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Special Issue "Cancer Prevention with Molecular Target Therapies"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 16 November 2020.

Special Issue Editor

Dr. Laura Paleari
Website
Guest Editor
A.Li.Sa., Azienda Ligure Sanitaria della Regione Liguria, Genoa, Italy
Interests: cancer prevention; molecular biology; drug repurposing; health technology assessment; pharmacoeconomics

Special Issue Information

Dear Colleagues,

Personalized medicine is playing an important role in cancer prevention. To date, it is clear that many cancers are molecularly distinct subtypes, and different therapeutic approaches would be required for each. Indeed, the identification of cancer susceptibility genes permits identifying patients “at risk” of developing neoplasia and supports modifying individual risk behaviors or the choice of preventive therapy. Additionally, the efficacy of various targeted therapies in different cancer subtypes suggests that treatment choices in a near future will be more and more centered on molecular signatures. Data from preclinical, clinical, and observational studies have revealed the ability to prevent cancer development for compounds with different indications than cancer. The concept of drug repurposing permits combinations that can target several critical pathways of a specific disease, decreasing the risk of resistance observed when using single agent targeted therapy.

This open-access Special Issue will bring together original research and review articles on molecular oncology with attention to early detection and prevention of cancer. It highlights new findings, methods, and technical advances in molecular cancer research. The main feature of this Special Issue is to provide an open-source sharing of significant works in the field of molecular oncology that can increase our understanding of cancer development, which may lead to the discovery of new molecular diagnostic technologies and targeted therapeutics.

Topics include but are not limited to:

1—Molecular methods to personalize cancer screening and detection;

2—Molecular target therapies to prevent cancer development and metastases;

3—Identification and new aspects of cellular signaling molecules and pathways for target discovery, drug design, and personalized and gender medicine;

4—Drug repurposing for cancer prevention;

5—Molecular modeling studies.

Dr. Laura Paleari
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 papers will be 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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 prevention
  • Target therapy
  • Personalized screening
  • Drug repurposing
  • Target discovery

Published Papers (9 papers)

