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Current Research on Cancer Biology and Therapeutics: Fourth 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: 29 June 2026 | Viewed by 7209

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Dr. Rafael Coveñas Rodríguez

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Laboratory of Neuroanatomy of the Peptidergic Systems, Institute of Neuroscience of Castilla and León (INCYL), University of Salamanca, c/Pintor Fernando Gallego 1, 37007 Salamanca, Spain
Interests: cancer and anticancer peptides; substance P/neurokinin-1 receptor system; neurokinin-1 receptor antagonists
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Special Issue Information

Dear Colleagues,

Cancer caused 10 million deaths in 2020 and remains a major health problem worldwide. Surgery, chemotherapy, and radiotherapy are the current cancer treatments, but unfortunately, their results are, in many cases, unsatisfactory. The development of promising cancer research fields (new cytostatics, stem cells, and the human genome) has not been translated into better perspectives for many cancer patients. To improve the diagnosis and treatment of tumors, novel specific anticancer strategies showing enhanced antitumor effects and decreased toxicity must be explored.

Cancer cells evade the immune system and show resistance to anticancer therapies, leading to cancer cell proliferation, survival, invasion, and metastasis. These mechanisms, as well as angiogenesis, are regulated by different ligands, receptors, and intracellular cascades that regulate the genetic/protein machinery of cancer cells; thus, anticancer drugs must specifically block these cellular events. This has opened up new research lines for exploring new therapeutic strategies focused on targetable molecules. Accordingly, the main aim of this Special Issue is to increase knowledge about potential targetable molecules involved in previous mechanisms, such as peptides, signal transduction molecules, transcription factors, kinases, DNA damage repair enzymes, and epigenetic regulatory proteins. Thus, new antiproliferative, antimetastatic, and antiangiogenic strategies are welcome, as well as apoptotic inducers, signal transduction inhibitors, cytotoxic peptide conjugate-based cancer therapy, gene expression modulators, hormone therapies, and peptide receptor radionuclide therapy. Studies focused on the function–structure relationships between ligands and receptors for the design and synthesis of new and more effective anticancer compounds are also welcome.

I hope that this Special Issue opens the door to developing promising molecular targets, blocking tumor development, and developing new compounds capable of specifically destroying tumor cells. New anticancer strategies targeting tumor-specific molecular derangements must serve to improve the diagnosis and treatment of tumors and increase the cure rate and quality of life of cancer patients

Dr. Rafael Coveñas Rodríguez
Guest Editor

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Keywords

cancer and anticancer peptides
substance P/neurokinin-1 receptor system
neurokinin-1 receptor antagonists

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Published Papers (9 papers)

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Research

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14 pages, 2556 KB

Open AccessArticle

Targeting Glutaminase Isoforms GLS and GLS2 in Luminal Breast Cancer

by Brendah K. Masisi, Rokaya El Ansari, Ali Fakroun, Büsra Erkan, Emad A. Rakha and Andrew R. Green

Int. J. Mol. Sci. 2026, 27(6), 2780; https://doi.org/10.3390/ijms27062780 - 19 Mar 2026

Viewed by 181

Abstract

Upregulation of glutaminase enzymatic activity promotes tumour cell proliferation. Its overexpression correlates with poor disease outcome in patients, including those with breast cancer. A selective glutaminase inhibitor, CB-839, which targets cancer cells by blocking glutamine conversion to glutamate, has shown promising preclinical results as a therapeutic target in triple-negative breast cancer treatment. The current study aimed to determine the importance of glutaminase in Oestrogen Receptor positive/luminal breast cancer to potentially identify therapeutic targets to treat this subtype. In vitro studies using luminal breast cancer cells were performed to investigate the effects of siRNA knockdown of glutaminase genes (GLS and GLS2) and inhibition using CB-839 on functional assays. Silencing GLS in luminal breast cancer cells significantly reduced cell proliferation whilst inducing apoptosis. A similar impact on cell proliferation was observed when silencing GLS2 in luminal B cells, but there was no observed effect on cell apoptosis and cell cycle. There was little effect of GLS inhibition using CB-839 in luminal breast cancer. This study demonstrates that glutaminase is necessary for luminal breast cancer growth and survival. Co-targeting GLS and GLS2 might be a novel approach for the treatment of this subclass. Further functional studies to evaluate the underlying molecular mechanisms of this process are warranted. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: Fourth Edition)

