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Cancers
Special Issues
New Findings in Targeting Cancer Proteins
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New Findings in Targeting Cancer Proteins

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: 20 January 2025 | Viewed by 6448

Special Issue Editors

Dr. Maristella Maggi

E-Mail Website
Guest Editor
Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
Interests: monoclonal antibodies; protein target; immunotherapy; signaling blockade; targeted therapy
Dr. Claudia Scotti

E-Mail Website
Guest Editor
Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
Interests: monoclonal antibodies; protein target; immunotherapy; signaling blockade; targeted therapy

Special Issue Information

Dear Colleagues,

Advancements in cancer cell molecular profiling, especially at the single cell level, are a source of valuable insights into the landscape of alterations in cancer genomic, genetic, and proteomics, providing new pathogenic mechanisms and a comprehensive panel of new targets for developing tumor-tailored therapies. In such a context, given their role in the development and progression of cancer, both Tumor Associated Antigens and Tumor-Specific Antigens are becoming increasingly relevant targets for therapy. In cancer, protein alterations can occur at various levels, including abnormal protein expression, post-translational modifications, and dysregulated protein–protein interactions. Many proteins involved in crucial cellular functions, such as cell cycle regulation, DNA repair, apoptosis, and angiogenesis, have been identified as significant players in tumorigenesis. It is possible by targeting these proteins to disrupt specific cancer-related processes and inhibit tumor growth.

Historically, protein targets involve primarily oncogenic proteins, such as the epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and B-Raf proto-oncogene (BRAF). Targeted therapies directed against these oncogenic proteins have shown remarkable success in specific cancer types. Moreover, the dysregulated activation of pathways involving oncoproteins contributes to tumor cell survival, proliferation, and resistance to treatment. Inhibitors targeting key proteins within these pathways, such as PI3K, AKT, and MEK, have demonstrated clinical efficacy in certain malignancies, including breast, colorectal, and melanoma cancers.

In recent years, the discovery of immune checkpoint proteins, such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which are not located on tumor cells, have revolutionized cancer treatment through immunotherapy, showing the importance of tackling the tumor microenvironment.

Despite the progress in targeting proteins for cancer therapy, several challenges remain, including acquired resistance, off-target side effects, target heterogeneity, and the activation of alternative pathways to escape drug inhibition.

In the Special Issue “New Findings in the Targeting of Cancer Proteins”, we aim to collect original articles and reviews presenting data on the newest findings in the field of protein-targeted cancer therapy, which nowadays holds the best promise for developing more effective and personalized treatment approaches.

Dr. Maristella Maggi
Dr. Claudia Scotti
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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). 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

  • monoclonal antibodies
  • protein target
  • immunotherapy
  • signaling blockade
  • targeted therapy

Published Papers (5 papers)

