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Molecular Advances in New Combination Therapies for Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 30 May 2024 | Viewed by 5694

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Special Issue Editors

Dr. Valeria Lucarini

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Guest Editor

Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
Interests: immunotherapy; chemotherapy; preclinical models; tumor microenvironment; combination anticancer therapies; target therapy

Dr. Camilla Palumbo

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Guest Editor

Department of Clinical Sciences and Translational Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy
Interests: molecular and cellular oncology; anticancer drugs sensitivity and resistance; combination therapy in cancer treatment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Increasingly, combination therapies are being used to treat many cancer patients. These treatments combine two or more drugs or therapies, such as chemotherapy, radiotherapy and immunotherapy. In recent decades, immunotherapy and targeted therapy have emerged as revolutionary options for cancer treatment, improving the survival of cancer patients. However, because tumors can become resistant to drugs and immunotherapy can only be used on a subset of patients, it is essential to find alternative therapeutic strategies. Therefore, the use of combination therapies represents a successful innovative strategy for cancer treatment and is more effective than monotherapy because it acts synergistically or additively on key pathways. Understanding the molecular biological characteristics of cancer facilitates the development of new approaches for combination therapies.

The purpose of this Special Issue is to collect original preclinical research articles or reviews on recent advances in the development of combination therapies used to treat cancer.

Dr. Valeria Lucarini
Dr. Camilla Palumbo
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

immunotherapy
target therapy
chemotherapy
tumor microenvironment
combination therapies
preclinical models

Published Papers (5 papers)

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Research

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19 pages, 4790 KiB

Open AccessArticle

Leucine Zipper Downregulated in Cancer-1 Interacts with Clathrin Adaptors to Control Epidermal Growth Factor Receptor (EGFR) Internalization and Gefitinib Response in EGFR-Mutated Non-Small Cell Lung Cancer

by Hsien-Neng Huang, Pin-Feng Hung, Yai-Ping Chen and Chia-Huei Lee

Int. J. Mol. Sci. 2024, 25(3), 1374; https://doi.org/10.3390/ijms25031374 - 23 Jan 2024

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Abstract

The epidermal growth factor receptor (EGFR) is a common driver of non-small cell lung cancer (NSCLC). Clathrin-mediated internalization (CMI) sustains EGFR signaling. AXL is associated with resistance to EGFR-tyrosine kinase inhibitors (TKIs) in EGFR-mutated (EGFR^M) NSCLC. We investigated the effects of Leucine zipper downregulated in cancer-1 (LDOC1) on EGFR CMI and NSCLC treatment. Coimmunoprecipitation, double immunofluorescence staining, confocal microscopy analysis, cell surface labelling assays, and immunohistochemistry studies were conducted. We revealed that LDOC1 interacts with clathrin adaptors through binding motifs. LDOC1 depletion promotes internalization and plasma membrane recycling of EGFR in EGFR^M NSCLC PC9 and HCC827 cells. Membranous and cytoplasmic EGFR decreased and increased, respectively, in LDOC1 (−) NSCLC tumors. LDOC1 depletion enhanced and sustained activation of EGFR, AXL, and HER2 and enhanced activation of HER3 in PC9 and HCC827 cells. Sensitivity to first-generation EGFR-TKIs (gefitinib and erlotinib) was significantly reduced in LDOC1-depleted PC9 and HCC827 cells. Moreover, LDOC1 downregulation was significantly associated (p < 0.001) with poor overall survival in patients with EGFR^M NSCLC receiving gefitinib (n = 100). In conclusion, LDOC1 may regulate the efficacy of first-generation EGFR-TKIs by participating in the CMI of EGFR. Accordingly, LDOC1 may function as a prognostic biomarker for EGFR^M NSCLC. Full article

(This article belongs to the Special Issue Molecular Advances in New Combination Therapies for Cancer)

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Graphical abstract

14 pages, 3195 KiB

Open AccessArticle

Therapeutic Effects of Perilla Phenols in Oral Squamous Cell Carcinoma

by Chia-Huei Lee, Yu-Hsin Tsao, Yui-Ping Weng, I-Ching Wang, Yao-Ping Chen and Pin-Feng Hung

Int. J. Mol. Sci. 2023, 24(19), 14931; https://doi.org/10.3390/ijms241914931 - 05 Oct 2023

Cited by 1 | Viewed by 959

Abstract

The herbal medicine perilla leaf extract (PLE) exhibits various pharmacological properties. We showed that PLE inhibits the viability of oral squamous cell carcinoma (OSCC) cells. HPLC analysis revealed that caffeic acid (CA) and rosmarinic acid (RA) are the two main phenols in PLE, and reduced OSCC cell viability in a dose-dependent manner. The optimal CA/RA combination ratio was 1:2 at concentrations of 300–500 μM but had no synergistic inhibitory effect on the viability of OSCC cells. CA, RA, or their combination effectively suppressed interleukin (IL)-1β secretion by OSCC OC3 cells. Long-term treatment with CA and CA/RA mixtures, respectively, induced EGFR activation, which might cause OC3 cells to become EGFR-dependent and consequently increased the sensitivity of OC3 cells to a low dose (5 μM) of the EGFR tyrosine kinase inhibitor gefitinib. Chronic treatment with CA, RA, or their combination exhibited an inhibitory effect more potent than that of low-dose (1 μM) cisplatin on the colony formation ability of OSCC cells; this may be attributed to the induction of apoptosis by these treatments. These findings suggest that perilla phenols, particularly CA and RA, can be used as adjuvant therapies to improve the efficacy of chemotherapy and EGFR-targeted therapy in OSCC. Full article

(This article belongs to the Special Issue Molecular Advances in New Combination Therapies for Cancer)

