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Novel Targeted Therapies in Cancer
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Novel Targeted Therapies in Cancer

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 (10 July 2023) | Viewed by 14571

Special Issue Editor

Prof. Dr. Evgeny Imyanitov

E-Mail Website
Guest Editor
1. Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
2. Department of Medical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
Interests: translational medicine; molecular diagnostics; molecular oncology; targeted therapy; clinical genetics

Special Issue Information

Dear Colleagues,

Identification of key pathways of cancer pathogenesis is among the most spectacular achievements of modern biomedical science. A handful of druggable vulnerabilities of malignant cells have been discovered in the past, being represented mainly by various dependencies from pathologically activated enzymes or tumor-selective deficiencies in cell maintenance mechanisms. This knowledge has led to the development of a new category of drugs, which are intentionally designed to target a certain biological molecule while avoiding off-target effects. There are a few dozen well-validated targets in cancer cells, with a few hundred novel drugs being approved or undergoing final phases of clinical development. These therapies have revolutionized the treatment of lung, colorectal, breast, ovarian, skin, and other malignancies. Current advances in targeted therapy for cancer deserve thorough discussion and are of significant interest for a wide audience of readers.

Prof. Dr. Evgeny Imyanitov
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

  • targeted therapy
  • cancer
  • precision medicine
  • kinase inhibitors
  • therapeutic antibodies
  • signaling pathways
  • cancer vulnerabilities

Published Papers (6 papers)

