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The Promise of Precision Oncology: Molecular Strategies, Methods, Pharmacogenomics and Informatics

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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: closed (31 October 2020) | Viewed by 46344

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Special Issue Editor

Prof. Dr. Eddy Yang

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Guest Editor

Department of Radiation Oncology, University of Alabama-Birmingham, 1720 2nd Ave South, Birmingham, AL 35294, USA
Interests: DNA repair; prostate cancer; breast cancer; epigenetics; immunotherapy; precision medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Precision medicine is an increasingly critical aspect of cancer care for our patients. Existing models use genomics to tailor patient treatment based on the presence of actionable tumor driver mutations. Using tumor sequencing to direct therapy has yielded promising results in some tumor types and driver pathways such that the paradigm for some cancer treatment is changing from being cancer subtype-specific to pathway-based. However, precision oncology is much more complex than simply assaying tumors for driver pathways as success is limited. Technological and scientific advances have allowed for more extensive molecular testing in addition to tumor DNA and RNA sequencing. This Special Issue of IJMS will review the successes and pitfalls of current precision oncology strategies, novel methods to analyze and incorporate large multi-dimensional datasets, pharmacogenomic considerations in personalizing therapy, the potential for drug repurposing, and the promise of artificial intelligence/informatics-based systems to aid in decision support. Research articles on these topics are also welcome.

Prof. Dr. Eddy Yang
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. 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.

Related Special Issue

The Promise of Precision Oncology 2.0: Molecular Strategies, Methods, Pharmacogenomics and Informatics in International Journal of Molecular Sciences (11 articles)

Published Papers (9 papers)

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Research

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12 pages, 1583 KiB

Open AccessArticle

Ligation-Mediated Polymerase Chain Reaction Detection of 8-Oxo-7,8-Dihydro-2′-Deoxyguanosine and 5-Hydroxycytosine at the Codon 176 of the p53 Gene of Hepatitis C-Associated Hepatocellular Carcinoma Patients

by Andrea Galli, Armelle Munnia, Filippo Cellai, Mirko Tarocchi, Elisabetta Ceni, Frederik Jan van Schooten, Roger Godschalk, Roger W. Giese and Marco Peluso

Int. J. Mol. Sci. 2020, 21(18), 6753; https://doi.org/10.3390/ijms21186753 - 15 Sep 2020

Cited by 4 | Viewed by 2048

Abstract

Molecular mechanisms underlying Hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC) pathogenesis are still unclear. Therefore, we analyzed the levels of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and other oxidative lesions at codon 176 of the p53 gene, as well as the generation of 3-(2-deoxy-β-d-erythro-pentafuranosyl)pyrimido[1,2-α]purin-10(3H)-one deoxyguanosine (M₁dG), in a cohort of HCV-related HCC patients from Italy. Detection of 8-oxodG and 5-hydroxycytosine (5-OHC) was performed by ligation mediated-polymerase chain reaction assay, whereas the levels of M₁dG were measured by chromatography and mass-spectrometry. Results indicated a significant 130% excess of 8-oxodG at –TGC– position of p53 codon 176 in HCV-HCC cases as compared to controls, after correction for age and gender, whereas a not significant increment of 5-OHC at –TGC– position was found. Then, regression models showed an 87% significant excess of M₁dG in HCV-HCC cases relative to controls. Our study provides evidence that increased adduct binding does not occur randomly on the sequence of the p53 gene but at specific sequence context in HCV-HCC patients. By-products of lipid peroxidation could also yield a role in HCV-HCC development. Results emphasize the importance of active oxygen species in inducing nucleotide lesions at a p53 mutational hotspot in HCV-HCC patients living in geographical areas without dietary exposure to aflatoxin B₁. Full article

(This article belongs to the Special Issue The Promise of Precision Oncology: Molecular Strategies, Methods, Pharmacogenomics and Informatics)