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Research

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Open AccessArticle
A Peptidic Thymidylate-Synthase Inhibitor Loaded on Pegylated Liposomes Enhances the Antitumour Effect of Chemotherapy Drugs in Human Ovarian Cancer Cells
Int. J. Mol. Sci. 2020, 21(12), 4452; https://doi.org/10.3390/ijms21124452 - 23 Jun 2020
Abstract
There is currently no effective long-term treatment for ovarian cancer (OC) resistant to poly-chemotherapy regimens based on platinum drugs. Preclinical and clinical studies have demonstrated a strong association between development of Pt-drug resistance and increased thymidylate synthase (hTS) expression, and the consequent cross-resistance [...] Read more.
There is currently no effective long-term treatment for ovarian cancer (OC) resistant to poly-chemotherapy regimens based on platinum drugs. Preclinical and clinical studies have demonstrated a strong association between development of Pt-drug resistance and increased thymidylate synthase (hTS) expression, and the consequent cross-resistance to the hTS inhibitors 5-fluorouracil (5-FU) and raltitrexed (RTX). In the present work, we propose a new tool to combat drug resistance. We propose to treat OC cell lines, both Pt-sensitive and -resistant, with dual combinations of one of the four chemotherapeutic agents that are widely used in the clinic, and the new peptide, hTS inhibitor, [D-Gln4]LR. This binds hTS allosterically and, unlike classical inhibitors that bind at the catalytic pocket, causes cell growth inhibition without inducing hTS overexpression. The dual drug combinations showed schedule-dependent synergistic antiproliferative and apoptotic effects. We observed that the simultaneous treatment or 24h pre-treatment of OC cells with the peptide followed by either agent produced synergistic effects even in resistant cells. Similar synergistic or antagonistic effects were obtained by delivering the peptide into OC cells either by means of a commercial delivery system (SAINT-PhD) or by pH sensitive PEGylated liposomes. Relative to non-PEGylated liposomes, the latter had been previously characterized and found to allow macrophage escape, thus increasing their chance to reach the tumour tissue. The transition from the SAINT-PhD delivery system to the engineered liposomes represents an advancement towards a more drug-like delivery system and a further step towards the use of peptides for in vivo studies. Overall, the results suggest that the association of standard drugs, such as cDDP and/or 5-FU and/or RTX, with the novel peptidic TS inhibitor encapsulated into PEGylated pH-sensitive liposomes can represent a promising strategy for fighting resistance to cDDP and anti-hTS drugs. Full article
(This article belongs to the Special Issue Cancer Prevention with Molecular Target Therapies)
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Open AccessArticle
Phosphodiesterase SMPDL3B Gene Expression as Independent Outcome Prediction Marker in Localized Prostate Cancer
Int. J. Mol. Sci. 2020, 21(12), 4373; https://doi.org/10.3390/ijms21124373 - 19 Jun 2020
Abstract
Current outcome prediction markers for localized prostate cancer (PCa) are insufficient. The impact of the lipid-modifying Sphingomyelin Phosphodiesterase Acid Like 3B (SMPDL3B) in PCa is unknown. Two cohorts of patients with PCa who underwent radical prostatectomy (n = 40, n = 56) [...] Read more.
Current outcome prediction markers for localized prostate cancer (PCa) are insufficient. The impact of the lipid-modifying Sphingomyelin Phosphodiesterase Acid Like 3B (SMPDL3B) in PCa is unknown. Two cohorts of patients with PCa who underwent radical prostatectomy (n = 40, n = 56) and benign prostate hyperplasia (BPH) controls (n = 8, n = 11) were profiled for SMPDL3B expression with qRT-PCR. Publicly available PCa cohorts (Memorial Sloane Kettering Cancer Centre (MSKCC; n = 131, n = 29 controls) and The Cancer Genome Atlas (TCGA; n = 497, n = 53 controls)) served for validation. SMPDL3B’s impact on proliferation and migration was analyzed in PC3 cells by siRNA knockdown. In both cohorts, a Gleason score and T stage independent significant overexpression of SMPDL3B was seen in PCa compared to BPH (p < 0.001 each). A lower expression of SMPDL3B was associated with a shorter overall survival (OS) (p = 0.005) in long term follow-up. A SMPDL3B overexpression in PCa tissue was confirmed in the validation cohorts (p < 0.001 each). In the TCGA patients with low SMPDL3B expression, biochemical recurrence-free survival (p = 0.011) and progression-free interval (p < 0.001) were shorter. Knockdown of SMPDL3B impaired PC3 cell migration but not proliferation (p = 0.0081). In summary, SMPLD3B is highly overexpressed in PCa tissue, is inversely associated with localized PCa prognosis, and impairs PCa cell migration. Full article