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Research

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12 pages, 1915 KiB  
Communication
Cost-Efficient Detection of NTRK1/2/3 Gene Fusions: Single-Center Analysis of 8075 Tumor Samples
by Aleksandr A. Romanko, Rimma S. Mulkidjan, Vladislav I. Tiurin, Evgeniya S. Saitova, Elena V. Preobrazhenskaya, Elena A. Krivosheyeva, Natalia V. Mitiushkina, Anna D. Shestakova, Evgeniya V. Belogubova, Alexandr O. Ivantsov, Aglaya G. Iyevleva and Evgeny N. Imyanitov
Int. J. Mol. Sci. 2023, 24(18), 14203; https://doi.org/10.3390/ijms241814203 - 17 Sep 2023
Cited by 4 | Viewed by 1316
Abstract
The majority of NTRK1, NTRK2, and NTRK3 rearrangements result in increased expression of the kinase portion of the involved gene due to its fusion to an actively transcribed gene partner. Consequently, the analysis of 5′/3′-end expression imbalances is potentially capable of [...] Read more.
The majority of NTRK1, NTRK2, and NTRK3 rearrangements result in increased expression of the kinase portion of the involved gene due to its fusion to an actively transcribed gene partner. Consequently, the analysis of 5′/3′-end expression imbalances is potentially capable of detecting the entire spectrum of NTRK gene fusions. Archival tumor specimens obtained from 8075 patients were subjected to manual dissection of tumor cells, DNA/RNA isolation, and cDNA synthesis. The 5′/3′-end expression imbalances in NTRK genes were analyzed by real-time PCR. Further identification of gene rearrangements was performed by variant-specific PCR for 44 common NTRK fusions, and, whenever necessary, by RNA-based next-generation sequencing (NGS). cDNA of sufficient quality was obtained in 7424/8075 (91.9%) tumors. NTRK rearrangements were detected in 7/6436 (0.1%) lung carcinomas, 11/137 (8.0%) pediatric tumors, and 13/851 (1.5%) adult non-lung malignancies. The highest incidence of NTRK translocations was observed in pediatric sarcomas (7/39, 17.9%). Increased frequency of NTRK fusions was seen in microsatellite-unstable colorectal tumors (6/48, 12.5%), salivary gland carcinomas (5/93, 5.4%), and sarcomas (7/143, 4.9%). None of the 1293 lung carcinomas with driver alterations in EGFR/ALK/ROS1/RET/MET oncogenes had NTRK 5′/3′-end expression imbalances. Variant-specific PCR was performed for 744 tumors with a normal 5′/3′-end expression ratio: there were no rearrangements in 172 EGFR/ALK/ROS1/RET/MET-negative lung cancers and 125 pediatric tumors, while NTRK3 fusions were detected in 2/447 (0.5%) non-lung adult malignancies. In conclusion, this study describes a diagnostic pipeline that can be used as a cost-efficient alternative to conventional methods of NTRK1–3 analysis. Full article
(This article belongs to the Special Issue Novel Targeted Therapies in Cancer)
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17 pages, 2433 KiB  
Article
Design, Synthesis and Anti-Melanoma Activity of Novel Annexin V Derivative with β3-Integrin Affinity
by Jingyi Zhu, Wenjuan Li and Jian Jing
Int. J. Mol. Sci. 2023, 24(13), 11107; https://doi.org/10.3390/ijms241311107 - 5 Jul 2023
Viewed by 1131
Abstract
Tumor tissues often exhibit unique integrin receptor presentation during development, such as high exposures of αvβ3 and αIIbβ3 integrins. These features are not present in normal tissues. The induction of selective thrombosis and infarction in the tumor-feeding [...] Read more.
Tumor tissues often exhibit unique integrin receptor presentation during development, such as high exposures of αvβ3 and αIIbβ3 integrins. These features are not present in normal tissues. The induction of selective thrombosis and infarction in the tumor-feeding vessels, as well as specific antagonism of αvβ3 integrin on the surface of tumor endothelial cells, is a potential novel antitumor strategy. The Echistatin–Annexin V (EAV) fusion protein is a novel Annexin V (ANV) derivative that possesses a high degree of αvβ3 and αIIbβ3 integrin receptor recognition and binding characteristics while retaining the specific binding ability of the natural ANV molecule for phosphatidylserine (PS). We systematically investigated the biological effects of this novel molecule with superimposed functions on mouse melanoma. We found that EAV inhibited the viability and migration of B16F10 murine melanoma cells in a dose-dependent manner, exhibited good tumor suppressive effects in a xenograft mouse melanoma model, strongly induced tumor tissue necrosis in mice, and targeted the inhibition of angiogenesis in mouse melanoma tumor tissue. EAV exhibited stronger biological effects than natural ANV molecules in inhibiting melanoma in mice. The unique biological effects of EAV are based on its high β3-type integrin receptor-specific recognition and binding ability, as well as its highly selective binding to PS molecules. Based on these findings, we propose that EAV-mediated tumor suppression is a novel and promising antitumor strategy that targets both PS- and integrin β3-positive tumor neovascularization and the tumor cells themselves, thus providing a possible mechanism for the treatment of melanoma. Full article
(This article belongs to the Special Issue Novel Targeted Therapies in Cancer)
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19 pages, 6924 KiB  
Article
Eltrombopag Inhibits Metastasis in Breast Carcinoma by Targeting HuR Protein
by Yao Chen, Rui Zhang, Liuqing Yang, Pei Zhang, Feiyun Wang, Guoqiang Lin, Jiange Zhang and Yuying Zhu
Int. J. Mol. Sci. 2023, 24(4), 3164; https://doi.org/10.3390/ijms24043164 - 5 Feb 2023
Viewed by 2155
Abstract
Eltrombopag is a small molecule TPO-R agonist that has been shown in our previous studies to inhibit tumor growth by targeting Human antigen R (HuR) protein. HuR protein not only regulates the mRNA stability of tumor growth-related genes, but it also regulates the [...] Read more.
Eltrombopag is a small molecule TPO-R agonist that has been shown in our previous studies to inhibit tumor growth by targeting Human antigen R (HuR) protein. HuR protein not only regulates the mRNA stability of tumor growth-related genes, but it also regulates the mRNA stability of a variety of cancer metastasis-related genes, such as Snail, Cox-2, and Vegf-c. However, the role and mechanisms of eltrombopag in breast cancer metastasis have not been fully investigated. The purpose of this study was to investigate whether eltrombopag can inhibit breast cancer metastasis by targeting HuR. Our study first found that eltrombopag can destroy HuR-AU-rich element (ARE) complexes at the molecular level. Secondly, eltrombopag was found to suppress 4T1 cell migration and invasion and inhibit macrophage-mediated lymphangiogenesis at the cellular level. In addition, eltrombopag exerted inhibitory effects on lung and lymph node metastasis in animal tumor metastasis models. Finally, it was verified that eltrombopag inhibited the expressions of Snail, Cox-2, and Vegf-c in 4T1 cells and Vegf-c in RAW264.7 cells by targeting HuR. In conclusion, eltrombopag displayed antimetastatic activity in breast cancer in an HuR dependent manner, which may provide a novel application for eltrombopag, hinting at the multiple effects of HuR inhibitors in cancer therapy. Full article
(This article belongs to the Special Issue Novel Targeted Therapies in Cancer)
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15 pages, 2089 KiB  
Article
AST-487 Inhibits RET Kinase Driven TERT Expression in Bladder Cancer
by Neeraj Agarwal, Qiong Zhou, Deepak Arya, Sébastien Rinaldetti, Jason Duex, Daniel V. LaBarbera and Dan Theodorescu
Int. J. Mol. Sci. 2022, 23(18), 10819; https://doi.org/10.3390/ijms231810819 - 16 Sep 2022
Viewed by 1999
Abstract
Mutations in the promoter of the human Telomerase Reverse Transcriptase (hTERT) gene are common and associated with its elevated expression in bladder cancer, melanoma, and glioblastoma. Though these mutations and TERT overexpression are associated with aggressive disease and poor outcome, an incomplete understanding [...] Read more.
Mutations in the promoter of the human Telomerase Reverse Transcriptase (hTERT) gene are common and associated with its elevated expression in bladder cancer, melanoma, and glioblastoma. Though these mutations and TERT overexpression are associated with aggressive disease and poor outcome, an incomplete understanding of mutant TERT regulation limits treatment options directed at this gene. Herein, we unravel a signaling pathway that leads to upregulated hTERT expression resulting from the −124 bp promoter mutation, the most frequent variant across human cancer. We employed engineered bladder cancer cells that harbor a GFP insertion at the TSS region on −124 hTERT promoter for high-content screening drug discovery using a focused library of ~800 kinase inhibitors. Studies using in vitro and in vivo models prioritized AST-487, an inhibitor of the wild-type, and mutant RET (rearranged during transfection) proto-oncogene as a novel drug inhibitor of both wild-type and mutant promoter-driven hTERT expression. We also identified the RET kinase pathway, targeted by AST-487, as a novel regulator of mutant hTERT promoter-driven transcription in bladder cancer cells. Collectively, our work provides new potential precision medicine approaches for cancer patients with upregulated hTERT expression, perhaps, especially those harboring mutations in both the RET gene and the hTERT promoter, such as in thyroid cancer. Full article
(This article belongs to the Special Issue Novel Targeted Therapies in Cancer)
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Review