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12 pages, 1561 KiB

Open AccessArticle

Synergistic Effects of Combination Therapy with AKT and mTOR Inhibitors on Bladder Cancer Cells

by Hyera Kim, Su Jin Lee, In Kyoung Lee, Suejean C. Min, Hyun Hwan Sung, Byong Chang Jeong, Jeeyun Lee and Se Hoon Park

Int. J. Mol. Sci. 2020, 21(8), 2825; https://doi.org/10.3390/ijms21082825 - 18 Apr 2020

Cited by 14 | Viewed by 3540

Abstract

Despite comprehensive genomic analyses, no targeted therapies are approved for bladder cancer. Here, we investigate whether a single and combination therapy with targeted agents exert antitumor effects on bladder cancer cells through genomic alterations using a three-dimensional (3D) high-throughput screening (HTS) platform. Seven human bladder cancer cell lines were used to screen 24 targeted agents. The effects of 24 targeted agents were dramatically different according to the genomic alterations of bladder cancer cells. BEZ235 (dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor) showed antitumor effects against most cell lines, while AZD2014 (mTOR inhibitor) had an IC50 value lower than 2 μM in 5637, J82, and RT4 cell lines. AZD5363 (protein kinase B (AKT) inhibitor) exerted antitumor effects on 5637, J82, and 253J-BV cells. J82 cells (PI3KCA and mTOR mutations) were sensitive to AZD5363, AZD2014, and BEZ235 alone or in AZD5363/AZD2014 and AZD5363/BEZ235 combinations. Although all single drugs suppressed cell proliferation, the combination of drugs exhibited synergistic effects on cell viability and colony formation. The synergistic effects of the combination therapy on the PI3K/Akt/mTOR pathway, apoptosis, and EMT were evident in Western blotting. Thus, the 3D culture-based HTS platform could serve as a useful preclinical tool to evaluate various drug combinations. Full article

(This article belongs to the Special Issue The Promise of Precision Oncology: Molecular Strategies, Methods, Pharmacogenomics and Informatics)

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11 pages, 2747 KiB

Open AccessArticle

Combined Targeting of Mutant p53 and Jumonji Family Histone Demethylase Augments Therapeutic Efficacy of Radiation in H3K27M DIPG

by Anatoly Nikolaev, John B. Fiveash and Eddy S. Yang

Int. J. Mol. Sci. 2020, 21(2), 490; https://doi.org/10.3390/ijms21020490 - 13 Jan 2020

Cited by 24 | Viewed by 4516

Abstract

Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brainstem tumor with a 5-year survival of <1%. Up to 80% of the DIPG tumors contain a specific K27M mutation in one of the two genes encoding histone H3 (H3K27M). Furthermore, p53 mutations found in >70–80% of H3K27M DIPG, and mutant p53 status is associated with a decreased response to radiation treatment and worse overall prognosis. Recent evidence indicates that H3K27M mutation disrupts tri-methylation at H3K27 leading to aberrant gene expression. Jumonji family histone demethylases collaborates with H3K27 mutation in DIPG by erasing H3K27 trimethylation and thus contributing to derepression of genes involved in tumorigenesis. Since the first line of treatment for pediatric DIPG is fractionated radiation, we investigated the effects of Jumonji demethylase inhibition with GSK-J4, and mutant p53 targeting/oxidative stress induction with APR-246, on radio-sensitization of human H3K27M DIPG cells. Both APR-246 and GSK-J4 displayed growth inhibitory effects as single agents in H3K27M DIPG cells. Furthermore, both of these agents elicited mild radiosensitizing effects in human DIPG cells (sensitizer enhancement ratios (SERs) of 1.12 and 1.35, respectively; p < 0.05). Strikingly, a combination of APR-246 and GSK-J4 displayed a significant enhancement of radiosensitization, with SER of 1.50 (p < 0.05) at sub-micro-molar concentrations of the drugs (0.5 μM). The molecular mechanism of the observed radiosensitization appears to involve DNA damage repair deficiency triggered by APR-246/GSK-J4, leading to the induction of apoptotic cell death. Thus, a therapeutic approach of combined targeting of mutant p53, oxidative stress induction, and Jumonji demethylase inhibition with radiation in DIPG warrants further investigation. Full article