(This article belongs to the Special Issue Cancer Prevention with Molecular Target Therapies)
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Open AccessArticle
Hedgehog Signal Inhibitor GANT61 Inhibits the Malignant Behavior of Undifferentiated Hepatocellular Carcinoma Cells by Targeting Non-Canonical GLI Signaling
Int. J. Mol. Sci. 2020, 21(9), 3126; https://doi.org/10.3390/ijms21093126 - 28 Apr 2020
Cited by 2
Abstract
The Hedgehog (HH)–GLI pathway plays an important role in cell dedifferentiation and is therefore pivotally involved in the malignant transformation of cancer cells. GANT61, a selective inhibitor of GLI1 and GLI2, was reported as a promising treatment for cancer in various tissues; however, [...] Read more.
The Hedgehog (HH)–GLI pathway plays an important role in cell dedifferentiation and is therefore pivotally involved in the malignant transformation of cancer cells. GANT61, a selective inhibitor of GLI1 and GLI2, was reported as a promising treatment for cancer in various tissues; however, the biological impact of GANT61 in hepatocellular carcinoma (HCC), especially in undifferentiated HCC cells, remains unclear. In this study, we investigated the antitumor effect of GANT61 using two undifferentiated hepatoma cell lines: HLE and HLF. Quantitative PCR and RT-PCR analyses revealed that these cells express GLI transcripts, showing mesenchymal phenotypes characterized by the loss of epithelial and hepatic markers and specific expression of epithelial–mesenchymal transition (EMT)-related genes. GANT61 significantly reduced the proliferation and cell viability after drug treatment using 5-FU and Mitomycin C. We showed that GLI transcript levels were down-regulated by the MEK inhibitor U0126 and the Raf inhibitor sorafenib, suggesting that non-canonical signaling including the Ras–Raf–MEK–ERK pathway is involved. Sphere formation and migration were significantly decreased by GANT61 treatment, and it is suggested that the underlying molecular mechanisms are the down-regulation of stemness-related genes (Oct4, Bmi1, CD44, and ALDH) and the EMT-related gene Snail1. The data presented here showed that direct inhibition of GLI might be beneficial for the treatment of dedifferentiated HCC. Full article
(This article belongs to the Special Issue Cancer Prevention with Molecular Target Therapies)
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Open AccessArticle
Efficacy of Immune Checkpoint Inhibitor Monotherapy for Advanced Non-Small-Cell Lung Cancer with ALK Rearrangement
Int. J. Mol. Sci. 2020, 21(7), 2623; https://doi.org/10.3390/ijms21072623 - 09 Apr 2020
Abstract
Programmed death-ligand 1 (PD-L1) expression is a predictor of immune checkpoint inhibitor (ICI) treatment efficacy. The clinical efficacy of ICIs for non-small-cell lung cancer (NSCLC) patients harboring major mutations, such as EGFR or ALK mutations, is limited. We genotyped 190 patients with advanced [...] Read more.
Programmed death-ligand 1 (PD-L1) expression is a predictor of immune checkpoint inhibitor (ICI) treatment efficacy. The clinical efficacy of ICIs for non-small-cell lung cancer (NSCLC) patients harboring major mutations, such as EGFR or ALK mutations, is limited. We genotyped 190 patients with advanced lung adenocarcinomas who received nivolumab or pembrolizumab monotherapy, and examined the efficacy in NSCLC patients with or without major mutations. Among the patients enrolled in the genotyping study, 47 patients harbored EGFR mutations, 25 patients had KRAS mutations, 5 patients had a HER2 mutation, 6 patients had a BRAF mutation, and 7 patients had ALK rearrangement. The status of PD-L1 expression was evaluated in 151 patients, and the rate of high PD-L1 expression (≥50%) was significantly higher in patients with ALK mutations. The progression-free survival was 0.6 (95% CI: 0.2–2.1) months for ALK-positive patients and 1.8 (95% CI: 1.2–2.1) months for EGFR-positive patients. All patients with ALK rearrangement showed disease progression within three months from the initiation of anti-PD-1 treatment. Our data suggested that ICI treatment was significantly less efficacious in patients with ALK rearrangement than in patients with EGFR mutations, and PD-L1 expression was not a critical biomarker for ICI treatment for patients with one of these mutations. Full article
