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Novel Therapeutic Targets in Cancers: 4th Edition

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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 (30 April 2026) | Viewed by 19194

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Editor

Dr. Elena Levantini

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Guest Editor

Consiglio Nazionale delle Ricerche, Istituto di Tecnologie Biomediche, via Moruzzi 1, 56124 Pisa, Italy
Interests: NSCLC; SCLC; murine models; tumor microenvironment; cancer stem cells; therapy resistance; therapeutic targeting; BMI1; scRNAseq; spatial transcriptomics; single-cell interactomes; gene regulation; transcription factors; KRAS; EGFR; miRNA
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Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous Special Issues “Novel Therapeutic Targets in Cancers” (https://www.mdpi.com/journal/ijms/special_issues/Therapeutic_Targets_Cancers ); “Novel Therapeutic Targets in Cancers 2.0” (https://www.mdpi.com/journal/ijms/special_issues/VJC6KR93C0); and “Novel Therapeutic Targets in Cancers: 3rd Edition” (https://www.mdpi.com/journal/ijms/special_issues/TF6N2JWG6Y).

In recent decades, novel precision oncology protocols have been developed and are now beginning to be adopted in routine clinical practice. However, despite major advances, the goal of transforming solid tumors into a chronic disease remains unfulfilled, and long-term remission has yet to be achieved.

Starting from preclinical models (cell lines, organoids, and murine models), we can identify oncogenic pathways, mechanisms of resistance, and novel avenues to inhibit tumor growth and metastatic spread that will eventually enter clinical trials. Novel technologies—such as those capable of pinpointing the contribution of tumor heterogeneity to transformation and dissemination, as well as tumor evolution during drug response and recurrence—are poised to revolutionize cancer treatment by expanding the therapeutic arsenal at our disposal. State-of-the-art precision medicine protocols require the convergence of multiple interdisciplinary contributions, including the identification of single-cell-specific genetic and epigenetic alterations, the discovery of diagnostic and prognostic biomarkers, the implementation of efficient and specific diagnostic tools, the design of genomic editing protocols, and the planning of well-designed therapeutic strategies that consider the best sequential options to delay/prevent the development of recurrence.

This Special Issue welcomes original research papers as well as concise review manuscripts from experts in these relevant fields. The Issue is supervised by Dr. Elena Levantini, assisted by our Topical Advisory Panel Member Dr. Giorgia Maroni.

Topics of interest include, but are not limited to, the following:

Solid tumor heterogeneity;
Targeted therapy, including target identification and validation;
Immune modulation;
RNA-based therapy;
Epigenetic therapy;
Combination therapy, considering also sequential treatments and drug holidays;
Cancer stem cell targeting;
Recurrence mechanisms;
Tumor evolution as defined by high-resolution transcriptomics;
Preclinical modeling of the heterogeneous tumor milieux.

Please note that manuscripts consisting solely of bioinformatics or computational analyses of public genomic or transcriptomic databases, without accompanying validation (either in an independent cohort or through biological validation in vitro or in vivo), are outside of the scope for this Special Issue.

Dr. Elena Levantini
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 250 words) can be sent to the Editorial Office for assessment.

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-anonymized 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
precision oncology
immune modulation
cancer stem cell targeting
RNA-based therapy

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Published Papers (10 papers)

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Research

Jump to: Review, Other

20 pages, 2102 KB

Open AccessArticle

Cellular Target Engagement and Dissociation Kinetics of Class I-Selective Histone Deacetylase (HDAC) Inhibitors

by Irina Honin, Zora Novakova, Felix Feller, Simon Schneider, Linda Schäker-Hübner, Cyril Barinka and Finn K. Hansen

Int. J. Mol. Sci. 2026, 27(7), 3036; https://doi.org/10.3390/ijms27073036 - 26 Mar 2026

