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Cancers
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Molecular Pharmacology of Anti-Cancer Drugs
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Molecular Pharmacology of Anti-Cancer Drugs

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

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 11626

Special Issue Editor

Prof. Dr. Robert Mader

E-Mail Website
Guest Editor
Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, 1090 Vienna, Austria
Interests: drug resistance; predictive biomarkers; gastrointestinal and breast neoplasms; exosomes; microRNA; molecular biology

Special Issue Information

Dear Colleagues,

The way we treat cancer has changed fundamentally in the last decade. This process was driven by two principal components: understanding and linking disease biology to cancer pharmacology and accelerated drug development yielding a dozen innovative cancer drugs each year.

Quickly after introducing comprehensive analytical methods such as gene expression arrays, pharmacological investigations moved their focus from isolated targets to pathway approaches followed by the application of systems biology to network pharmacology, which is still in its infancy. Figuring out what an inhibitor does in a cellular context paves the way for genetic engineering of molecular animal models often directly translated in human trials.

Understanding cancer’s response considering the individual aberrant genetic background yields actual information for precision medicine. Exploring the copying mechanisms of the malignancy after exposure to treatments provides hints about compensatory strategies resulting in drug resistance, but also how to tackle the Achilles heel of cancer progression.

These are exciting times in molecular pharmacology, whose contribution to cancer treatment increases from year to year. This Special Edition will cover hot topics in this area, explain how far we have gone in a few years, and provide a glimpse of the future of our discipline.

Prof. Dr. Robert Mader
Guest Editor

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

  • molecular pharmacology
  • precision medicine
  • druggable genes
  • signal inhibition
  • non-coding RNA
  • exosomes
  • stress tolerance
  • drug resistance
  • network pharmacology
  • predictive biomarkers

Published Papers (4 papers)