(This article belongs to the Special Issue The Promise of Precision Oncology: Molecular Strategies, Methods, Pharmacogenomics and Informatics)

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13 pages, 1078 KiB

Open AccessArticle

An Improved Prediction Model for Ovarian Cancer Using Urinary Biomarkers and a Novel Validation Strategy

by Shin-Wha Lee, Ha-Young Lee, Hyo Joo Bang, Hye-Jeong Song, Sek Won Kong and Yong-Man Kim

Int. J. Mol. Sci. 2019, 20(19), 4938; https://doi.org/10.3390/ijms20194938 - 05 Oct 2019

Cited by 31 | Viewed by 3126

Abstract

This study was designed to analyze urinary proteins associated with ovarian cancer (OC) and investigate the potential urinary biomarker panel to predict malignancy in women with pelvic masses. We analyzed 23 biomarkers in urine samples obtained from 295 patients with pelvic masses scheduled for surgery. The concentration of urinary biomarkers was quantitatively assessed by the xMAP bead-based multiplexed immunoassay. To identify the performance of each biomarker in predicting cancer over benign tumors, we used a repeated leave-group-out cross-validation strategy. The prediction models using multimarkers were evaluated to develop a urinary ovarian cancer panel. After the exclusion of 12 borderline tumors, the urinary concentration of 17 biomarkers exhibited significant differences between 158 OCs and 125 benign tumors. Human epididymis protein 4 (HE4), vascular cell adhesion molecule (VCAM), and transthyretin (TTR) were the top three biomarkers representing a higher concentration in OC. HE4 demonstrated the highest performance in all samples withOC(mean area under the receiver operating characteristic curve (AUC) 0.822, 95% CI: 0.772–0.869), whereas TTR showed the highest efficacy in early-stage OC (AUC 0.789, 95% CI: 0.714–0.856). Overall, HE4 was the most informative biomarker, followed by creatinine, carcinoembryonic antigen (CEA), neural cell adhesion molecule (NCAM), and TTR using the least absolute shrinkage and selection operator (LASSO) regression models. A multimarker panel consisting of HE4, creatinine, CEA, and TTR presented the best performance with 93.7% sensitivity (SN) at 70.6% specificity (SP) to predict OC over the benign tumor. This panel performed well regardless of disease status and demonstrated an improved performance by including menopausal status. In conclusion, the urinary biomarker panel with HE4, creatinine, CEA, and TTR provided promising efficacy in predicting OC over benign tumors in women with pelvic masses. It was also a non-invasive and easily available diagnostic tool. Full article

(This article belongs to the Special Issue The Promise of Precision Oncology: Molecular Strategies, Methods, Pharmacogenomics and Informatics)

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16 pages, 2985 KiB

Open AccessArticle

Integrated Analysis of miRNA and mRNA Endorses a Twenty miRNAs Signature for Colorectal Carcinoma

by Andrea Angius, Paolo Uva, Giovanna Pira, Maria Rosaria Muroni, Giovanni Sotgiu, Laura Saderi, Elena Uleri, Maurizio Caocci, Gabriele Ibba, Maria Rosaria Cesaraccio, Caterina Serra, Ciriaco Carru, Alessandra Manca, Francesca Sanges, Alberto Porcu, Antonia Dolei, Antonio Mario Scanu, Paolo Cossu Rocca and Maria Rosaria De Miglio

Int. J. Mol. Sci. 2019, 20(16), 4067; https://doi.org/10.3390/ijms20164067 - 20 Aug 2019

