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Advance in Targeted Cancer Therapy and Mechanisms of Resistance—2nd Edition
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Advance in Targeted Cancer Therapy and Mechanisms of Resistance—2nd Edition

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 (30 June 2024) | Viewed by 13558

Special Issue Editors

Dr. Patrick Ming-Kuen Tang

E-Mail Website
Guest Editor
State Key Laboratory of Translational Oncology, Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
Interests: tumor microenvironment; drug resistance; immunotherapy; cell engineering; gene therapy
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Dongmei Zhang

E-Mail Website
Guest Editor
College of Pharmacy, Jinan University, Guangzhou 510632, China
Interests: pharmacology; oncology; drug delivery; pericytes; angiogenesis; endothelial progenitor cell; extracellular vesicle; tyrosine kinase inhibitor
Special Issues, Collections and Topics in MDPI journals
Dr. Yan-Fang Xian

E-Mail Website
Guest Editor
School of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong
Interests: Chinese medicine; pancreatic cancer; prostate cancer; herb-drug interaction; resistance
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are launching a Special Issue entitled “Advance in Targeted Cancer Therapy and Mechanisms of Resistance—2nd Edition” with the aim of rapidly sharing novel findings about anti-cancer therapy and their barriers in the research of molecular aspects of all types of human cancers.

We encourage submissions of high-quality manuscripts that provide novel mechanistic insights and details of the molecular signatures of oncogenic transformation, ranging from basic sciences to preclinical research as well as clinical study. Particularly, studies that focus on translating basic molecular knowledge to new applications in oncology are the most welcome.

The scope of this Special Issue includes, but is not limited to, the following topics:

  • Biological processes or molecular pathways for cancer development and progression.
  • Mechanisms of primary and secondary drug resistance.
  • Immunodynamics in tumour microenvironment regulating drug response.
  • Genomic profiling or any other ‘systems biology’ approaches in understanding acquired resistance.
  • Research that leads to novel therapies against advanced cancers and resistance.
  • Natural compound-based targeted therapy.

More published papers can be found in the closed Special Issue of our first edition: Advance in Targeted Cancer Therapy and Mechanisms of Resistance. We are looking forward to receiving your high-quality submissions.

Dr. Patrick Ming-Kuen Tang
Prof. Dr. Dongmei Zhang
Dr. Yan-Fang Xian
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 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
  • drug resistance
  • tumor microenvironment
  • cancer progression
  • molecular profiling
  • immunosurveillance
  • immunotherapy
  • gene therapy
  • biomarker

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Further information on MDPI's Special Issue polices can be found here.

Published Papers (8 papers)