(This article belongs to the Special Issue Cancer Prevention with Molecular Target Therapies)
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Open AccessArticle
Aromatase Inhibitors as Adjuvant Treatment for ER/PgR Positive Stage I Endometrial Carcinoma: A Retrospective Cohort Study
Int. J. Mol. Sci. 2020, 21(6), 2227; https://doi.org/10.3390/ijms21062227 - 23 Mar 2020
Abstract
Objective: Although endometrial cancer (EC) is a hormone dependent neoplasm, there are no recommendations for the determination of steroid hormone receptors in the tumor tissue and no hormone therapy has ever been assessed in the adjuvant setting. The purpose of this study was [...] Read more.
Objective: Although endometrial cancer (EC) is a hormone dependent neoplasm, there are no recommendations for the determination of steroid hormone receptors in the tumor tissue and no hormone therapy has ever been assessed in the adjuvant setting. The purpose of this study was to explore the effect of adjuvant aromatase inhibitors (AIs) on progression-free survival (PFS) and overall survival (OS) in patients with early stage and steroid receptors-positive EC. Methods: We retrospectively analyzed clinical and pathological factors in 73 patients with high-risk (49.3%) or low-risk (50.7%) stage I (n = 71) or II (n = 2) endometrial cancer who received by their preference after counseling either no treatment (reference group) or AI. Prognostic factors were well balanced between groups. Expression of estrogen receptor (ER), progesterone receptor (PgR), and Ki-67 index was correlated with clinical outcomes. Results: Univariate and multivariate Cox proportional regression analyses, adjusted for age, grade, stage, depth of myometrial invasion, lymphovascular space invasion, BMI, ER, PgR and Ki-67 labeling index levels, showed that PFS and OS had a trend to be longer in patients receiving AI than in the reference group HR= 0.23 (95% CI; 0.04–1.27) for PFS and HR= 0.11 (95% CI; 0.01–1.36) for OS. Conclusion: Compared with no treatment, AI exhibited a trend toward a benefit on PFS and OS in patients with early stage hormone receptor-positive EC. Given the exploratory nature of our study, randomized clinical trials for ER/PgR positive EC patients are warranted to assess the clinical benefit of AI and the potential predictive role of steroid receptors and Ki-67. Full article
(This article belongs to the Special Issue Cancer Prevention with Molecular Target Therapies)
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Open AccessCommunication
Beta3-Tubulin Is Critical for Microtubule Dynamics, Cell Cycle Regulation, and Spontaneous Release of Microvesicles in Human Malignant Melanoma Cells (A375)
Int. J. Mol. Sci. 2020, 21(5), 1656; https://doi.org/10.3390/ijms21051656 - 28 Feb 2020
Abstract
Microtubules (MTs), microfilaments, and intermediate filaments, the main constituents of the cytoskeleton, undergo continuous structural changes (metamorphosis), which are central to cellular growth, division, and release of microvesicles (MVs). Altered MTs dynamics, uncontrolled proliferation, and increased production of MVs are hallmarks of carcinogenesis. [...] Read more.
Microtubules (MTs), microfilaments, and intermediate filaments, the main constituents of the cytoskeleton, undergo continuous structural changes (metamorphosis), which are central to cellular growth, division, and release of microvesicles (MVs). Altered MTs dynamics, uncontrolled proliferation, and increased production of MVs are hallmarks of carcinogenesis. Class III beta-tubulin (β3-tubulin), one of seven β-tubulin isotypes, is a primary component of MT, which correlates with enhanced neoplastic cell survival, metastasis and resistance to chemotherapy. We studied the effects of β3-tubulin gene silencing on MTs dynamics, cell cycle, and MVs release in human malignant melanoma cells (A375). The knockdown of β3-tubulin induced G2/M cell cycle arrest, impaired MTs dynamics, and reduced spontaneous MVs release. Additional studies are therefore required to elucidate the pathophysiologic and therapeutic role of β3-tubulin in melanoma. Full article
(This article belongs to the Special Issue Cancer Prevention with Molecular Target Therapies)
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Review

