a potential therapeutic target in MM and provides novel mechanistic insights into its significant role in combating bortezomib resistance. Full article

(This article belongs to the Special Issue Emerging Targets and Therapeutic Strategies in Cancer)

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Review

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11 pages, 1663 KiB

Open AccessReview

Inosine Triphosphate Pyrophosphatase (ITPase): Functions, Mutations, Polymorphisms and Its Impact on Cancer Therapies

by Mazin A. Zamzami

Cells 2022, 11(3), 384; https://doi.org/10.3390/cells11030384 - 24 Jan 2022

Cited by 4 | Viewed by 2926

Abstract

Inosine triphosphate pyrophosphatase (ITPase) is an enzyme encoded by the ITPA gene and functions to prevent the incorporation of noncanonical purine nucleotides into DNA and RNA. Specifically, the ITPase catalyzed the hydrolysis of (deoxy) nucleoside triphosphates ((d) NTPs) into the corresponding nucleoside monophosphate with the concomitant release of pyrophosphate. Recently, thiopurine drug metabolites such as azathioprine have been included in the lists of ITPase substrates. Interestingly, inosine or xanthosine triphosphate (ITP/XTP) and their deoxy analogs, deoxy inosine or xanthosine triphosphate (dITP/dXTP), are products of important biological reactions such as deamination that take place within the cellular compartments. However, the incorporation of ITP/XTP, dITP/dXTP, or the genetic deficiency or polymorphism of the ITPA gene have been implicated in many human diseases, including infantile epileptic encephalopathy, early onset of tuberculosis, and the responsiveness of patients to cancer therapy. This review provides an up-to-date report on the ITPase enzyme, including information regarding its discovery, analysis, and cellular localization, its implication in human diseases including cancer, and its therapeutic potential, amongst others. Full article

(This article belongs to the Special Issue Emerging Targets and Therapeutic Strategies in Cancer)

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19 pages, 7538 KiB

Open AccessReview

Role and Involvement of TENM4 and miR-708 in Breast Cancer Development and Therapy

by Giulia Peppino, Federica Riccardo, Maddalena Arigoni, Elisabetta Bolli, Giuseppina Barutello, Federica Cavallo and Elena Quaglino

Cells 2022, 11(1), 172; https://doi.org/10.3390/cells11010172 - 5 Jan 2022

Cited by 4 | Viewed by 2990

Abstract

Teneurin 4 (TENM4) is a transmembrane protein that is codified by the ODZ4 gene and is involved in nervous system development, neurite outgrowth, and neuronal differentiation. In line with its involvement in the nervous system, TENM4 has also been implicated in several mental disorders such as bipolar disorder, schizophrenia, and autism. TENM4 mutations and rearrangements have recently been identified in a number of tumors. This, combined with impaired expression in tumors, suggests that it may potentially be involved in tumorigenesis. Most of the TENM4 mutations that are observed in tumors occur in breast cancer, in which TENM4 plays a role in cells’ migration and stemness. However, the functional role that TENM4 plays in breast cancer still needs to be better evaluated, and further studies are required to better understand the involvement of TENM4 in breast cancer progression. Herein, we review the currently available data for TENM4′s role in breast cancer and propose its use as both a novel target with which to ameliorate patient prognosis and as a potential biomarker. Moreover, we also report data on the tumorigenic role of miR-708 deregulation and the possible use of this miRNA as a novel therapeutic molecule, as miR-708 is spliced out from TENM4 mRNA. Full article

(This article belongs to the Special Issue Emerging Targets and Therapeutic Strategies in Cancer)

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