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Cancer: Novel Approaches in the Discovery and Design of Targeted Therapies

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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 May 2022) | Viewed by 22294

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Special Issue Editor

Dr. Morito Kurata

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Guest Editor

Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
Interests: oncogene; tumorigenesis; drug resistance; crispr screening; pathology

Special Issue Information

Dear Colleagues,

Efforts to discover drugs that can cure cancers are continuing. Tyrosine kinase inhibitors, such as imatinib, represent a significant achievement for the treatment of chronic myelogenous leukemia with a BCR-ABL translocation. BCR-ABL has a strong oncogenic effect and represents a good target for inhibition; therefore, finding oncogenic molecules is a straightforward way to find molecular targets. However, inhibitors for strong oncogenes, such as MYC and RAS, are not used at the clinical phage. Improved chemical approaches or other regulators of these genes await discovery. By contrast, molecular targets can be found using a variety of strategies. Comprehensive screening is one promising approach for identifying new oncogenic targets of cancer cell survival. The recent development of CRISPR screening now provides a powerful tool for finding essential molecules relevant to cancers. A CRISPR library can identify essential cancer-specific molecules that could also be therapeutic targets. CRISPR screenings with novel modified methods have revealed synergistic and synthetic lethal combinations of drugs. In addition, a CRISPR library can induce drug resistance by random mutation, and this would be useful for overcoming the serious concerns of drug resistance. This Special Issue focuses on studies related to basic strategies and comprehensive screening for molecular targets for cancer cures. Up-to-date review articles and commentaries are also welcome.

Dr. Morito Kurata
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.

Keywords

Cancer
Molecular Targeted therapy
Oncogene
Drug resisntance
CRISPR screening
Synthetic lethal
Synergistic drug

Published Papers (7 papers)

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Research

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13 pages, 2186 KiB

Open AccessArticle

Efficient Identification of the MYC Regulator with the Use of the CRISPR Library and Context-Matched Database Screenings

by Yosuke Tanaka, Hidetaka Kambayashi, Akiko Yamamoto, Iichiroh Onishi, Keisuke Sugita, Miwa Matsumura, Sachiko Ishibashi, Masumi Ikeda, Kouhei Yamamoto, Masanobu Kitagawa and Morito Kurata

Int. J. Mol. Sci. 2022, 23(14), 7723; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147723 - 13 Jul 2022

Cited by 1 | Viewed by 1695

Abstract

MYC is a major oncogene that plays an important role in cell proliferation in human cancers. Therefore, the mechanism behind MYC regulation is a viable therapeutic target for the treatment of cancer. Comprehensive and efficient screening of MYC regulators is needed, and we had previously established a promoter screening system using fluorescent proteins and the CRISPR library. For the efficient identification of candidate genes, a database was used, for which mRNA expression was correlated with MYC using datasets featuring “Similar” and “Not exactly similar” contexts. INTS14 and ERI2 were identified using datasets featuring the “Similar” context group, and INTS14 and ERI2 were capable of enhancing MYC promoter activity. In further database analysis of human cancers, a higher expression of MYC mRNA was observed in the INTS14 mRNA high-expressing prostate and liver cancers. The knockdown of INTS14 in prostate cell lines resulted in decreased MYC mRNA and protein expression and also induced G0/1 arrest. This study confirmed that CRISPR screening combined with context-matched database screening is effective in identifying genes that regulate the MYC promoter. This method can be applied to other genes and is expected to be useful in identifying the regulators of other proto-oncogenes. Full article

(This article belongs to the Special Issue Cancer: Novel Approaches in the Discovery and Design of Targeted Therapies)

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14 pages, 36195 KiB

Open AccessArticle

PTK7, a Catalytically Inactive Receptor Tyrosine Kinase, Increases Oncogenic Phenotypes in Xenograft Tumors of Esophageal Squamous Cell Carcinoma KYSE-30 Cells

by Won-Sik Shin, Mi-Kyung Park, Jae Hoon Kim, Si Won Oh, Ji-Yun Jang, Ho Lee and Seung-Taek Lee

Int. J. Mol. Sci. 2022, 23(4), 2391; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042391 - 21 Feb 2022

Cited by 8 | Viewed by 2473

Abstract

Protein tyrosine kinase 7 (PTK7), a catalytically defective receptor protein tyrosine kinase, is upregulated in tumor tissues and cell lines of esophageal squamous cell carcinoma (ESCC). We showed that PTK7 plays an oncogenic role in various ESCC cell lines. However, its role as an oncogene has not been demonstrated in vivo. Here, we examined the influence of PTK7 on the tumorigenic potential of ESCC KYSE-30 cells, which are known to establish xenograft tumors. Overexpression of PTK7 enhanced the proliferation, adhesion, wound healing, and migration of KYSE-30 cells, and these effects were reversed by the knockdown of PTK7. PTK7 overexpression and knockdown, respectively, increased and decreased the tyrosine phosphorylation of cellular proteins and the phosphorylation of ERK, AKT, and FAK, which are important for cell proliferation, survival, adhesion, and migration. Additionally, PTK7 overexpression and silencing, respectively, increased and decreased the weight, volume, and number of Ki-67-positive proliferating cells in xenograft tumors of KYSE-30 cells. Therefore, we propose that PTK7 plays an important role in the tumorigenesis of ESCC cells in vivo and is a potential therapeutic target for ESCC. Full article