Cited by 32 | Viewed by 5901

Abstract

Colorectal cancer (CRC) ranks as the most frequent carcinoma worldwide. CRC patients show strong prognostic differences and responses to treatment, and 20% have incurable metastatic disease at diagnosis. We considered it essential to investigate mechanisms that control cellular regulatory networks, such as the miRNA–mRNA interaction, known to be involved in cancer pathogenesis. We conducted a human miRNome analysis by TaqMan low density array, comparing CRC to normal colon tissue (NCT, and experimentally identified gene targets of miRNAs deregulated, by anti-correlation analysis, with the CRC whole-transcriptome profile obtained from RNASeq experiments. We identified an integrated signature of 20 deregulated miRNAs in CRC. Enrichment analyses of the gene targets controlled by these miRNAs brought to light 25 genes, members of pathways known to lead to cell growth and death (CCND1, NKD1, FZD3, MAD2L1, etc.), such as cell metabolism (ACSL6, PRPS1-2). A screening of prognosis-mediated miRNAs underlined that the overexpression of miR-224 promotes CRC metastasis, and is associated with high stage and poor survival. These findings suggest that the biology and progression of CRC depend on deregulation of multiple miRNAs that cause a complex dysfunction of cellular molecular networks. Our results have further established miRNA–mRNA interactions and defined multiple pathways involved in CRC pathogenesis. Full article

(This article belongs to the Special Issue The Promise of Precision Oncology: Molecular Strategies, Methods, Pharmacogenomics and Informatics)

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24 pages, 2149 KiB

Open AccessArticle

H19-Dependent Transcriptional Regulation of β3 and β4 Integrins Upon Estrogen and Hypoxia Favors Metastatic Potential in Prostate Cancer

by Lorenza Bacci, Aurora Aiello, Cristian Ripoli, Rossella Loria, Dario Pugliese, Francesco Pierconti, Dante Rotili, Lidia Strigari, Francesco Pinto, Pier Francesco Bassi, Antonello Mai, Claudio Grassi, Alfredo Pontecorvi, Rita Falcioni, Antonella Farsetti and Simona Nanni

Int. J. Mol. Sci. 2019, 20(16), 4012; https://doi.org/10.3390/ijms20164012 - 17 Aug 2019

Cited by 22 | Viewed by 3396

Abstract

Estrogen and hypoxia promote an aggressive phenotype in prostate cancer (PCa), driving transcription of progression-associated genes. Here, we molecularly dissect the contribution of long non-coding RNA H19 to PCa metastatic potential under combined stimuli, a topic largely uncovered. The effects of estrogen and hypoxia on H19 and cell adhesion molecules’ expression were investigated in PCa cells and PCa-derived organotypic slice cultures (OSCs) by qPCR and Western blot. The molecular mechanism was addressed by chromatin immunoprecipitations, overexpression, and silencing assays. PCa cells’ metastatic potential was analyzed by in vitro cell-cell adhesion, motility test, and trans-well invasion assay. We found that combined treatment caused a significant H19 down-regulation as compared with hypoxia. In turn, H19 acts as a transcriptional repressor of cell adhesion molecules, as revealed by up-regulation of both β3 and β4 integrins and E-cadherin upon H19 silencing or combined treatment. Importantly, H19 down-regulation and β integrins induction were also observed in treated OSCs. Combined treatment increased both cell motility and invasion of PCa cells. Lastly, reduction of β integrins and invasion was achieved through epigenetic modulation of H19-dependent transcription. Our study revealed that estrogen and hypoxia transcriptionally regulate, via H19, cell adhesion molecules redirecting metastatic dissemination from EMT to a β integrin-mediated invasion. Full article

(This article belongs to the Special Issue The Promise of Precision Oncology: Molecular Strategies, Methods, Pharmacogenomics and Informatics)

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Review

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20 pages, 909 KiB

Open AccessReview

Molecular Targets in Precision Chemoprevention of Colorectal Cancer: An Update from Pre-Clinical to Clinical Trials

by Nagendra S. Yarla, Venkateshwar Madka, Gopal Pathuri and Chinthalapally V. Rao

Int. J. Mol. Sci. 2020, 21(24), 9609; https://doi.org/10.3390/ijms21249609 - 17 Dec 2020