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17 pages, 4557 KB

Open AccessArticle

Paired-Box (PAX) Gene Signatures as a Biomarker of Breast Cancer Progression

by Manuel Scimeca, Maria Paola Scioli, Valeria Palumbo, Lukas Funke, Jonathan Woodsmith, Francesca Servadei, Erica Giacobbi, Christian Seghetti, Oreste Claudio Buonomo, Eleonora Candi, Michele Treglia, Luigi Tonino Marsella, Gerry Melino, Alessandro Mauriello and Rita Bonfiglio

Int. J. Mol. Sci. 2026, 27(4), 1988; https://doi.org/10.3390/ijms27041988 - 19 Feb 2026

Viewed by 398

Abstract

Breast cancer is the leading cause of cancer-related death in women, and despite advances in preventive screening as well as in molecular classification, many patients still do not benefit from existing therapies, highlighting the importance of identifying new molecular determinants of treatment resistance. The Paired-box (PAX) family of developmental transcription factors are central regulators of tissue morphogenesis and lineage specification, yet their reactivation in tumors and contribution to breast cancer progression remain only partially defined. Here, a multi-level analysis integrating RNA sequencing and protein profiling in twenty-one primary breast carcinomas shows that distinct PAX members are directly correlated to distinct fundamental cancer hallmarks, including proliferation, cell death, epithelial–mesenchymal transition, immune evasion, and genomic instability. Specifically, PAX1 and PAX9 correlates with both cell death and proliferative markers, indicating dual roles in the regulation of cell fate. PAX1 and PAX9 correlate with both proliferative and apoptotic markers, indicating dual roles in cell fate regulation. PAX3, PAX5, and PAX8 are mainly associated with immune checkpoint expression, including PD-L1 and TIGIT, while PAX6 is linked to microsatellite instability and tumor mutational burden, implicating it in genomic dysregulation. Therefore, PAX-based molecular signatures identify that accurately predict lymph node metastasis at transcriptomic (PAX2–PAX7) levels. These findings establish PAX transcription factors as key modulators of breast cancer biology and support their potential as clinically relevant biomarkers for prognostic refinement and therapeutic stratification. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: Fourth Edition)

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17 pages, 4601 KB

Open AccessArticle

Microenvironment Rheology Modulates the Effect of the Anticancer Peptide CIGB300 on 3D Head and Neck Tumoroids

by Silvia Buonvino, Giorgia Paduano, Valeria Stefanizzi, Hilda Garay, Silvio Perea, Beatrice Macchi, Mariano Venanzi and Sonia Melino

Int. J. Mol. Sci. 2026, 27(4), 1973; https://doi.org/10.3390/ijms27041973 - 19 Feb 2026

Viewed by 328

Abstract

3D cell systems for in vitro experimental studies are able to mimic the in vivo efficacy of drugs before they are tested on animals. However, many studies are still needed in order to mimic the physiological environment with 3D cell-growth systems. The mechano-physical properties of the microenvironment are relevant for the invasiveness of cancer cells and for their drug resistance. In this study, 3D tumoroids of human oral squamous cell carcinoma (OSCC) CAL27 cells of different stiffnesses were produced using a tunable PEG–silk fibroin hydrogel (PSF), and the antitumor activity of the peptide CIGB300, an anticancer therapeutic peptide, with respect to these 3D tumoroid models was assessed. Furthermore, spectroscopic studies on the CIGB300 peptide are reported regarding its structure, stability, aggregation and diffusion properties. For the first time, the diffusion of the peptide CIGB300 in tunable silk fibroin hydrogels of different stiffnesses is investigated over time via fluorescence spectroscopy as a potential tool in drug-screening using hydrogel-based 3D tumoroids. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: Fourth Edition)