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Research

18 pages, 2672 KiB  
Article
Application of mTORC1 Inhibitors for Tissue-Agnostic Management of Standard-Therapy-Refractory Solid Tumors
by Hossein Taghizadeh, Agnieszka Maj-Hes, Gerald W. Prager, Leonhard Müllauer and Robert M. Mader
Cancers 2022, 14(8), 1936; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14081936 - 12 Apr 2022
Cited by 1 | Viewed by 1523
Abstract
In this analysis, we examined the efficacy, feasibility, and limitations of the application of mTOR inhibitors based on the individual molecular profiles of pretreated cancer patients after the failure of all standard treatments in the palliative setting. In this single-center, real-world analysis of [...] Read more.
In this analysis, we examined the efficacy, feasibility, and limitations of the application of mTOR inhibitors based on the individual molecular profiles of pretreated cancer patients after the failure of all standard treatments in the palliative setting. In this single-center, real-world analysis of our platform for precision medicine, we analyzed the molecular characteristics of 71 cancer patients. The tumor samples of the patients were analyzed using next-generation sequencing panels of mutation hotspots, microsatellite stability testing, and immunohistochemistry. All profiles were reviewed by a multidisciplinary team to provide a targeted treatment recommendation after a consensus discussion. Seventy-one cancer patients with activation of the mTOR pathway were offered an mTORC1-inhibitor-based targeted therapy, and twenty-three (32.4%) of them eventually received the targeted therapy. Only three patients (4.2%) achieved stable disease, of whom one experienced progressive disease again after 9.1 months. The median time to treatment failure was 2.8 months. In total, 110 mutations were detected in 60 patients (84.5%). The three most frequent mutations were found in TP53, PTEN, and KRAS, which accounted for over 50% (56.4%) of all mutations. In sum, in selected patients with heavily pretreated solid tumors with activation of the mTOR pathway, the antitumoral activity of mTORC1 inhibition was weak. Full article
(This article belongs to the Special Issue Molecular Pharmacology of Anti-Cancer Drugs)
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15 pages, 2557 KiB  
Article
miR-1227 Targets SEC23A to Regulate the Shedding of Large Extracellular Vesicles
by Andrew Chin, Javier Mariscal, Minhyung Kim, Giorgia Guerra, Blandine Victor, Chen Qian, Elisabetta Broseghini, Edwin Posadas, Michael R. Freeman, Shivani Sharma, Paolo Gandellini, Nadia Zaffaroni, Sungyong You, Keith Syson Chan, Jlenia Guarnerio, Muller Fabbri and Dolores Di Vizio
Cancers 2021, 13(22), 5850; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225850 - 22 Nov 2021
Cited by 3 | Viewed by 2404
Abstract
Cancer cells shed a heterogenous mixture of extracellular vesicles (EVs), differing in both size and composition, which likely influence physiological processes in different manners. However, how cells differentially control the shedding of these EV populations is poorly understood. Here, we show that miR-1227, [...] Read more.
Cancer cells shed a heterogenous mixture of extracellular vesicles (EVs), differing in both size and composition, which likely influence physiological processes in different manners. However, how cells differentially control the shedding of these EV populations is poorly understood. Here, we show that miR-1227, which is enriched in prostate cancer EVs, compared to the cell of origin, but not in EVs derived from prostate benign epithelial cells, induces the shedding of large EVs (such as large oncosomes), while inhibiting the shedding of small EVs (such as exosomes). RNA sequencing from cells stably expressing miR-1227, a modified RISCTRAP assay that stabilizes and purifies mRNA-miR-1227 complexes for RNA sequencing, and in silico target prediction tools were used to identify miR-1227 targets that may mediate this alteration in EV shedding. The COPII vesicle protein SEC23A emerged and was validated by qPCR, WBlot, and luciferase assays as a direct target of miR-1227. The inhibition of SEC23A was sufficient to induce the shedding of large EVs. These results identify a novel mechanism of EV shedding, by which the inhibition of SEC23A by miR-1227 induces a shift in EV shedding, favoring the shedding of large EV over small EV. Full article
(This article belongs to the Special Issue Molecular Pharmacology of Anti-Cancer Drugs)
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21 pages, 8608 KiB  
Article
Dual Targeting of EGFR with PLK1 Exerts Therapeutic Synergism in Taxane-Resistant Lung Adenocarcinoma by Suppressing ABC Transporters
by Sol-Bi Shin, Dae-Hoon Kim, Da-Eun Kim, Mark Borris D. Aldonza, Yoosik Kim and Hyungshin Yim
Cancers 2021, 13(17), 4413; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13174413 - 01 Sep 2021
Cited by 4 | Viewed by 3371
Abstract
To overcome the limitations of chemoresistance, combination therapies using druggable targets have been investigated. Our previous studies led us to hypothesize that the downregulation of PLK1 expression or activity can be one strategy to overcome the hurdles of taxane resistance by the downregulation [...] Read more.
To overcome the limitations of chemoresistance, combination therapies using druggable targets have been investigated. Our previous studies led us to hypothesize that the downregulation of PLK1 expression or activity can be one strategy to overcome the hurdles of taxane resistance by the downregulation of ABC transporters. To explore this, various versions of PLK1 including a constitutively active version, kinase-dead form, and polo-box domain mutant were expressed in paclitaxel-resistant lung adenocarcinoma (LUADTXR). Targeting PLK1 using shRNA or non-functional mutants downregulated ABCB1, ABCC9, and ABCG2 in LUADTXR cells, which was similar to the downregulation effects from treatment with PLK1 inhibitors. The high expression of EGFR in LUAD led us to administer gefitinib, showing a markedly reduced EGFR level in LUADTXR cells. When gefitinib and PLK1 inhibitors were combined, LUADTXR cells tended to undergo apoptosis more effectively than parental cells, showing a synergistic effect on the downregulation of ABC transporters through c-Myc and AP-1. Clinical data provide evidence for the relevance between survival rates and expressions of PLK1 and EGFR in LUAD patients. Based on these results, we suggest that a combination of gefitinib and PLK1 inhibitors exerts strong synergism in LUADTXR, which helps to overcome the limitations associated with taxanes. Full article
(This article belongs to the Special Issue Molecular Pharmacology of Anti-Cancer Drugs)
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27 pages, 12032 KiB  
Article
Effect of Pterostilbene, a Natural Derivative of Resveratrol, in the Treatment of Colorectal Cancer through Top1/Tdp1-Mediated DNA Repair Pathway
by Yutian Zhang, Ying Li, Changcheng Sun, Xiang Chen, Luyao Han, Tingqiang Wang, Jinfeng Liu, Xijing Chen and Di Zhao
Cancers 2021, 13(16), 4002; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164002 - 09 Aug 2021
Cited by 19 | Viewed by 3073
Abstract
Topoisomerase 1 (Top1) inhibitor is an effective anticancer drug, but several factors limit its clinical application such as drug inactivation, tyrosyl-DNA phosphodiesterase 1 (Tdp1)-mediated tumor drug resistance, and its toxicity. Our previous study identified pterostilbene (PTE) and resveratrol (RE) to suppress these two [...] Read more.
Topoisomerase 1 (Top1) inhibitor is an effective anticancer drug, but several factors limit its clinical application such as drug inactivation, tyrosyl-DNA phosphodiesterase 1 (Tdp1)-mediated tumor drug resistance, and its toxicity. Our previous study identified pterostilbene (PTE) and resveratrol (RE) to suppress these two proteins by binding to their active center. PTE and RE could inhibit the proliferation of various colorectal cancer cells, induce cell apoptosis, and make cell cycle stay in G2/M phase in vitro. PTE and RE could decrease Top1 and Tdp1 contents and mRNA expression in wild-type, constructed Tdp1 overexpressing CL187, Top1- or Tdp1- silenced CL187 cell lines. PTE exhibited excellent antitumor activity in subcutaneous CL187 transplantation model (TGI = 79.14 ± 2.85%, 200 mg/kg, i.p.) and orthotopic transplantation model (TGI = 76.57 ± 6.34%, 100 mg/kg, i.p.; TGI = 72.79 ± 4.06%, 500 mg/kg, i.g.) without significant toxicity. PTE had no significant inhibitory effect on non-tumor cell proliferation in vitro and would not induce damage to liver, kidney, and other major organs. Overall, PTE and RE can inhibit the activity of Top1 enzyme and inhibit the DNA damage repair pathway mediated by Top1/Tdp1, and can effectively inhibit colorectal cancer development with low toxicity, thus they have great potential to be developed into a new generation of anti-tumor drugs. Full article
(This article belongs to the Special Issue Molecular Pharmacology of Anti-Cancer Drugs)
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