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Open AccessReview
Microbiota-Associated Therapy for Non-Alcoholic Steatohepatitis-Induced Liver Cancer: A Review
Int. J. Mol. Sci. 2020, 21(17), 5999; https://doi.org/10.3390/ijms21175999 - 20 Aug 2020
Abstract
Even though advancement in medicine has contributed to the control of many diseases to date, cancer therapy continues to pose several challenges. Hepatocellular carcinoma (HCC) etiology is multifactorial. Recently, non-alcoholic fatty liver disease (NAFLD) has been considered as an important risk factor of [...] Read more.
Even though advancement in medicine has contributed to the control of many diseases to date, cancer therapy continues to pose several challenges. Hepatocellular carcinoma (HCC) etiology is multifactorial. Recently, non-alcoholic fatty liver disease (NAFLD) has been considered as an important risk factor of HCC. NAFLD can be divided into non-alcoholic simple fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) based on histopathological features. Recently, studies have indicated that the gut microbiota is associated with NAFLD and HCC. Therefore, in this review, we have discussed the effects of gut microbiota-related mechanisms, including dysbiosis and gut barrier function, and gut microbiota-derived metabolites on NAFLD and HCC pathogenesis and the potential therapeutic strategies for NAFLD and HCC. With a better understanding of the gut microbiota composition and function, new and improved diagnostic, prognostic, and therapeutic strategies for common liver diseases can be developed. Full article
(This article belongs to the Special Issue Cancer Prevention with Molecular Target Therapies)
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Open AccessReview
Evolution of Urothelial Bladder Cancer in the Context of Molecular Classifications
Int. J. Mol. Sci. 2020, 21(16), 5670; https://doi.org/10.3390/ijms21165670 - 07 Aug 2020
Abstract
Bladder cancer is a heterogeneous disease that is not depicted by current classification systems. It was originally classified into non-muscle invasive and muscle invasive. However, clinically and genetically variable tumors are summarized within both classes. A definition of three groups may better account [...] Read more.
Bladder cancer is a heterogeneous disease that is not depicted by current classification systems. It was originally classified into non-muscle invasive and muscle invasive. However, clinically and genetically variable tumors are summarized within both classes. A definition of three groups may better account for the divergence in prognosis and probably also choice of treatment. The first group represents mostly non-invasive tumors that reoccur but do not progress. Contrarily, the second group represent non-muscle invasive tumors that likely progress to the third group, the muscle invasive tumors. High throughput tumor profiling improved our understanding of the biology of bladder cancer. It allows the identification of molecular subtypes, at least three for non-muscle invasive bladder cancer (Class I, Class II and Class III) and six for muscle-invasive bladder cancer (luminal papillary, luminal non-specified, luminal unstable, stroma-rich, basal/squamous and neuroendocrine-like) with distinct clinical and molecular phenotypes. Molecular subtypes can be potentially used to predict the response to treatment (e.g., neoadjuvant chemotherapy and immune checkpoint inhibitors). Moreover, they may allow to characterize the evolution of bladder cancer through different pathways. However, to move towards precision medicine, the understanding of the biological meaning of these molecular subtypes and differences in the composition of cell subpopulations will be mandatory. Full article
(This article belongs to the Special Issue Cancer Prevention with Molecular Target Therapies)
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Open AccessReview
Repurposing Tyrosine Kinase Inhibitors to Overcome Multidrug Resistance in Cancer: A Focus on Transporters and Lysosomal Sequestration
Int. J. Mol. Sci. 2020, 21(9), 3157; https://doi.org/10.3390/ijms21093157 - 30 Apr 2020
Cited by 1
Abstract
Tyrosine kinase inhibitors (TKIs) are being increasingly used to treat various malignancies. Although they were designed to target aberrant tyrosine kinases, they are also intimately linked with the mechanisms of multidrug resistance (MDR) in cancer cells. MDR-related solute carrier (SLC) and ATB-binding cassette [...] Read more.
Tyrosine kinase inhibitors (TKIs) are being increasingly used to treat various malignancies. Although they were designed to target aberrant tyrosine kinases, they are also intimately linked with the mechanisms of multidrug resistance (MDR) in cancer cells. MDR-related solute carrier (SLC) and ATB-binding cassette (ABC) transporters are responsible for TKI uptake and efflux, respectively. However, the role of TKIs appears to be dual because they can act as substrates and/or inhibitors of these transporters. In addition, several TKIs have been identified to be sequestered into lysosomes either due to their physiochemical properties or via ABC transporters expressed on the lysosomal membrane. Since the development of MDR represents a great concern in anticancer treatment, it is important to elucidate the interactions of TKIs with MDR-related transporters as well as to improve the properties that would prevent TKIs from diffusing into lysosomes. These findings not only help to avoid MDR, but also help to define the possible impact of combining TKIs with other anticancer drugs, leading to more efficient therapy and fewer adverse effects in patients. Full article
(This article belongs to the Special Issue Cancer Prevention with Molecular Target Therapies)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: The chemosensitizers and multidrug resistance modulators of phytochemicals in cancers

Title: Pharmacogenomics of Breast Cancer – Highlighting CYP2D6 and Tamoxifen

Title: Targeted therapies in early stage NSCLC

Title: Phosphodiesterase SMPDL3B as PSA-independent outcome prediction marker in localized prostate cancer

Title: Bladder cancer: molecular classifications and their potential clinical application

Title: Survival of lung cancer patients dependent on the LOH status for DMP1, ARF, and p53

Title: STAT3 and STAT3 inhibitors in cancer

Title: The development of molecular target therapies in acute myeloid leukemia

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