Cited by 1 | Viewed by 882

Abstract

Histone deacetylases (HDACs) 1–3 are key regulators of gene expression and represent important therapeutic targets in cancer, neurodegenerative, and immune disorders. Many potent class I HDAC inhibitors display slow- and tight-binding kinetics, which profoundly influence their efficacy and pharmacodynamics. In particular, their dissociation rate (off-kinetic) is critical, since prolonged target engagement greatly influences drug efficacy in vivo. However, the off-kinetics of HDAC inhibitors are often overlooked in the early stages of drug development. Here, we investigated the dissociation kinetics of tucidinostat, trapoxin A, and TNG260 in comparison to the pan-HDAC inhibitor vorinostat. Using biochemical 100-fold jump dilution assays, NanoBRET assays, and cellular washout experiments, we characterized the dissociation of these compounds from purified proteins and in a cellular context. Tucidinostat showed moderately slow off-kinetics, while the clinical candidate TNG260 demonstrated pronounced tight-binding properties. Trapoxin A displayed remarkable discrepancies between assays, as it showed fast dissociation kinetics in the biochemical assay, but tight-binding properties in a cellular setting. These findings not only address the previously unexplored dissociation kinetics of two clinically relevant inhibitors, but also underscore the importance of comprehensive kinetic profiling of novel HDAC inhibitors in cellular models. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers: 4th Edition)

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15 pages, 2045 KB

Open AccessArticle

Analysis of Consensus Molecular Subtypes of Colorectal Cancer in Oman with Clinicopathologic Correlation

by Shaista Rehman, Asem Shalaby, Said A. Al-Busafi, Moon Fai Chan, Shaima Al Khabouri, Mustafa Al Hinai, Adhari Al Zaabi, Mohammad Al Masqari, Asim Qureshi and Mohammed Al-Azri

Int. J. Mol. Sci. 2026, 27(4), 2038; https://doi.org/10.3390/ijms27042038 - 21 Feb 2026

Cited by 3 | Viewed by 1481 | Correction

Abstract

Colorectal cancer (CRC) is a major public health challenge in Oman and a leading cause of cancer-related mortality. The rising incidence has been associated with lifestyle changes, urbanization, and genetic factors. The CRC Subtyping Consortium has defined four consensus molecular subtypes (CMS1–CMS4); however, data on their distribution in the Gulf region, including Oman, remain limited. This study aimed to characterize the distribution of CMS subtypes in Omani CRC patients and assess their clinicopathologic correlations using a practical immunohistochemistry (IHC) panel supplemented by a limited targeted molecular approach. This study included 273 CRC patients diagnosed between 2023 and 2024 at two major referral hospitals in Muscat. Initially, the mismatch repair (MMR)-deficient tumors (dMMR) were assigned as CMS1, while the MMR-proficient (pMMR) tumors were further evaluated for β-catenin, P53, KRAS, and TGF-β expression. Mutations in BRAF, TP53, and KRAS were analyzed by sequencing. The cohort comprised 51.6% males, with a mean age of 59.1 years. Most tumors were left-sided (70.7%). dMMR (CMS1) comprised 31 cases (11.35%). Out of the pMMR tumors, 111 cases (40.65%) showed positive expression of β-catenin and P53 (CMS2), 63 cases (23.0%) showed KRAS mutations (CMS3), and 68 cases (24.9%) showed TGF-β-positive expression (CMS4). The cases were predominantly concentrated in Muscat (41%). This study demonstrated the feasibility and clinical relevance of CMS-based classification in Oman and its potential role in precision oncology and healthcare planning. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers: 4th Edition)

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22 pages, 3028 KB

Open AccessArticle

Altered Expression of Mitochondrial Succinate Dehydrogenase Subunit D Influences Breast Cancer Progression

by Jannatul Aklima, Israt Jahan, Khadiza Jahan, Utpal Barua, Shanjida Akter Touse, Shakera Ahmed, Ramendu Parial, Sunanda Baidya and Abu Shadat Mohammod Noman

Int. J. Mol. Sci. 2026, 27(4), 1722; https://doi.org/10.3390/ijms27041722 - 11 Feb 2026