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Research

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17 pages, 5757 KiB  
Article
Generation of Novel Tumour-Selective SEA Superantigen-Based Peptides with Improved Safety and Efficacy for Precision Cancer Immunotherapy
by Sara S. Bashraheel, Haya Al-Sulaiti and Sayed K. Goda
Int. J. Mol. Sci. 2024, 25(17), 9423; https://doi.org/10.3390/ijms25179423 - 30 Aug 2024
Viewed by 672
Abstract
Bacterial superantigens are T-cell-stimulatory protein molecules which produce massive cytokines and cause human diseases. Due to their ability to activate up to 20% of resting T-cells, they have effectively killed T-cell-dependent tumours in vivo. However, the intrinsic toxicity of whole SAg molecules highlights [...] Read more.
Bacterial superantigens are T-cell-stimulatory protein molecules which produce massive cytokines and cause human diseases. Due to their ability to activate up to 20% of resting T-cells, they have effectively killed T-cell-dependent tumours in vivo. However, the intrinsic toxicity of whole SAg molecules highlights the urgent need to develop more effective and safer SAg-based immunotherapy. With its unique approach, our study is a significant step towards developing safer tumour-targeted superantigen peptides (TTSP). We identified the T-cell activation function regions on the SEA superantigen and produced variants with minimal lethality, ensuring a safer approach to cancer treatment. This involved the creation of twenty 50-amino-acid-long overlapping peptides covering the full-length SEA superantigen (P1-P20). We then screened these peptides for T-cell activation, successfully isolating two peptides (P5 and P15) with significant T-cell activation. These selected peptides were used to design and synthesise tumour-targeted superantigen peptides, which were linked to a cancer-specific third loop (L3) of transforming growth factor-α (TGF-α), TGFαL3 from either a C’ or N’ terminal with an eight-amino-acid flexible linker in between. We also produced several P15 variants by changing single amino acids or by amino acid deletions. The novel molecules were then investigated for cytokine production and tumour-targeted killing. The findings from our previous study and the current work open up new avenues for peptide-based immunotherapy, particularly when combined with other immunotherapy techniques, thereby ensuring effective and safer cancer treatment. Full article
(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance—2nd Edition)
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24 pages, 4659 KiB  
Article
The Expression Profiles of lncRNAs Are Associated with Neoadjuvant Chemotherapy Resistance in Locally Advanced, Luminal B-Type Breast Cancer
by Miguel González-Woge, Laura Contreras-Espinosa, José Antonio García-Gordillo, Sergio Aguilar-Villanueva, Enrique Bargallo-Rocha, Paula Cabrera-Galeana, Tania Vasquez-Mata, Ximena Cervantes-López, Diana Sofía Vargas-Lías, Rogelio Montiel-Manríquez, Luis Bautista-Hinojosa, Rosa Rebollar-Vega, Clementina Castro-Hernández, Rosa María Álvarez-Gómez, Inti Alberto De La Rosa-Velázquez, José Díaz-Chávez, Francisco Jiménez-Trejo, Cristian Arriaga-Canon and Luis Alonso Herrera
Int. J. Mol. Sci. 2024, 25(15), 8077; https://doi.org/10.3390/ijms25158077 - 24 Jul 2024
Viewed by 1198
Abstract
lncRNAs are noncoding transcripts with tissue and cancer specificity. Particularly, in breast cancer, lncRNAs exhibit subtype-specific expression; they are particularly upregulated in luminal tumors. However, no gene signature-based laboratory tests have been developed for luminal breast cancer identification or the differential diagnosis of [...] Read more.
lncRNAs are noncoding transcripts with tissue and cancer specificity. Particularly, in breast cancer, lncRNAs exhibit subtype-specific expression; they are particularly upregulated in luminal tumors. However, no gene signature-based laboratory tests have been developed for luminal breast cancer identification or the differential diagnosis of luminal tumors, since no luminal A- or B-specific genes have been identified. Particularly, luminal B patients are of clinical interest, since they have the most variable response to neoadjuvant treatment; thus, it is necessary to develop diagnostic and predictive biomarkers for these patients to optimize treatment decision-making and improve treatment quality. In this study, we analyzed the lncRNA expression profiles of breast cancer cell lines and patient tumor samples from RNA-Seq data to identify an lncRNA signature specific for luminal phenotypes. We identified an lncRNA signature consisting of LINC01016, GATA3-AS1, MAPT-IT1, and DSCAM-AS1 that exhibits luminal subtype-specific expression; among these lncRNAs, GATA3-AS1 is associated with the presence of residual disease (Wilcoxon test, p < 0.05), which is related to neoadjuvant chemotherapy resistance in luminal B breast cancer patients. Furthermore, analysis of GATA3-AS1 expression using RNA in situ hybridization (RNA ISH) demonstrated that this lncRNA is detectable in histological slides. Similar to estrogen receptors and Ki67, both commonly detected biomarkers, GATA3-AS1 proves to be a suitable predictive biomarker for clinical application in breast cancer laboratory tests. Full article