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Research

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14 pages, 20945 KiB  
Article
Heterogeneous Profile of ROR1 Protein Expression across Tumor Types
by Maria Gabriela Raso, Elizve Barrientos Toro, Kurt Evans, Yasmeen Rizvi, Rossana Lazcano, Argun Akcakanat, Patrizia Sini, Francesca Trapani, Eva Johanna Madlener, Lorenz Waldmeier, Alexander Lazar and Funda Meric-Bernstam
Cancers 2024, 16(10), 1874; https://doi.org/10.3390/cancers16101874 - 15 May 2024
Viewed by 548
Abstract
The Wnt receptor ROR1 has generated increased interest as a cancer therapeutic target. Research on several therapeutic approaches involving this receptor is ongoing; however, ROR1 tissue expression remains understudied. We performed an immunohistochemistry analysis of ROR1 protein expression in a large cohort of [...] Read more.
The Wnt receptor ROR1 has generated increased interest as a cancer therapeutic target. Research on several therapeutic approaches involving this receptor is ongoing; however, ROR1 tissue expression remains understudied. We performed an immunohistochemistry analysis of ROR1 protein expression in a large cohort of multiple tumor and histologic types. We analyzed 12 anonymized multi-tumor tissue microarrays (TMAs), including mesothelioma, esophageal and upper gastrointestinal carcinomas, and uterine endometrioid carcinoma, among other tumor types. Additionally, we studied 5 different sarcoma types of TMAs and 6 patient-derived xenografts (PDX) TMAs developed from 19 different anatomic sites and tumor histologic types. A total of 1142 patient cases from different histologic types and 140 PDXs placed in TMAs were evaluated. Pathologists assessed the percentage of tumor cells in each case that were positive for ROR1 and the intensity of staining. For determining the prevalence of staining for each tumor type, a case was considered positive if >1% of its tumor cells showed ROR1 staining. Our immunohistochemistry assays revealed a heterogeneous ROR1 expression profile. A high prevalence of ROR1 expression was found in mesothelioma (84.6%), liposarcoma (36.1%), gastrointestinal stromal tumors (33.3%), and uterine endometrioid carcinoma (28.9%). Other histologic types such as breast, lung, renal cell, hepatocellular, urothelial carcinoma, and colon carcinomas; glioblastoma; cholangiocarcinoma; and leiomyosarcoma showed less ROR1 overall expression, ranging between 0.9 and 13%. No ROR1 expression was seen in mesenchymal chondrosarcoma, rhabdomyosarcoma, or gastric adenocarcinoma cases. Overall, ROR1 expression was relatively infrequent and low in most tumor types investigated; however, ROR1 expression was infrequent but high in selected tumor types, such as gastroesophageal GIST, suggesting that ROR1 prescreening may be preferable for those indications. Further, mesothelioma exhibited frequent and high levels of ROR1 expression, which represents a previously unrecognized therapeutic opportunity. These findings can contribute to the development of ROR1-targeted therapies. Full article
(This article belongs to the Special Issue New Findings in Targeting Cancer Proteins)
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16 pages, 3209 KiB  
Article
The Genomic, Transcriptomic, and Immunologic Landscape of HRAS Mutations in Solid Tumors
by Samuel A. Kareff, Asaad Trabolsi, Harris B. Krause, Timothy Samec, Andrew Elliott, Estelamari Rodriguez, Coral Olazagasti, Dionysios C. Watson, Matias A. Bustos, Dave S. B. Hoon, Stephanie L. Graff, Emmanuel S. Antonarakis, Sanjay Goel, George Sledge and Gilberto Lopes
Cancers 2024, 16(8), 1572; https://doi.org/10.3390/cancers16081572 - 19 Apr 2024
Viewed by 1067
Abstract
Tipifarnib is the only targeted therapy breakthrough for HRAS-mutant (HRASmt) recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The molecular profiles of HRASmt cancers are difficult to explore given the low frequency of HRASmt. This study [...] Read more.
Tipifarnib is the only targeted therapy breakthrough for HRAS-mutant (HRASmt) recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The molecular profiles of HRASmt cancers are difficult to explore given the low frequency of HRASmt. This study aims to understand the molecular co-alterations, immune profiles, and clinical outcomes of 524 HRASmt solid tumors including urothelial carcinoma (UC), breast cancer (BC), non-small-cell lung cancer (NSCLC), melanoma, and HNSCC. HRASmt was most common in UC (3.0%), followed by HNSCC (2.82%), melanoma (1.05%), BC (0.45%), and NSCLC (0.44%). HRASmt was absent in Her2+ BC regardless of hormone receptor status. HRASmt was more frequently associated with squamous compared to non-squamous NSCLC (60% vs. 40% in HRASwt, p = 0.002). The tumor microenvironment (TME) of HRASmt demonstrated increased M1 macrophages in triple-negative BC (TNBC), HNSCC, squamous NSCLC, and UC; increased M2 macrophages in TNBC; and increased CD8+ T-cells in HNSCC (all p < 0.05). Finally, HRASmt was associated with shorter overall survival in HNSCC (HR: 1.564, CI: 1.16–2.11, p = 0.003) but not in the other cancer types examined. In conclusion, this study provides new insights into the unique molecular profiles of HRASmt tumors that may help to identify new targets and guide future clinical trial design. Full article
(This article belongs to the Special Issue New Findings in Targeting Cancer Proteins)
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19 pages, 22477 KiB  
Article
RNF149 Promotes HCC Progression through Its E3 Ubiquitin Ligase Activity
by Zhaoyu Guo, Pei Jiang, Qian Dong, Yiming Zhang, Kaikun Xu, Yuanjun Zhai, Fuchu He, Chunyan Tian and Aihua Sun
Cancers 2023, 15(21), 5203; https://doi.org/10.3390/cancers15215203 - 29 Oct 2023
Viewed by 1341
Abstract
Hepatocellular carcinoma (HCC) accounts for over 80% of cases among liver cancer, with high incidence and poor prognosis. Thus, it is of valuable clinical significance for discovery of potential biomarkers and drug targets for HCC. In this study, based on the proteomic profiling [...] Read more.
Hepatocellular carcinoma (HCC) accounts for over 80% of cases among liver cancer, with high incidence and poor prognosis. Thus, it is of valuable clinical significance for discovery of potential biomarkers and drug targets for HCC. In this study, based on the proteomic profiling data of paired early-stage HCC samples, we found that RNF149 was strikingly upregulated in tumor tissues and correlated with poor prognosis in HCC patients, which was further validated by IHC staining experiments of an independent HCC cohort. Consistently, overexpression of RNF149 significantly promoted cell proliferation, migration, and invasion of HCC cells. We further proved that RNF149 stimulated HCC progression via its E3 ubiquitin ligase activity, and identified DNAJC25 as its new substrate. In addition, bioinformatics analysis showed that high expression of RNF149 was correlated with immunosuppressive tumor microenvironment (TME), indicating its potential role in immune regulation of HCC. These results suggest that RNF149 could exert protumor functions in HCC in dependence of its E3 ubiquitin ligase activity, and might be a potential prognostic marker and therapeutic target for HCC treatment. Full article
(This article belongs to the Special Issue New Findings in Targeting Cancer Proteins)
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Review