Viewed by 926

Abstract

Mitochondrial succinate dehydrogenase subunits are differentially expressed in multiple tumor types, suggesting their role as a cancer type-dependent metabolic target. However, information on the expression of SDH subunits in breast cancer (BC), particularly in South Asian populations, remains scarce. So, we analyze the expression profile of all four SDH subunits in breast cancer patients from Bangladesh. qRT-PCR was carried out to analyze the mRNA expression of four SDH subunits in Luminal A, Luminal B, Her2+, and triple-negative breast cancer subtypes and the results were compared with The Cancer Genome Atlas (TCGA) database. All four succinate dehydrogenase subunits were significantly upregulated in tumor tissues when compared to controls and showed an alignment with the TCGA except SDHD, which was significantly downregulated in TCGA. Subtype-specific analysis demonstrated differential expression patterns. SDHD upregulation has also been connected to worse outcomes for patients which indicates its role in cancer progression. Furthermore, we found a significant upregulation of METTL3 in our patient cohort. Taken together, the elevated SDHD and METTL3 expression suggests a potential epigenetic mechanism-driven SDHD activation, highlighting its previously unreported role in breast cancer biology and revealing a distinct pattern of SDH dysregulation in the Bangladeshi breast cancer population. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers: 4th Edition)

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24 pages, 5634 KB

Open AccessArticle

Ovarian Cancer Susceptibility and Chemosensitivity to KRAS Modulation

by Alexandra Maria Psaras, Steven J. McKay, Janelle Vasquez Vilela, Eddison Ospina Sanchez, Marina G. Cintrón, Kayla K. Elder and Tracy A. Brooks

Int. J. Mol. Sci. 2026, 27(3), 1571; https://doi.org/10.3390/ijms27031571 - 5 Feb 2026

Viewed by 1138

Abstract

KRAS is frequently amplified or overexpressed in ovarian cancer and represents a potential therapeutic target for overcoming chemoresistance. We employed complementary approaches—CRISPR/Cas9 gene editing, Tet-ON inducible knockdown, polypurine reverse Hoogsteen hairpin (PPRH) oligonucleotides, and the pan-KRAS inhibitor BI2865—to investigate whether KRAS modulation enhances chemotherapeutic efficacy in ovarian cancer models. CRISPR-mediated KRAS knockdown in SKOV-3 cells dramatically altered three-dimensional spheroid morphology, reducing the average area six-fold, and significantly enhanced sensitivity to both cisplatin and paclitaxel in 3D cultures, where paclitaxel resistance was completely reversed. The Tet-ON system demonstrated dose-dependent chemosensitization with optimal effects at intermediate KRAS knockdown levels (~50–60%). PPRH oligonucleotides at sub-cytotoxic concentrations (50 nM) reduced cisplatin and paclitaxel IC₅₀ values by approximately 50% in 2D cultures. Pharmacological KRAS inhibition with BI2865 produced striking synergy with paclitaxel (several hundred-fold sensitizations in 2D; complete reversal of 3D resistance), and additive effects with cisplatin. In KRAS-amplified Kuramochi cells (representing high-grade serous ovarian carcinoma), BI2865 enhanced paclitaxel efficacy, despite greater baseline chemoresistance. These findings establish KRAS as a promising chemosensitization target in ovarian cancer, with particular potential for taxane-based combination therapies. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers: 4th Edition)

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14 pages, 3536 KB

Open AccessArticle

FOXA1 in Ovarian Cancer: A Potential Therapeutic Target to Enhance Immunotherapy Efficacy

by Taewan Kim, Jaesung Ryu, Hyejeong Kong, Beamjun Park, Kwangseock Kim, Eunjung Yang, Taesung Ahn and Seob Jeon

Int. J. Mol. Sci. 2026, 27(3), 1194; https://doi.org/10.3390/ijms27031194 - 24 Jan 2026