(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance—2nd Edition)
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14 pages, 17301 KiB  
Article
CHI3L1 as a Prognostic Biomarker and Therapeutic Target in Glioma
by Jue Zhou, Dongxu Zhao, Haoyuan Tan, Jin Lan and Yinghui Bao
Int. J. Mol. Sci. 2024, 25(13), 7094; https://doi.org/10.3390/ijms25137094 - 28 Jun 2024
Viewed by 1166
Abstract
The role of Chitinase-3-like protein 1 (CHI3L1) in tumor progression has been gradually clarified in different kinds of solid tumors. Hence, we aim to elucidate its prognostic value for glioma. In this study, we analyzed RNA sequencing data combined with corresponding clinical information [...] Read more.
The role of Chitinase-3-like protein 1 (CHI3L1) in tumor progression has been gradually clarified in different kinds of solid tumors. Hence, we aim to elucidate its prognostic value for glioma. In this study, we analyzed RNA sequencing data combined with corresponding clinical information obtained from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases. Differentially expressed genes (DEGs) were acquired based on CHI3L1 expression profiles and were used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Cox regression, least absolute shrinkage and selection operator (LASSO) regression methods, along with a nomogram, were employed to establish a predictive model. Compared with the corresponding non-tumor tissues, CHI3L1 expression was significantly upregulated in various types of solid tumors, correlating with poor clinical outcomes including glioma. GO analysis identified oxidative stress-related genes (ORGs) that were differentially expressed and modulated by CHI3L1, with 11 genes subsequently identified as potential predictors, using Univariate-Cox regression and LASSO regression. In addition, an index of oxidative stress-related genes (ORGI) was established, demonstrating its prognostic value in conjunction with CHI3L1 expression. The aberrant expression of CHI3L1 was proved in glioma patients through immunohistochemistry (IHC). Meanwhile, the knockdown of CHI3L1 inhibited glioma growth in vitro, and real-time Quantitative PCR (qPCR) confirmed decreased ORG expression upon CHI3L1 knockdown, suggesting the potential prognostic value of CHI3L1 as a therapeutic target for glioma. Full article
(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance—2nd Edition)
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17 pages, 3277 KiB  
Article
A Multi-Omics Approach Reveals Enrichment in Metabolites Involved in the Regulation of the Glutathione Pathway in LIN28B-Dependent Cancer Cells
by Matteo Stocchero, Diana Corallo, Silvia Bresolin, Marcella Pantile, Paola Pirillo, Roberta Bortolozzi, Sara Menegazzo, Daniele Boso, Giampietro Viola, Eugenio Baraldi, Alessandra Biffi, Giuseppe Giordano and Sanja Aveic
Int. J. Mol. Sci. 2024, 25(3), 1602; https://doi.org/10.3390/ijms25031602 - 27 Jan 2024
Viewed by 1469
Abstract
The RNA-binding protein LIN28B, identified as an independent risk factor in high-risk neuroblastoma patients, is implicated in adverse treatment outcomes linked to metastasis and chemoresistance. Despite its clinical significance, the impact of LIN28B on neuroblastoma cell metabolism remains unexplored. This study employs a [...] Read more.
The RNA-binding protein LIN28B, identified as an independent risk factor in high-risk neuroblastoma patients, is implicated in adverse treatment outcomes linked to metastasis and chemoresistance. Despite its clinical significance, the impact of LIN28B on neuroblastoma cell metabolism remains unexplored. This study employs a multi-omics approach, integrating transcriptome and metabolome data, to elucidate the global metabolic program associated with varying LIN28B expression levels over time. Our findings reveal that escalating LIN28B expression induces a significant metabolic rewiring in neuroblastoma cells. Specifically, LIN28B prompts a time-dependent increase in the release rate of metabolites related to the glutathione and aminoacyl-tRNA biosynthetic pathways, concomitant with a reduction in glucose uptake. These results underscore the pivotal role of LIN28B in governing neuroblastoma cell metabolism and suggest a potential disruption in the redox balance of LIN28B-bearing cells. This study offers valuable insights into the molecular mechanisms underlying LIN28B-associated adverse outcomes in neuroblastoma, paving the way for targeted therapeutic interventions. Full article