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17 pages, 1031 KiB  
Review
Antibody-Drug Conjugates for Breast Cancer Treatment: Emerging Agents, Targets and Future Directions
by Tinglin Yang, Wenhui Li, Tao Huang and Jun Zhou
Int. J. Mol. Sci. 2023, 24(15), 11903; https://doi.org/10.3390/ijms241511903 - 25 Jul 2023
Cited by 3 | Viewed by 4344
Abstract
To achieve the scheme of “magic bullets” in antitumor therapy, antibody-drug conjugates (ADCs) were developed. ADCs consist of antibodies targeting tumor-specific antigens, chemical linkers, and cytotoxic payloads that powerfully kill cancer cells. With the approval of ado-trastuzumab emtansine (T-DM1) and fam-trastuzumab deruxtecan (T-DXd), [...] Read more.
To achieve the scheme of “magic bullets” in antitumor therapy, antibody-drug conjugates (ADCs) were developed. ADCs consist of antibodies targeting tumor-specific antigens, chemical linkers, and cytotoxic payloads that powerfully kill cancer cells. With the approval of ado-trastuzumab emtansine (T-DM1) and fam-trastuzumab deruxtecan (T-DXd), the therapeutic potentials of ADCs in breast cancer have come into the spotlight. Nearly 30 ADCs for breast cancer are under exploration to move targeted therapy forward. In this review, we summarize the presenting and emerging agents and targets of ADCs. The ADC structure and development history are also concluded. Moreover, the challenges faced and prospected future directions in this field are reviewed, which give insights into novel treatments with ADCs for breast cancer. Full article
(This article belongs to the Special Issue Novel Targeted Therapies in Cancer)
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17 pages, 2179 KiB  
Review
Mechanisms of Neutrophil Extracellular Trap Formation and Regulation in Cancers
by Zhiyuan Zhang, Ruiying Niu, Longhao Zhao, Yufei Wang and Guangwei Liu
Int. J. Mol. Sci. 2023, 24(12), 10265; https://doi.org/10.3390/ijms241210265 - 17 Jun 2023
Cited by 4 | Viewed by 2629
Abstract
As one of the most important components of the innate immune system, neutrophils are always at the forefront of the response to diseases. The immune functions of neutrophils include phagocytosis, degranulation, production of reactive oxygen species, and the production of neutrophil extracellular traps [...] Read more.
As one of the most important components of the innate immune system, neutrophils are always at the forefront of the response to diseases. The immune functions of neutrophils include phagocytosis, degranulation, production of reactive oxygen species, and the production of neutrophil extracellular traps (NETs). NETs are composed of deconcentrated chromatin DNA, histones, myeloperoxidase (MPO) and neutrophil elastase (NE), playing an important role in the resistance to some pathogenic microbial invasions. Until recent years, when NETs were found to play a critical role in cancer. NETs play bidirectional regulation both positive and negative roles in the development and progression of cancer. Targeted NETs may provide new therapeutic strategies for the treatment of cancer. However, the molecular and cellular regulatory mechanisms underlying the formation and role of NET in cancer remain unclear. This review just summarizes the recent progress in regulatory mechanisms about the formation of NETs and their role in cancers. Full article
(This article belongs to the Special Issue Novel Targeted Therapies in Cancer)
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