Cited by 12 | Viewed by 3286

Abstract

Colorectal cancer (CRC) is one of the leading causes of cancer deaths worldwide. The initiation and progression of CRC is a multi-step process that proceeds via precursor lesions to carcinoma, with each stage characterized by its distinct molecular and tissue microenvironment changes. Precursor lesions of CRC, aberrant crypt foci, and adenoma exhibit drastic changes in genetic, transcriptomic, and proteomic profiles compared to normal tissue. The identification of these changes is essential and provides further validation as an initiator or promoter of CRC and, more so, as lesion-specific druggable molecular targets for the precision chemoprevention of CRC. Mutated/dysregulated signaling (adenomatous polyposis coli, β-catenin, epidermal growth factor receptor, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), tumor protein53, Akt, etc.), inflammatory (cyclooxygenase-2, microsomal prostaglandin E synthase-1, inducible nitric oxide synthase, and other pro-inflammatory mediators), and metabolic/growth factor (fatty acid synthase, β-Hydroxy β-methylglutaryl-CoA reductase, and ornithine decarboxylase) related targets are some of the well-characterized molecular targets in the precision chemoprevention of CRC. In this review, we discuss precursor-lesion specific targets of CRC and the current status of pre-clinical studies regarding clinical interventions and combinations for better efficacy and safety toward future precision clinical chemoprevention. In addition, we provide a brief discussion on the usefulness of secondary precision chemopreventive targets for tertiary precision chemoprevention to improve the disease-free and overall survival of advanced stage CRC patients. Full article

(This article belongs to the Special Issue The Promise of Precision Oncology: Molecular Strategies, Methods, Pharmacogenomics and Informatics)

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13 pages, 401 KiB

Open AccessReview

The Need for Multi-Omics Biomarker Signatures in Precision Medicine

by Michael Olivier, Reto Asmis, Gregory A. Hawkins, Timothy D. Howard and Laura A. Cox

Int. J. Mol. Sci. 2019, 20(19), 4781; https://doi.org/10.3390/ijms20194781 - 26 Sep 2019

Cited by 262 | Viewed by 15718

Abstract

Recent advances in omics technologies have led to unprecedented efforts characterizing the molecular changes that underlie the development and progression of a wide array of complex human diseases, including cancer. As a result, multi-omics analyses—which take advantage of these technologies in genomics, transcriptomics, epigenomics, proteomics, metabolomics, and other omics areas—have been proposed and heralded as the key to advancing precision medicine in the clinic. In the field of precision oncology, genomics approaches, and, more recently, other omics analyses have helped reveal several key mechanisms in cancer development, treatment resistance, and recurrence risk, and several of these findings have been implemented in clinical oncology to help guide treatment decisions. However, truly integrated multi-omics analyses have not been applied widely, preventing further advances in precision medicine. Additional efforts are needed to develop the analytical infrastructure necessary to generate, analyze, and annotate multi-omics data effectively to inform precision medicine-based decision-making. Full article

(This article belongs to the Special Issue The Promise of Precision Oncology: Molecular Strategies, Methods, Pharmacogenomics and Informatics)

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13 pages, 647 KiB

Open AccessReview

SUMOylation in Glioblastoma: A Novel Therapeutic Target

by Brandon M. Fox, Andrew Janssen, Dagoberto Estevez-Ordonez, Florian Gessler, Nunzio Vicario, Gustavo Chagoya, Galal Elsayed, Houman Sotoudeh, William Stetler, Gregory K. Friedman and Joshua D. Bernstock

Int. J. Mol. Sci. 2019, 20(8), 1853; https://doi.org/10.3390/ijms20081853 - 15 Apr 2019

Cited by 10 | Viewed by 4165

Abstract

Protein SUMOylation is a dynamic post-translational modification which is involved in a diverse set of physiologic processes throughout the cell. Of note, SUMOylation also plays a role in the pathobiology of a myriad of cancers, one of which is glioblastoma (GBM). Accordingly, herein, we review core aspects of SUMOylation as it relates to GBM and in so doing highlight putative methods/modalities capable of therapeutically engaging the pathway for treatment of this deadly neoplasm. Full article

(This article belongs to the Special Issue The Promise of Precision Oncology: Molecular Strategies, Methods, Pharmacogenomics and Informatics)

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