(This article belongs to the Special Issue Cancer: Novel Approaches in the Discovery and Design of Targeted Therapies)

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18 pages, 5398 KiB

Open AccessArticle

Novel Nitrogen-Based Chalcone Analogs Provoke Substantial Apoptosis in HER2-Positive Human Breast Cancer Cells via JNK and ERK1/ERK2 Signaling Pathways

by Balsam Rizeq, Ishita Gupta, Hadeel Kheraldine, Dana Elkhalifa, Halema F. Al-Farsi, Ala-Eddin Al Moustafa and Ashraf Khalil

Int. J. Mol. Sci. 2021, 22(17), 9621; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179621 - 06 Sep 2021

Cited by 5 | Viewed by 2200

Abstract

Natural chalcones possess antitumor properties and play a role as inducers of apoptosis, antioxidants and cytotoxic compounds. We recently reported that novel nitrogen chalcone-based compounds, which were generated in our lab, have specific effects on triple-negative breast cancer cells. However, the outcome of these two new compounds on human epidermal growth factor receptor 2 (HER2)-positive breast cancer remains nascent. Thus, we herein investigated the effects of these compounds (DK-13 and DK-14) on two HER2-positive breast cancer cell lines, SKBR3 and ZR75. Our data revealed that these compounds inhibit cell proliferation, deregulate cell-cycle progression and significantly induce cell apoptosis in both cell lines. Furthermore, the two chalcone compounds cause a significant reduction in the cell invasion ability of SKBR3 and ZR75 cancer cells. In parallel, we found that DK-13 and DK-14 inhibit colony formation of both cell lines in comparison to their matched controls. On the other hand, we noticed that these two compounds can inhibit angiogenesis in the chorioallantoic membrane model. The molecular pathway analysis of chalcone compounds exposed cells revealed that these compounds inhibit the expression of both JNK1/2/3 and ERK1/2, the major plausible molecular pathways behind these events. Our findings implicate that DK-13 and DK-14 possess effective chemotherapeutic outcomes against HER2-positive breast cancer via the ERK1/2 and JNK1/2/3 signaling pathways. Full article

(This article belongs to the Special Issue Cancer: Novel Approaches in the Discovery and Design of Targeted Therapies)

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17 pages, 3458 KiB

Open AccessArticle

NMNAT1 Is a Survival Factor in Actinomycin D-Induced Osteosarcoma Cell Death

by Alexandra Kiss, Csaba Csikos, Zsolt Regdon, Zsuzsanna Polgár, László Virág and Csaba Hegedűs

Int. J. Mol. Sci. 2021, 22(16), 8869; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168869 - 18 Aug 2021

Cited by 2 | Viewed by 3134

Abstract

Osteosarcoma is a frequent and extremely aggressive type of pediatric cancer. New therapeutic approaches are needed to improve the overall survival of osteosarcoma patients. Our previous results suggest that NMNAT1, a key enzyme in nuclear NAD⁺ synthesis, facilitates the survival of cisplatin-treated osteosarcoma cells. A high-throughput cytotoxicity screening was performed to identify novel pathways or compounds linked to the cancer-promoting role of NMNAT1. Nine compounds caused higher toxicity in the NMNAT1 KO U2OS cells compared to their wild type counterparts, and actinomycin D (ActD) was the most potent. ActD-treatment of NMNAT1 KO cells increased caspase activity and secondary necrosis. The reduced NAD⁺ content in NMNAT1 KO cells was further decreased by ActD, which partially inhibited NAD⁺-dependent enzymes, including the DNA nick sensor enzyme PARP1 and the NAD⁺-dependent deacetylase SIRT1. Impaired PARP1 activity increased DNA damage in ActD-treated NMNAT1 knockout cells, while SIRT1 impairment increased acetylation of the p53 protein, causing the upregulation of pro-apoptotic proteins (NOXA, BAX). Proliferation was decreased through both PARP- and SIRT-dependent pathways. On the one hand, PARP inhibitors sensitized wild type but not NMNAT1 KO cells to ActD-induced anti-clonogenic effects; on the other hand, over-acetylated p53 induced the expression of the anti-proliferative p21 protein leading to cell cycle arrest. Based on our results, NMNAT1 acts as a survival factor in ActD-treated osteosarcoma cells. By inhibiting both PARP1- and SIRT1-dependent cellular pathways, NMNAT1 inhibition can be a promising new tool in osteosarcoma chemotherapy. Full article