(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance—2nd Edition)
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17 pages, 8516 KiB  
Article
CRISPR/Cas9-Mediated CtBP1 Gene Editing Enhances Chemosensitivity and Inhibits Metastatic Potential in Esophageal Squamous Cell Carcinoma Cells
by Javed Akhtar, Muhammad Imran and Guanyu Wang
Int. J. Mol. Sci. 2023, 24(18), 14030; https://doi.org/10.3390/ijms241814030 - 13 Sep 2023
Viewed by 1652
Abstract
Innovative therapeutic strategies for esophageal squamous cell carcinoma (ESCC) are urgently required due to the limited effectiveness of standard chemotherapies. C-Terminal Binding Protein 1 (CtBP1) has been implicated in various cancers, including ESCC. However, the precise expression patterns and functional roles of CtBP1 [...] Read more.
Innovative therapeutic strategies for esophageal squamous cell carcinoma (ESCC) are urgently required due to the limited effectiveness of standard chemotherapies. C-Terminal Binding Protein 1 (CtBP1) has been implicated in various cancers, including ESCC. However, the precise expression patterns and functional roles of CtBP1 in ESCC remain inadequately characterized. In this study, we aimed to investigate CtBP1 expression and its role in the resistance of ESCC to paclitaxel, an effective chemotherapeutic agent. Western blotting and immunofluorescence were applied to assess CtBP1 expression in the TE-1 and KYSE-50 cell lines. We observed the marked expression of CtBP1, which was associated with enhanced proliferation, invasion, and metastasis in these cell lines. Further, we successfully generated paclitaxel resistant ESCC cell lines and conducted cell viability assays. We employed the CRISPR/Cas9 genome editing system to disable the CtBP1 gene in ESCC cell lines. Through the analysis of the drug dose–response curve, we assessed the sensitivity of these cell lines in different treatment groups. Remarkably, CtBP1-disabled cell lines displayed not only improved sensitivity but also a remarkable inhibition of proliferation, invasion, and metastasis. This demonstrates that CtBP1 may promote ESCC cell malignancy and confer paclitaxel resistance. In summary, our study opens a promising avenue for targeted therapies, revealing the potential of CtBP1 inhibition to enhance the effectiveness of paclitaxel treatment for the personalized management of ESCC. Full article
(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance—2nd Edition)
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13 pages, 2248 KiB  
Article
AMPK/FOXO3a Pathway Increases Activity and/or Expression of ATM, DNA-PKcs, Src, EGFR, PDK1, and SOD2 and Induces Radioresistance under Nutrient Starvation
by Yusuke Urushihara, Takuma Hashimoto, Yohei Fujishima and Yoshio Hosoi
Int. J. Mol. Sci. 2023, 24(16), 12828; https://doi.org/10.3390/ijms241612828 - 15 Aug 2023
Cited by 1 | Viewed by 1571
Abstract
Most solid tumors contain hypoxic and nutrient-deprived microenvironments. The cancer cells in these microenvironments have been reported to exhibit radioresistance. We have previously reported that nutrient starvation increases the expression and/or activity of ATM and DNA-PKcs, which are involved in the repair of [...] Read more.
Most solid tumors contain hypoxic and nutrient-deprived microenvironments. The cancer cells in these microenvironments have been reported to exhibit radioresistance. We have previously reported that nutrient starvation increases the expression and/or activity of ATM and DNA-PKcs, which are involved in the repair of DNA double-strand breaks induced by ionizing radiation. In the present study, to elucidate the molecular mechanisms underlying these phenomena, we investigated the roles of AMPK and FOXO3a, which play key roles in the cellular response to nutrient starvation. Nutrient starvation increased clonogenic cell survival after irradiation and increased the activity and/or expression of AMPKα, FOXO3a, ATM, DNA-PKcs, Src, EGFR, PDK1, and SOD2 in MDA-MB-231 cells. Knockdown of AMPKα using siRNA suppressed the activity and/or expression of FOXO3a, ATM, DNA-PKcs, Src, EGFR, PDK1, and SOD2 under nutrient starvation. Knockdown of FOXO3a using siRNA suppressed the activity and/or expression of AMPKα, ATM, DNA-PKcs, FOXO3a, Src, EGFR, PDK1, and SOD2 under nutrient starvation. Nutrient starvation decreased the incidence of apoptosis after 8 Gy irradiation. Knockdown of FOXO3a increased the incidence of apoptosis after irradiation under nutrient starvation. AMPK and FOXO3a appear to be key molecules that induce radioresistance under nutrient starvation and may serve as targets for radiosensitization. Full article
(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance—2nd Edition)
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Review

