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Cancers
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Targeting the (Un)Usual Suspects in Cancer
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Targeting the (Un)Usual Suspects in Cancer

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

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 30193

Special Issue Editors

Dr. Valerio Costa

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Guest Editor
Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", IGB-CNR, 80131 Naples, Italy
Interests: PPARG; adipose tissue; obesity; gene expression; alternative splicing
Special Issues, Collections and Topics in MDPI journals
Dr. Elisa Giovannetti

E-Mail Website
Guest Editor
Department of Medical Oncology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
Interests: pharmacology; drug resistance; pharmacogenetics; predictive biomarkers; liquid biopsies; preclinical models; pancreatic cancer; NSCLC; mesothelioma
Special Issues, Collections and Topics in MDPI journals
Dr. Enza Lonardo

E-Mail Website
Guest Editor
Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’ (IGB), CNR, Via Pietro Castellino 111, 80131 Naples, Italy
Interests: 3D cancer models; pancreatic cancer; colorectal cancer; tumor microenvironment; TGFb
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Since the launch of the "war on cancer" 50 years ago with the US National Cancer Act, several therapeutic strategies promoting cancer cell death have been developed, and a wide range of cancer treatments is now available. However, most of the conventional treatments do not selectively kill tumor cells, and others suffer from tumor cells' heterogeneity, which makes it challenging to identify the appropriate targets.

In this scenario, the identification of new drugs or drug combinations targeting well-known signaling pathways, as well as the repurposing of approved drugs showing previously unexplored anti-tumor activities, can provide a renewed spectrum of therapeutic options in oncology. Moreover, it has been demonstrated that for some tumors (such as colorectal and pancreatic cancer) even highly selective therapies do not completely eradicate the disease, as they do not target the niche of cancer stem cells able to reconstitute and perpetuate the malignancy. Hence, targeting pathways that are unique to cancer stem cells’ maintenance and disrupting the crosstalk between tumor cells and the microenvironment represent fundamental approaches in the “war on cancer”.

The list of tumor hallmarks and of cancer-causing culprits has been updated in the last decade, including new cellular processes (i.e., metabolism) and molecular factors (i.e., non-coding RNAs) as relevant contributors to tumor onset, progression, and drug sensitivity. Indeed, despite metabolic alterations being reported about a century ago, the strategy of targeting tumor metabolism has become a topic of renewed interest. Likewise, growing evidence indicates a previously unrecognized role for long non-coding RNAs (lncRNAs) as oncogenes and tumor suppressors by means of their ability to regulate each and every cancer hallmark. These findings, and especially the cancer-specific expression of most of them, established the rationale for assessing lncRNAs as therapeutic targets, as their silencing would not cause side effects on other tissues/cell types.

This Special Issue will collect original articles and reviews about well-established and innovative approaches to target:

  • oncogenic signaling pathways;
  • cancer stem cells;
  • metabolic reprogramming;
  • long non-coding RNAs.

The Special Issue will comprise, among the others, selected papers from the proceedings of the 29th IGB Workshop: Targeting the (un)usual suspects in cancer (https://29thigbworkshop.sciforum.net/) 2–3 December, 2021.

Dr. Valerio Costa
Dr. Elisa Giovannetti
Dr. Enza Lonardo
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

  • oncogenic signaling pathways
  • cancer stem cells
  • metabolic reprogramming
  • long non-coding RNAs

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Published Papers (7 papers)

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Editorial

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4 pages, 183 KiB  
Editorial
Revolutionizing Cancer Treatment: Unveiling New Frontiers by Targeting the (Un)Usual Suspects
by Valerio Costa, Elisa Giovannetti and Enza Lonardo
Cancers 2024, 16(1), 132; https://doi.org/10.3390/cancers16010132 - 27 Dec 2023
Viewed by 1128
Abstract
This Special Issue includes original articles and reviews on both established and innovative approaches to cancer targeting, showcased at the 29th IGB Workshop titled “Targeting the (un)usual suspects in cancer” “https://29thigbworkshop [...] Full article
(This article belongs to the Special Issue Targeting the (Un)Usual Suspects in Cancer)