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21 pages, 14859 KB

Open AccessArticle

Punicalin Modulates Angiogenesis and Tumor Microenvironment-Related Processes in Triple-Negative Breast Cancer and Endothelial Cells

by Maria Carmen Banqueri-Pegalajar, Joel D. Posligua-García, Carlos Ulises Cárdenas-Vela, Manuel Bernal and Miguel Ángel Medina

Int. J. Mol. Sci. 2026, 27(3), 1533; https://doi.org/10.3390/ijms27031533 - 4 Feb 2026

Viewed by 545

Abstract

The tumor microenvironment plays a critical role in cancer progression, with oxidative stress, autophagy, angiogenesis, and cell migration acting as tightly interconnected processes. Natural bioactive compounds have emerged as promising modulators of these pathways; however, their cell type-specific effects within the TME remain poorly understood. In this study, we investigate the effects of punicalin on triple-negative breast cancer and endothelial cells, with a focus on redox homeostasis and autophagy as upstream regulatory mechanisms. Punicalin reduced oxidative stress in MDA-MB-231 cells under basal conditions and strongly attenuated hydrogen peroxide-induced stress, whereas HMEC-1 cells exhibited concentration- and condition-dependent reactive oxygen species (ROS) modulation. Autophagy assays revealed no significant modulation in tumor cells, while a consistent and pronounced decrease in autophagic activity was observed in endothelial cells under both basal and nutrient-deprivation conditions. Functionally, punicalin decreased tumor cell migration and impaired HMEC-1 migration, while HUVEC migration remained largely unaffected. Tube formation assays demonstrated significant inhibition of angiogenic capacity. Taken together, these findings demonstrate that punicalin selectively modulates oxidative stress and autophagy, leading to functional alterations in migration and angiogenesis. By highlighting its selective impact on microvascular endothelial cells while sparing normal endothelium, this study provides a strong rationale for further preclinical evaluation of punicalin. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: Fourth Edition)

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18 pages, 2181 KB

Open AccessArticle

GLI2 and FLNB Define Periocular Morphoeic Basal Cell Carcinoma

by John C. Bladen, Jun Wang, Mariya Moosajee, Muhammad Rahman, Ajanthah Sangaralingam, Vijay K. Gogna, Claude Chelala, Edel A. O’Toole and Michael P. Philpott

Int. J. Mol. Sci. 2025, 26(23), 11377; https://doi.org/10.3390/ijms262311377 - 25 Nov 2025

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Abstract

Morphoeic basal cell carcinoma (mBCC) has a higher risk of local recurrence than the more indolent nodular (nodBCC) subtype. Little is known about the genetic and molecular makeup of mBCC that determines its invasive behaviour: a comparison of mBCC with nodBCC was carried out. Whole-exome sequencing (WES) of 20 BCC tumours (10 eyelid morphoeic and 10 nodular) underwent driver gene detection using OncodriveFM and MutSigCV, followed by a randomisation analysis procedure. Samples underwent RNA sequencing, gene-set enrichment analysis and candidates verified by RT-PCR. PTCH1, FLNB, and double-knockdown human keratinocyte models were used to validate phenotype and gene expression. Hedgehog pathway analysis of 20 additional BCCs underwent immunostaining verification. Our analysis revealed FLNB as a potential driver with a mutational cluster in FLNB Filamin domain 24 and a 4-fold reduction in expression compared to normal eyelids in mBCC only. FLNB knockdown demonstrated an mBCC phenotype. Aberrant Gli2 dominant hedgehog (Hh) signalling was seen in mBCC on three molecular levels: mutational significance, transcriptome profile, and protein expression. Gli2-dominant Hh overexpression was seen in the tumour plus stroma of eyelid morphoeic but not nodular BCC. FLNB is a potential tumour suppressor, with its loss producing a morphoeic phenotype in vitro. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: Fourth Edition)