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18 pages, 1738 KiB  
Review
Monoclonal Antibodies for Targeted Fluorescence-Guided Surgery: A Review of Applicability across Multiple Solid Tumors
by Stefano Giuliani, Irene Paraboschi, Angus McNair, Myles Smith, Kenneth S. Rankin, Daniel S. Elson, Vinidh Paleri, Daniel Leff, Graeme Stasiuk and John Anderson
Cancers 2024, 16(5), 1045; https://doi.org/10.3390/cancers16051045 - 4 Mar 2024
Viewed by 1105
Abstract
This study aims to review the status of the clinical use of monoclonal antibodies (mAbs) that have completed or are in ongoing clinical trials for targeted fluorescence-guided surgery (T-FGS) for the intraoperative identification of the tumor margins of extra-hematological solid tumors. For each [...] Read more.
This study aims to review the status of the clinical use of monoclonal antibodies (mAbs) that have completed or are in ongoing clinical trials for targeted fluorescence-guided surgery (T-FGS) for the intraoperative identification of the tumor margins of extra-hematological solid tumors. For each of them, the targeted antigen, the mAb generic/commercial name and format, and clinical indications are presented, together with utility, doses, and the timing of administration. Based on the current scientific evidence in humans, the top three mAbs that could be prepared in a GMP-compliant bank ready to be delivered for surgical purposes are proposed to speed up the translation to the operating room and produce a few readily available “off-the-shelf” injectable fluorescent probes for safer and more effective solid tumor resection. Full article
(This article belongs to the Special Issue New Findings in Targeting Cancer Proteins)
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40 pages, 1015 KiB  
Review
Hepatocellular Carcinoma: Old and Emerging Therapeutic Targets
by Greta Pessino, Claudia Scotti, Maristella Maggi and Immuno-HUB Consortium
Cancers 2024, 16(5), 901; https://doi.org/10.3390/cancers16050901 - 23 Feb 2024
Viewed by 1815
Abstract
Liver cancer, predominantly hepatocellular carcinoma (HCC), globally ranks sixth in incidence and third in cancer-related deaths. HCC risk factors include non-viral hepatitis, alcohol abuse, environmental exposures, and genetic factors. No specific genetic alterations are unequivocally linked to HCC tumorigenesis. Current standard therapies include [...] Read more.
Liver cancer, predominantly hepatocellular carcinoma (HCC), globally ranks sixth in incidence and third in cancer-related deaths. HCC risk factors include non-viral hepatitis, alcohol abuse, environmental exposures, and genetic factors. No specific genetic alterations are unequivocally linked to HCC tumorigenesis. Current standard therapies include surgical options, systemic chemotherapy, and kinase inhibitors, like sorafenib and regorafenib. Immunotherapy, targeting immune checkpoints, represents a promising avenue. FDA-approved checkpoint inhibitors, such as atezolizumab and pembrolizumab, show efficacy, and combination therapies enhance clinical responses. Despite this, the treatment of hepatocellular carcinoma (HCC) remains a challenge, as the complex tumor ecosystem and the immunosuppressive microenvironment associated with it hamper the efficacy of the available therapeutic approaches. This review explores current and advanced approaches to treat HCC, considering both known and new potential targets, especially derived from proteomic analysis, which is today considered as the most promising approach. Exploring novel strategies, this review discusses antibody drug conjugates (ADCs), chimeric antigen receptor T-cell therapy (CAR-T), and engineered antibodies. It then reports a systematic analysis of the main ligand/receptor pairs and molecular pathways reported to be overexpressed in tumor cells, highlighting their potential and limitations. Finally, it discusses TGFβ, one of the most promising targets of the HCC microenvironment. Full article
(This article belongs to the Special Issue New Findings in Targeting Cancer Proteins)
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