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16 pages, 924 KiB  
Review
Targeting BTK in B Cell Malignancies: From Mode of Action to Resistance Mechanisms
by Samir Mouhssine, Nawar Maher, Bassam Francis Matti, Alaa Fadhil Alwan and Gianluca Gaidano
Int. J. Mol. Sci. 2024, 25(6), 3234; https://doi.org/10.3390/ijms25063234 - 12 Mar 2024
Cited by 6 | Viewed by 2992
Abstract
The B cell receptor (BCR) signaling pathway plays a crucial role in B cell development and contributes to the pathogenesis of B cell neoplasms. In B cell malignancies, the BCR is constitutively active through both ligand-dependent and ligand-independent mechanisms, resulting in continuous Bruton [...] Read more.
The B cell receptor (BCR) signaling pathway plays a crucial role in B cell development and contributes to the pathogenesis of B cell neoplasms. In B cell malignancies, the BCR is constitutively active through both ligand-dependent and ligand-independent mechanisms, resulting in continuous Bruton tyrosine kinase (BTK) signaling activation, which provides a survival and proliferation advantage to the neoplastic clone. Among B cell malignancies, those in which the most significant results were obtained by treatment with BTK inhibitors (BTKi) include chronic lymphocytic leukemia, mantle cell lymphoma, lymphoplasmacytic lymphoma, and diffuse large B cell lymphoma. Covalent BTKi (namely ibrutinib, acalabrutinib, and zanubrutinib) functions by irreversibly blocking BTK through covalent binding to the cysteine residue 481 (Cys-481) in the ATP-binding domain. Despite the high efficacy and safety of BTKi treatment, a significant fraction of patients affected by B cell malignancies who are treated with these drugs experience disease relapse. Several mechanisms of resistance to covalent BTKi, including Cys-481 mutations of BTK, have been investigated in B cell malignancies. Non-covalent BTKi, such as pirtobrutinib, have been developed and proven effective in patients carrying both Cys-481-mutated and unmutated BTK. Moreover, targeting BTK with proteolysis-targeting chimeras (PROTACs) represents a promising strategy to overcome resistance to BTKi in B cell neoplasms. Full article
(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance—2nd Edition)
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18 pages, 567 KiB  
Review
Genetic and Epigenetic Characteristics in Isolated Pancreatic Metastases of Clear-Cell Renal Cell Carcinoma
by Franz Sellner, Eva Compérat and Martin Klimpfinger
Int. J. Mol. Sci. 2023, 24(22), 16292; https://doi.org/10.3390/ijms242216292 - 14 Nov 2023
Cited by 2 | Viewed by 1716
Abstract
Isolated pancreatic metastases of renal cell carcinoma (IsPMRCC) are a rare manifestation of metastatic, clear-cell renal cell carcinoma (RCC) in which distant metastases occur exclusively in the pancreas. In addition to the main symptom of the isolated occurrence of pancreatic metastases, the entity [...] Read more.
Isolated pancreatic metastases of renal cell carcinoma (IsPMRCC) are a rare manifestation of metastatic, clear-cell renal cell carcinoma (RCC) in which distant metastases occur exclusively in the pancreas. In addition to the main symptom of the isolated occurrence of pancreatic metastases, the entity surprises with additional clinical peculiarities: (a) the unusually long interval of about 9 years between the primary RCC and the onset of pancreatic metastases; (b) multiple pancreatic metastases occurring in 36% of cases; (c) favourable treatment outcomes with a 75% 5-year survival rate; and (d) volume and growth-rate dependent risk factors generally accepted to be relevant for overall survival in metastatic surgery are insignificant in isPMRCC. The genetic and epigenetic causes of exclusive pancreatic involvement have not yet been investigated and are currently unknown. Conversely, according to the few available data in the literature, the following genetic and epigenetic peculiarities can already be identified as the cause of the protracted course: 1. high genetic stability of the tumour cell clones in both the primary tumour and the pancreatic metastases; 2. a low frequency of copy number variants associated with aggressiveness, such as 9p, 14q and 4q loss; 3. in the chromatin-modifying genes, a decreased rate of PAB1 (3%) and an increased rate of PBRM1 (77%) defects are seen, a profile associated with a favourable course; 4. an increased incidence of KDM5C mutations, which, in common with increased PBRM1 alterations, is also associated with a favourable outcome; and 5. angiogenetic biomarkers are increased in tumour tissue, while inflammatory biomarkers are decreased, which explains the good response to TKI therapy and lack of sensitivity to IT. Full article
(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance—2nd Edition)
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