Research

Jump to: Editorial, Review

21 pages, 1961 KiB  
Article
Prognostic Significance of Integrin Subunit Alpha 2 (ITGA2) and Role of Mechanical Cues in Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma (PDAC)
by Alessandro Gregori, Cecilia Bergonzini, Mjriam Capula, Giulia Mantini, Fatemeh Khojasteh-Leylakoohi, Annalisa Comandatore, Ghazaleh Khalili-Tanha, Alireza Khooei, Luca Morelli, Amir Avan, Erik H. Danen, Thomas Schmidt and Elisa Giovannetti
Cancers 2023, 15(3), 628; https://doi.org/10.3390/cancers15030628 - 19 Jan 2023
Cited by 11 | Viewed by 4034
Abstract
Introduction: PDAC is an extremely aggressive tumor with a poor prognosis and remarkable therapeutic resistance. The dense extracellular matrix (ECM) which characterizes PDAC progression is considered a fundamental determinant of chemoresistance, with major contributions from mechanical factors. This study combined biomechanical and pharmacological [...] Read more.
Introduction: PDAC is an extremely aggressive tumor with a poor prognosis and remarkable therapeutic resistance. The dense extracellular matrix (ECM) which characterizes PDAC progression is considered a fundamental determinant of chemoresistance, with major contributions from mechanical factors. This study combined biomechanical and pharmacological approaches to evaluate the role of the cell-adhesion molecule ITGA2, a key regulator of ECM, in PDAC resistance to gemcitabine. Methods: The prognostic value of ITGA2 was analysed in publicly available databases and tissue-microarrays of two cohorts of radically resected and metastatic patients treated with gemcitabine. PANC-1 and its gemcitabine-resistant clone (PANC-1R) were analysed by RNA-sequencing and label-free proteomics. The role of ITGA2 in migration, proliferation, and apoptosis was investigated using hydrogel-coated wells, siRNA-mediated knockdown and overexpression, while collagen-embedded spheroids assessed invasion and ECM remodeling. Results: High ITGA2 expression correlated with shorter progression-free and overall survival, supporting its impact on prognosis and the lack of efficacy of gemcitabine treatment. These findings were corroborated by transcriptomic and proteomic analyses showing that ITGA2 was upregulated in the PANC-1R clone. The aggressive behavior of these cells was significantly reduced by ITGA2 silencing both in vitro and in vivo, while PANC-1 cells growing under conditions resembling PDAC stiffness acquired resistance to gemcitabine, associated to increased ITGA2 expression. Collagen-embedded spheroids of PANC-1R showed a significant matrix remodeling and spreading potential via increased expression of CXCR4 and MMP2. Additionally, overexpression of ITGA2 in MiaPaCa-2 cells triggered gemcitabine resistance and increased proliferation, both in vitro and in vivo, associated to upregulation of phospho-AKT. Conclusions: ITGA2 emerged as a new prognostic factor, highlighting the relevance of stroma mechanical properties as potential therapeutic targets to counteract gemcitabine resistance in PDAC. Full article
(This article belongs to the Special Issue Targeting the (Un)Usual Suspects in Cancer)
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18 pages, 3411 KiB  
Article
CRISPR/Cas9 Edited RAS & MEK Mutant Cells Acquire BRAF and MEK Inhibitor Resistance with MEK1 Q56P Restoring Sensitivity to MEK/BRAF Inhibitor Combo and KRAS G13D Gaining Sensitivity to Immunotherapy
by Elizabeth Turner, Luping Chen, John G. Foulke, Zhizhan Gu and Fang Tian
Cancers 2022, 14(21), 5449; https://doi.org/10.3390/cancers14215449 - 5 Nov 2022
Cited by 5 | Viewed by 3554
Abstract
BRAF V600E mutation drives uncontrolled cell growth in most melanomas. While BRAF V600E tumors are initially responsive to BRAF inhibitors, prolonged treatment results in inhibitor resistance and tumor regrowth. Clinical data have linked the NRAS Q61K, KRAS G13D and MEK1 Q56P mutations [...] Read more.
BRAF V600E mutation drives uncontrolled cell growth in most melanomas. While BRAF V600E tumors are initially responsive to BRAF inhibitors, prolonged treatment results in inhibitor resistance and tumor regrowth. Clinical data have linked the NRAS Q61K, KRAS G13D and MEK1 Q56P mutations to the BRAF inhibitor resistance. However, development of novel therapeutics is hindered by the lack of relevant isogeneic cell models. We employed CRISPR/Cas9 genome engineering to introduce NRAS Q61K, KRAS G13D and MEK1 Q56P mutations into the A375 melanoma cell line with endogenously high expression of BRAF V600E. The resulting isogenic cell lines are resistant to BRAF inhibitors. The A375 MEK1 Q56P isogenic cells are additionally resistant to MEK inhibitors as single agent, but interestingly, these cells become sensitive to MEK/BRAF inhibitor combo. Our results suggest that resistance in the NRAS and MEK isogenic lines is driven by constitutive MEK/ERK signaling, while the resistance in the KRAS isogenic line is driven by EGFR overexpression. Interestingly, the KRAS G13D isogenic line displays elevated PD-L1 expression suggesting the KRAS G13D mutation could be a potential indication for immunotherapy. Overall, these three novel isogenic cell models with endogenous level RAS and MEK1 point mutations provide direct bio-functional evidence demonstrating that acquiring a drug-resistant gene drives tumor cell survival and may simultaneously introduce new indications for combo therapy or immunotherapy in the clinic. Full article