Viewed by 927

Abstract

This study aimed to elucidate the oncogenic role of FOXA1(forkhead box A1) in ovarian cancer and to evaluate its potential as both a therapeutic target and a diagnostic biomarker. We further investigated whether FOXA1 inhibition could enhance responsiveness to immune checkpoint blockade and overcome chemoresistance. A total of seventy-six ovarian tissue samples were analyzed, including nine normal, thirty-four benign, and thirty-three malignant specimens. IHC (immunohistochemistry) staining was performed to assess FOXA1 expression and its correlation with tumor stage. Functional studies were conducted using FOXA1 siRNA in SK-OV3 and HEYA8 cell lines. Changes in cell proliferation, migration, invasion, and wound-healing ability were evaluated following FOXA1 silencing. Quantitative RT-PCR was used to measure the expression of FOXA1 and EMT (epithelial–mesenchymal transition)-related genes. The effects of FOXA1 inhibition on sensitivity to carboplatin and the immune checkpoint inhibitor atezolizumab were also examined. IHC analysis revealed significant differences in FOXA1 expression among normal, benign, and malignant tissues, with levels correlating with tumor stage. FOXA1 silencing significantly reduced proliferation and decreased migration and invasion by 60–80%, accompanied by marked downregulation of EMT-related genes. Moreover, FOXA1 inhibition enhanced atezolizumab responsiveness and reduced carboplatin resistance in ovarian cancer cells. In summary, FOXA1 acts as an oncogenic driver in ovarian cancer, promoting proliferation, invasion, and EMT activation. Its overexpression correlates with disease progression, supporting its potential as a biomarker and therapeutic target. Targeting FOXA1 could enhance immunotherapy efficacy and help overcome chemoresistance in ovarian cancer. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers: 4th Edition)

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17 pages, 1647 KB

Open AccessArticle

Inhibitors of De Novo Guanylate Biosynthesis Enhance the Potency of MAPK Cascade Inhibitors Against Colorectal Cancer

by Alexei A. Maslov, Nicholas H. Trageser, Julia V. Kichina, Haya Elamir, Evelyn Gardner, Frances Teaman, Vera Vishwanath, Scott M. Dugas, Anna Bianchi-Smiraglia, Katerina I. Leonova, Katerina V. Gurova, Mikhail A. Nikiforov and Eugene S. Kandel

Int. J. Mol. Sci. 2025, 26(24), 11959; https://doi.org/10.3390/ijms262411959 - 11 Dec 2025

Viewed by 931

Abstract

Despite continuing improvement in the standard of care, the clinical outcomes in metastatic colorectal cancer (CRC) remain poor, especially among patients whose tumors carry activating mutations in BRAF or RAS-family oncogenes. These mutations initiate a series of oncogenic signal transduction events, known as the mitogen-activated protein kinase (MAPK) cascade. While therapeutic targeting of this pathway achieved impressive results in other malignancies, the effectiveness of this approach remains low in CRC. In the current study, we observed that inhibitors of GTP production synergize with various inhibitors of the MAPK cascade in suppressing a variety of CRC cell lines. Furthermore, we discovered that an inhibitor of guanylate biosynthesis increases the efficacy of MAPK cascade inhibitors against human CRC grown in mice. Moreover, a combination of MEK and guanylate biosynthesis inhibitors is more potent than the MEK inhibitor alone in increasing the efficacy of immune therapy in an immunocompetent mouse model. Considering that guanylate biosynthesis inhibitors are already used in clinical practice for other applications, their use in synergistic combinations with the inhibitors of the MAPK cascade may present an actionable strategy to increase the efficacy of the latter. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers: 4th Edition)

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Review

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71 pages, 6749 KB

Open AccessReview

RNA-Based Therapeutic Strategies in Multiple Myeloma: From Molecular Targets to Delivery and Clinical Translation

by Maksim V. Baranov, Igor Shalik, Angela Tsvetkova, Anna Streltsova, Dmitriy Ovcharenko, Roman Ivanov and Vasiliy Reshetnikov

Int. J. Mol. Sci. 2026, 27(2), 843; https://doi.org/10.3390/ijms27020843 - 14 Jan 2026