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16 pages, 681 KB

Open AccessArticle

SOX9, GATA3, and GATA4 Overexpression in Liposarcomas: Insights into the Molecular Biology of Adipocytic Sarcomas

by Andrei-Ionuț Patrichi, Zsolt Kovács, Ioan Jung and Simona Gurzu

Int. J. Mol. Sci. 2025, 26(22), 10981; https://doi.org/10.3390/ijms262210981 - 13 Nov 2025

Viewed by 482

Abstract

Liposarcomas represent a heterogeneous group of malignant mesenchymal neoplasms, with diverse histological subtypes and molecular alterations. This study aimed to investigate the gene expression profiles of SOX9, GATA3, and GATA4 in liposarcoma subtypes and to assess their associations with clinicopathological parameters. Forty-two formalin-fixed, paraffin-embedded liposarcoma samples were analyzed. Total RNA was extracted, reverse-transcribed, and quantified by qRT-PCR using GAPDH as an endogenous control. Relative quantification (RQ) values were categorized, and statistical analyses included Fisher’s exact test, Kaplan–Meier survival analysis, and Cox proportional hazards modeling. SOX9 expression significantly varied among histological subtypes (p = 0.017), with ALT/WDLS cases showing a predominance of high-level expression (RQ > 50 in 12/15 cases), in contrast to myxoid subtypes clustering mainly in the 10–50 RQ range. GATA4 overexpression correlated with smaller tumor size (<100 mm) (p = 0.049), being more frequent in 15/20 small tumors compared to 10/22 larger ones. GATA3 and GATA4 demonstrated the strongest inter-gene correlation (r = 0.68, p < 0.05), suggesting possible functional interplay. Kaplan–Meier analysis revealed no statistically significant survival differences for individual gene expression, but a high combined GATA3–GATA4 signature was associated with a favorable trend. These findings indicate that SOX9, GATA3, and GATA4 are broadly upregulated in liposarcomas, with subtype- and size-dependent expression patterns. The strong association between GATA3 and GATA4 expression supports their potential synergistic role in tumor biology. Integration of these molecular markers into diagnostic and prognostic workflows may enhance subtype characterization and inform targeted therapeutic strategies. Further studies in larger cohorts are warranted to validate these biomarkers and explore their mechanistic interplay in liposarcoma pathogenesis. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: Fourth Edition)

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18 pages, 2130 KB

Open AccessArticle

STAT3 Inhibition to Treat Ulcerative Colitis-Associated Colorectal Cancer

by Prema Robinson, Zal Italia, Zara Italia, Tan Hoang, Emma Rodriguez, T. Kris Eckols, Moses Kasembeli, Leticia Hamana Zorrilla, Luisa Maren Solis Soto, Rajasekaran Mahalingam and David J. Tweardy

Int. J. Mol. Sci. 2025, 26(21), 10808; https://doi.org/10.3390/ijms262110808 - 6 Nov 2025