(This article belongs to the Special Issue Targeting the (Un)Usual Suspects in Cancer)
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17 pages, 2520 KiB  
Article
Biodegradable Ultrasmall-in-Nano Architectures Loaded with Cisplatin Prodrug in Combination with Ionizing Radiation Induces DNA Damage and Apoptosis in Pancreatic Ductal Adenocarcinoma
by Pei Pei Che, Ana Katrina Mapanao, Alessandro Gregori, Maria Laura Ermini, Agata Zamborlin, Mjriam Capula, Danitsja Ngadimin, Ben J. Slotman, Valerio Voliani, Peter Sminia and Elisa Giovannetti
Cancers 2022, 14(12), 3034; https://doi.org/10.3390/cancers14123034 - 20 Jun 2022
Cited by 12 | Viewed by 2932
Abstract
Considering the dismal survival rate, novel therapeutic strategies are warranted to improve the outcome of pancreatic ductal adenocarcinoma (PDAC). Combining nanotechnology for delivery of chemotherapeutics—preferably radiosensitizing agents—is a promising approach to enhance the therapeutic efficacy of chemoradiation. We assessed the effect of biodegradable [...] Read more.
Considering the dismal survival rate, novel therapeutic strategies are warranted to improve the outcome of pancreatic ductal adenocarcinoma (PDAC). Combining nanotechnology for delivery of chemotherapeutics—preferably radiosensitizing agents—is a promising approach to enhance the therapeutic efficacy of chemoradiation. We assessed the effect of biodegradable ultrasmall-in-nano architectures (NAs) containing gold ultra-small nanoparticles (USNPs) enclosed in silica shells loaded with cisplatin prodrug (NAs-cisPt) combined with ionizing radiation (IR). The cytotoxic effects and DNA damage induction were evaluated in PDAC cell lines (MIA PaCa2, SUIT2-028) and primary culture (PDAC3) in vitro and in the chorioallantoic membrane (CAM) in ovo model. Unlike NAs, NAs-cisPt affected the cell viability in MIA PaCa2 and SUIT2-028 cells. Furthermore, NAs-cisPt showed increased γH2AX expression up to 24 h post-IR and reduced β-globin amplifications resulting in apoptosis induction at DNA and protein levels. Similarly, combined treatment of NAs-cisPt + IR in PDAC3 and SUIT2-028 CAM models showed enhanced DNA damage and apoptosis leading to tumor growth delay. Our results demonstrate an increased cytotoxic effect of NAs-cisPt, particularly through its release of the cisplatin prodrug. As cisplatin is a well-known radiosensitizer, administration of cisplatin prodrug in a controlled fashion through encapsulation is a promising new treatment approach which merits further investigation in combination with other radiosensitizing agents. Full article
(This article belongs to the Special Issue Targeting the (Un)Usual Suspects in Cancer)
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16 pages, 2995 KiB  
Article
Integrated Network Pharmacology Approach for Drug Combination Discovery: A Multi-Cancer Case Study
by Antonio Federico, Michele Fratello, Giovanni Scala, Lena Möbus, Alisa Pavel, Giusy del Giudice, Michele Ceccarelli, Valerio Costa, Alfredo Ciccodicola, Vittorio Fortino, Angela Serra and Dario Greco
Cancers 2022, 14(8), 2043; https://doi.org/10.3390/cancers14082043 - 18 Apr 2022
Cited by 14 | Viewed by 4723
Abstract
Despite remarkable efforts of computational and predictive pharmacology to improve therapeutic strategies for complex diseases, only in a few cases have the predictions been eventually employed in the clinics. One of the reasons behind this drawback is that current predictive approaches are based [...] Read more.
Despite remarkable efforts of computational and predictive pharmacology to improve therapeutic strategies for complex diseases, only in a few cases have the predictions been eventually employed in the clinics. One of the reasons behind this drawback is that current predictive approaches are based only on the integration of molecular perturbation of a certain disease with drug sensitivity signatures, neglecting intrinsic properties of the drugs. Here we integrate mechanistic and chemocentric approaches to drug repositioning by developing an innovative network pharmacology strategy. We developed a multilayer network-based computational framework integrating perturbational signatures of the disease as well as intrinsic characteristics of the drugs, such as their mechanism of action and chemical structure. We present five case studies carried out on public data from The Cancer Genome Atlas, including invasive breast cancer, colon adenocarcinoma, lung squamous cell carcinoma, hepatocellular carcinoma and prostate adenocarcinoma. Our results highlight paclitaxel as a suitable drug for combination therapy for many of the considered cancer types. In addition, several non-cancer-related genes representing unusual drug targets were identified as potential candidates for pharmacological treatment of cancer. Full article
(This article belongs to the Special Issue Targeting the (Un)Usual Suspects in Cancer)
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Review