Cited by 1 | Viewed by 3307

Abstract

Multiple myeloma (MM) is a challenging hematologic malignancy characterized by clonal plasma cell proliferation, often leading to significant morbidity and mortality worldwide. Despite advances in chemotherapy and CAR-T therapies, MM remains incurable due to tumor heterogeneity, immune evasion, and microenvironment remodeling—exacerbated by toxicities like cytokine release syndrome and myelosuppression. This urgent unmet need demands innovative strategies. In this review, we assess cutting-edge RNA-based therapeutics for MM modulation, drawing on preclinical and clinical evidence on modalities including mRNA vaccines, small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), and microRNA (miRNA) mimics/inhibitors. We further explore RNA-engineered cell therapies, such as transient CAR-T platforms and lipid nanoparticle-delivered systems targeting the bone marrow niche. By integrating these insights, we underscore RNA technologies’ transformative potential to achieve durable remissions, overcome resistance, and reduce costs—paving the way for personalized, safer treatments in refractory MM. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers: 4th Edition)

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61 pages, 5074 KB

Open AccessReview

Anoikis: To Die or Not to Die?

by Tomas Koltai and Larry Fliegel

Int. J. Mol. Sci. 2026, 27(2), 579; https://doi.org/10.3390/ijms27020579 - 6 Jan 2026

Cited by 4 | Viewed by 3342

Abstract

Epithelial, endothelial, and many connective tissue cells are normally attached to the extracellular matrix (ECM). These cells rely on the ECM for structural support, signaling, and regulation of their behavior. When these cells lose this attachment or are in an inappropriate location, these cells soon die by a mechanism called anoikis (homelessness). Anoikis is a programmed cell death of an apoptotic nature; however, it can, in certain cases, be overcome, and detached cells can survive in the absence of the correct signals from the ECM. This is the case of malignant cells, where anoikis resistance is a prerequisite for invasion and metastasis. Without anoikis resistance (anchorage-independency), tumors would be unable to abandon their normal sites and would invade neighboring tissues and metastasize at distant locations. Anoikis is the natural barrier against cancer progression. Therefore, overcoming anoikis is a major step in cellular transformation. Cancer cells have developed many successful strategies to bypass anoikis. The main mechanism, albeit not the only one, involves hyper-activating survival pathways and over-expressing anti-apoptotic molecules. There is a strong and intertwining association between epithelial–mesenchymal transition and anoikis resistance that is discussed in depth. A better understanding of these anoikis resistance mechanisms has led to the research and development of pharmaceuticals that can counteract them. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers: 4th Edition)

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30 pages, 2183 KB

Open AccessReview

Interferon-Based Therapeutics in Cancer Therapy: Past, Present, and Future

by Kristina Vorona, Anastasia Ryapolova, Olesya Sokolova, Alexander Karabelsky, Roman Ivanov, Vasiliy Reshetnikov and Ekaterina Minskaia

Int. J. Mol. Sci. 2025, 26(23), 11679; https://doi.org/10.3390/ijms262311679 - 2 Dec 2025

Cited by 3 | Viewed by 5159

Abstract

Interferons (IFNs) are well-known immunostimulants involved in both innate and adaptive immune responses. These multifunctional proteins mediate an early antiviral response and have pronounced immunomodulatory and antiproliferative properties. Due to their potency, IFNs have been used not only in the treatment of viral infections but also various other diseases. However, the use of IFNs in antitumor therapy has been limited by the frequent severe side effects, which reduced their appeal for the treatment of cancer. In this review, we focused on current data on recombinant IFNs used for anticancer therapy, as well as the development of promising IFN-based gene therapy approaches, with a focus on their safety and therapeutic efficacy. We also highlighted various types of IFNs and their application niches in the treatment of not only cancers in combination therapy but also of certain rare diseases. Taken together, this review improves our understanding of the existing IFN applications in cancer therapy, the disadvantages of using IFNs, and possible approaches for their improvement. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Cancers: 4th Edition)

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