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20 pages, 6898 KiB

Open AccessArticle

Functional Profiling of Soft Tissue Sarcoma Using Mechanistic Models

by Miriam Payá-Milans, María Peña-Chilet, Carlos Loucera, Marina Esteban-Medina and Joaquín Dopazo

Int. J. Mol. Sci. 2023, 24(19), 14732; https://doi.org/10.3390/ijms241914732 - 29 Sep 2023

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Abstract

Soft tissue sarcoma is an umbrella term for a group of rare cancers that are difficult to treat. In addition to surgery, neoadjuvant chemotherapy has shown the potential to downstage tumors and prevent micrometastases. However, finding effective therapeutic targets remains a research challenge. Here, a previously developed computational approach called mechanistic models of signaling pathways has been employed to unravel the impact of observed changes at the gene expression level on the ultimate functional behavior of cells. In the context of such a mechanistic model, RNA-Seq counts sourced from the Recount3 resource, from The Cancer Genome Atlas (TCGA) Sarcoma project, and non-diseased sarcomagenic tissues from the Genotype-Tissue Expression (GTEx) project were utilized to investigate signal transduction activity through signaling pathways. This approach provides a precise view of the relationship between sarcoma patient survival and the signaling landscape in tumors and their environment. Despite the distinct regulatory alterations observed in each sarcoma subtype, this study identified 13 signaling circuits, or elementary sub-pathways triggering specific cell functions, present across all subtypes, belonging to eight signaling pathways, which served as predictors for patient survival. Additionally, nine signaling circuits from five signaling pathways that highlighted the modifications tumor samples underwent in comparison to normal tissues were found. These results describe the protective role of the immune system, suggesting an anti-tumorigenic effect in the tumor microenvironment, in the process of tumor cell detachment and migration, or the dysregulation of ion homeostasis. Also, the analysis of signaling circuit intermediary proteins suggests multiple strategies for therapy. Full article

(This article belongs to the Special Issue Molecular Advances in New Combination Therapies for Cancer)

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Review

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28 pages, 1417 KiB

Open AccessReview

Efficacy of Cold Atmospheric Plasma vs. Chemotherapy in Triple-Negative Breast Cancer: A Systematic Review

by Catarina Almeida-Ferreira, Carlos Miguel Marto, Chrislaura Carmo, Joana Almeida-Ferreira, Cristina Frutuoso, Maria João Carvalho, Maria Filomena Botelho and Mafalda Laranjo

Int. J. Mol. Sci. 2024, 25(6), 3254; https://doi.org/10.3390/ijms25063254 - 13 Mar 2024

Viewed by 1016

Abstract

Breast cancer is a growing disease, with a high worldwide incidence and mortality rate among women. Among the various types, the treatment of triple-negative breast cancer (TNBC) remains a challenge. Considering the recent advances in cold atmospheric plasma (CAP) cancer research, our goal was to evaluate efficacy data from studies based on chemotherapy and CAP in TNBC cell lines and animal models. A search of the literature was carried out in the PubMed, Web of Science, Cochrane Library, and Embase databases. Of the 10,999 studies, there were fifty-four in vitro studies, three in vivo studies, and two in vitro and in vivo studies included. MDA-MB-231 cells were the most used. MTT, MTS, SRB, annexin-V/propidium iodide, trypan blue, and clonogenic assay were performed to assess efficacy in vitro, increasing the reliability and comprehensiveness of the data. There was found to be a decrease in cell proliferation after both chemotherapy and CAP; however, different protocol settings, including an extensive range of drug doses and CAP exposure times, were reported. For both therapies, a considerable reduction in tumor volume was observed in vivo compared with that of the untreated group. The treatment of TNBC cell lines with CAP proved successful, with apoptosis emerging as the predominant type of cellular death. This systematic review presents a comprehensive overview of the treatment landscape in chemotherapy and CAP regarding their efficacy in TNBC cell lines. Full article

(This article belongs to the Special Issue Molecular Advances in New Combination Therapies for Cancer)

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28 pages, 1757 KiB

Open AccessReview

Chloroquine and Chemotherapeutic Compounds in Experimental Cancer Treatment

by Natalia I. Agalakova

Int. J. Mol. Sci. 2024, 25(2), 945; https://doi.org/10.3390/ijms25020945 - 12 Jan 2024

Viewed by 1036

Abstract

Chloroquine (CQ) and its derivate hydroxychloroquine (HCQ), the compounds with recognized ability to suppress autophagy, have been tested in experimental works and in clinical trials as adjuvant therapy for the treatment of tumors of different origin to increase the efficacy of cytotoxic agents. Such a strategy can be effective in overcoming the resistance of cancer cells to standard chemotherapy or anti-angiogenic therapy. This review presents the results of the combined application of CQ/HCQ with conventional chemotherapy drugs (doxorubicin, paclitaxel, platinum-based compounds, gemcitabine, tyrosine kinases and PI3K/Akt/mTOR inhibitors, and other agents) for the treatment of different malignancies obtained in experiments on cultured cancer cells, animal xenografts models, and in a few clinical trials. The effects of such an approach on the viability of cancer cells or tumor growth, as well as autophagy-dependent and -independent molecular mechanisms underlying cellular responses of cancer cells to CQ/HCQ, are summarized. Although the majority of experimental in vitro and in vivo studies have shown that CQ/HCQ can effectively sensitize cancer cells to cytotoxic agents and increase the potential of chemotherapy, the results of clinical trials are often inconsistent. Nevertheless, the pharmacological suppression of autophagy remains a promising tool for increasing the efficacy of standard chemotherapy, and the development of more specific inhibitors is required. Full article

(This article belongs to the Special Issue Molecular Advances in New Combination Therapies for Cancer)

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