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30 pages, 3997 KiB  
Review
Chromatin and Cancer: Implications of Disrupted Chromatin Organization in Tumorigenesis and Its Diversification
by Poonam Sehgal and Pankaj Chaturvedi
Cancers 2023, 15(2), 466; https://doi.org/10.3390/cancers15020466 - 11 Jan 2023
Cited by 7 | Viewed by 3930
Abstract
A hallmark of cancers is uncontrolled cell proliferation, frequently associated with an underlying imbalance in gene expression. This transcriptional dysregulation observed in cancers is multifaceted and involves chromosomal rearrangements, chimeric transcription factors, or altered epigenetic marks. Traditionally, chromatin dysregulation in cancers has been [...] Read more.
A hallmark of cancers is uncontrolled cell proliferation, frequently associated with an underlying imbalance in gene expression. This transcriptional dysregulation observed in cancers is multifaceted and involves chromosomal rearrangements, chimeric transcription factors, or altered epigenetic marks. Traditionally, chromatin dysregulation in cancers has been considered a downstream effect of driver mutations. However, here we present a broader perspective on the alteration of chromatin organization in the establishment, diversification, and therapeutic resistance of cancers. We hypothesize that the chromatin organization controls the accessibility of the transcriptional machinery to regulate gene expression in cancerous cells and preserves the structural integrity of the nucleus by regulating nuclear volume. Disruption of this large-scale chromatin in proliferating cancerous cells in conventional chemotherapies induces DNA damage and provides a positive feedback loop for chromatin rearrangements and tumor diversification. Consequently, the surviving cells from these chemotherapies become tolerant to higher doses of the therapeutic reagents, which are significantly toxic to normal cells. Furthermore, the disorganization of chromatin induced by these therapies accentuates nuclear fragility, thereby increasing the invasive potential of these tumors. Therefore, we believe that understanding the changes in chromatin organization in cancerous cells is expected to deliver more effective pharmacological interventions with minimal effects on non-cancerous cells. Full article
(This article belongs to the Special Issue Targeting the (Un)Usual Suspects in Cancer)
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27 pages, 4415 KiB  
Review
The Fra-1/AP-1 Oncoprotein: From the “Undruggable” Transcription Factor to Therapeutic Targeting
by Laura Casalino, Francesco Talotta, Amelia Cimmino and Pasquale Verde
Cancers 2022, 14(6), 1480; https://doi.org/10.3390/cancers14061480 - 14 Mar 2022
Cited by 25 | Viewed by 7987
Abstract
The genetic and epigenetic changes affecting transcription factors, coactivators, and chromatin modifiers are key determinants of the hallmarks of cancer. The acquired dependence on oncogenic transcriptional regulators, representing a major determinant of cancer cell vulnerability, points to transcription factors as ideal therapeutic targets. [...] Read more.
The genetic and epigenetic changes affecting transcription factors, coactivators, and chromatin modifiers are key determinants of the hallmarks of cancer. The acquired dependence on oncogenic transcriptional regulators, representing a major determinant of cancer cell vulnerability, points to transcription factors as ideal therapeutic targets. However, given the unavailability of catalytic activities or binding pockets for small-molecule inhibitors, transcription factors are generally regarded as undruggable proteins. Among components of the AP-1 complex, the FOS-family transcription factor Fra-1, encoded by FOSL1, has emerged as a prominent therapeutic target. Fra-1 is overexpressed in most solid tumors, in response to the BRAF-MAPK, Wnt-beta-catenin, Hippo-YAP, IL-6-Stat3, and other major oncogenic pathways. In vitro functional analyses, validated in onco-mouse models and corroborated by prognostic correlations, show that Fra-1-containing dimers control tumor growth and disease progression. Fra-1 participates in key mechanisms of cancer cell invasion, Epithelial-to-Mesenchymal Transition, and metastatic spreading, by driving the expression of EMT-inducing transcription factors, cytokines, and microRNAs. Here we survey various strategies aimed at inhibiting tumor growth, metastatic dissemination, and drug resistance by interfering with Fra-1 expression, stability, and transcriptional activity. We summarize several tools aimed at the design and tumor-specific delivery of Fra-1/AP-1-specific drugs. Along with RNA-based therapeutics targeting the FOSL1 gene, its mRNA, or cognate regulatory circRNAs, we will examine the exploitation of blocking peptides, small molecule inhibitors, and innovative Fra-1 protein degraders. We also consider the possible caveats concerning Fra-1 inhibition in specific therapeutic contexts. Finally, we discuss a recent suicide gene therapy-based approach, aimed at selectively killing the Fra-1-overexpressing neoplastic cells. Full article
(This article belongs to the Special Issue Targeting the (Un)Usual Suspects in Cancer)
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