(This article belongs to the Special Issue Cancer: Novel Approaches in the Discovery and Design of Targeted Therapies)

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Review

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15 pages, 1242 KiB

Open AccessReview

To Discover the Efficient and Novel Drug Targets in Human Cancers Using CRISPR/Cas Screening and Databases

by Iichiroh Onishi, Kouhei Yamamoto, Yuko Kinowaki, Masanobu Kitagawa and Morito Kurata

Int. J. Mol. Sci. 2021, 22(22), 12322; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212322 - 15 Nov 2021

Cited by 7 | Viewed by 3399

Abstract

CRISPR/Cas has emerged as an excelle nt gene-editing technology and is used worldwide for research. The CRISPR library is an ideal tool for identifying essential genes and synthetic lethality targeted for cancer therapies in human cancers. Synthetic lethality is defined as multiple genetic abnormalities that, when present individually, do not affect function or survival, but when present together, are lethal. Recently, many CRISPR libraries are available, and the latest libraries are more accurate and can be applied to few cells. However, it is easier to efficiently search for cancer targets with their own screenings by effectively using databases of CRISPR screenings, such as Depmap portal, PICKLES (Pooled In-Vitro CRISPR Knockout Library Essentiality Screens), iCSDB, Project Score database, and CRISP-view. This review will suggest recent optimal CRISPR libraries and effective databases for Novel Approaches in the Discovery and Design of Targeted Therapies. Full article

(This article belongs to the Special Issue Cancer: Novel Approaches in the Discovery and Design of Targeted Therapies)

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29 pages, 10243 KiB

Open AccessReview

Nanobodies Enhancing Cancer Visualization, Diagnosis and Therapeutics

by Dhaneshree Bestinee Naidoo and Anil Amichund Chuturgoon

Int. J. Mol. Sci. 2021, 22(18), 9778; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189778 - 10 Sep 2021

Cited by 12 | Viewed by 3306

Abstract

Worldwide, cancer is a serious health concern due to the increasing rates of incidence and mortality. Conventional cancer imaging, diagnosis and treatment practices continue to substantially contribute to the fight against cancer. However, these practices do have some risks, adverse effects and limitations, which can affect patient outcomes. Although antibodies have been developed, successfully used and proven beneficial in various oncology practices, the use of antibodies also comes with certain challenges and limitations (large in size, poor tumor penetration, high immunogenicity and a long half-life). Therefore, it is vital to develop new ways to visualize, diagnose and treat cancer. Nanobodies are novel antigen-binding fragments that possess many advantageous properties (small in size, low immunogenicity and a short half-life). Thus, the use of nanobodies in cancer practices may overcome the challenges experienced with using traditional antibodies. In this review, we discuss (1) the challenges with antibody usage and the superior qualities of nanobodies; (2) the use of antibodies and nanobodies in cancer imaging, diagnosis, drug delivery and therapy (surgery, radiotherapy, chemotherapy and immunotherapy); and (3) the potential improvements in oncology practices due to the use of nanobodies as compared to antibodies. Full article

(This article belongs to the Special Issue Cancer: Novel Approaches in the Discovery and Design of Targeted Therapies)

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Graphical abstract

23 pages, 701 KiB

Open AccessReview

Overview of Ferroptosis and Synthetic Lethality Strategies

by Yuko Kinowaki, Towako Taguchi, Iichiroh Onishi, Susumu Kirimura, Masanobu Kitagawa and Kouhei Yamamoto

Int. J. Mol. Sci. 2021, 22(17), 9271; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179271 - 27 Aug 2021

Cited by 19 | Viewed by 4919

Abstract

Ferroptosis, a term first proposed in 2012, is iron-dependent, non-apoptotic regulatory cell death induced by erastin. Ferroptosis was originally discovered during synthetic lethal screening for drugs sensitive to RAS mutant cells, and is closely related to synthetic lethality. Ferroptosis sensitizes cancer stem cells and tumors that undergo epithelial−mesenchymal transition and are resistant to anticancer drugs or targeted therapy. Therefore, ferroptosis-inducing molecules are attractive new research targets. In contrast, synthetic lethal strategies approach mechanisms and genetic abnormalities that cannot be directly targeted by conventional therapeutic strategies, such as RAS mutations, hypoxia, and abnormalities in the metabolic environment. They also target the environment and conditions specific to malignant cells, have a low toxicity to normal cells, and can be used in combination with known drugs to produce new ones. However, the concept of synthetic lethality has not been widely adopted with ferroptosis. In this review, we surveyed the literature on ferroptosis-related factors and synthetic lethality to examine the potential therapeutic targets in ferroptosis-related molecules, focusing on factors related to synthetic lethality, discovery methods, clinical application stages, and issues in drug discovery. Full article

(This article belongs to the Special Issue Cancer: Novel Approaches in the Discovery and Design of Targeted Therapies)

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