Viewed by 1486

Abstract

In patients with inflammatory bowel disease (IBD), colorectal cancer (CRC) occurs with 20-to-30-fold higher frequency, is more advanced at diagnosis, and has a worse prognosis than in the general population. To improve their treatment options, we determined if targeting STAT3 with TTI-101, a small-molecule STAT3 inhibitor, was beneficial in the azoxymethane (AOM)-disodium sulfate (DSS) mouse model of colitis-associated CRC. C57BL/6 mice received a single intraperitoneal injection of AOM followed by three cycles of 5% DSS in drinking water before receiving TTI-101 (50 mg/kg by oral gavage, OG, and daily) or vehicle for 28 days. TTI-101 treatment reduced adenoma numbers by 89% from 1.14 ± 1.07 in vehicle-treated mice to 0.13 ± 0.35 in TTI-101-treated mice (p ≤ 0.05, Kruskal–Wallis test). Levels of activated STAT3 (pY-STAT3) were increased 3.3-fold in the epithelium and stroma of dysplastic mucosa (147 ± 46; mean ± SD; and n = 4) vs. normal mucosa (45 ± 26; n = 7; and p ≤ 0.05, Kruskal–Wallis test) and were correlated with the adenoma number. TTI-101 was detected at pharmacologically relevant levels in the plasma and colons of TTI-101-treated AOM-DSS mice and was concentrated within colon tissue; plasma TTI-101 levels inversely correlated to pY-STAT3 levels. Importantly, TTI-101 normalized the colon transcriptome of AOM-DSS mice and reduced the expression of STAT3- and STAT1-upregulated genes associated with CRC oncogenesis. Thus, TTI-101 treatment may benefit IBD patients with CRC. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: Fourth Edition)

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Review

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39 pages, 1762 KB

Open AccessReview

Hereditary Endometrial Cancer: Lynch Syndrome, Mismatch Repair Deficiency, and Emerging Genetic Predispositions—A Comprehensive Review with Clinical and Laboratory Guidelines

by Andrzej Kluk, Hanna Gryczka, Małgorzata Braszka, Rafał Ałtyn, Hanna Markiewicz, Jan K. Ślężak, Ewa Dwojak, Joanna Czerniak, Paweł Zieliński, Bartosz J. Płachno and Paula Dobosz

Int. J. Mol. Sci. 2026, 27(3), 1304; https://doi.org/10.3390/ijms27031304 - 28 Jan 2026

Viewed by 1262

Abstract

Endometrial cancer is the most common gynaecologic malignancy in high-income countries, with a rising incidence largely driven by reproductive factors, obesity, and prolonged exposure to unopposed oestrogens. Although most cases are sporadic, approximately 2–5% are associated with hereditary cancer syndromes, of which Lynch syndrome represents the most important contributor. Lynch syndrome results from germline mutations in DNA mismatch repair (MMR) genes and is associated with a substantially increased lifetime risk of endometrial cancer, reaching up to 71% in carriers of MutS homologue 6 (MSH6) mutations. Hereditary cancer predisposition typically follows an autosomal dominant inheritance pattern and may be suspected based on clinical warning signs such as early disease onset, multiple primary malignancies, a strong family history, or the presence of microsatellite instability in tumour tissue. In addition to Lynch syndrome, rarer genetic conditions—including Cowden syndrome (PTEN), Li–Fraumeni syndrome (TP53), polymerase proofreading–associated polyposis (POLE/POLD1), and hereditary breast and ovarian cancer syndromes (BRCA1/2)—also contribute to hereditary endometrial cancer risk. Recognition of these genetic backgrounds is essential for accurate diagnosis, personalised surveillance, and the implementation of targeted preventive and therapeutic strategies. Despite major advances in molecular diagnostics, hereditary endometrial cancer remains frequently underdiagnosed, leading to missed opportunities for cancer prevention among affected individuals and their families. This comprehensive review summarises current evidence on hereditary predispositions to endometrial cancer, with a particular emphasis on Lynch syndrome, and discusses underlying genetic mechanisms, inheritance patterns, diagnostic strategies, and clinical implications for screening, genetic counselling, and treatment optimisation. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: Fourth Edition)

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32 pages, 1788 KB

Open AccessReview

Luteinizing Hormone-Releasing Hormone (LHRH)-Targeted Treatment in Ovarian Cancer

by Pallavi Nayak, Michela Varani, Anna Giorgio, Giuseppe Campagna, Donatella Caserta and Alberto Signore

Int. J. Mol. Sci. 2025, 26(24), 11884; https://doi.org/10.3390/ijms262411884 - 9 Dec 2025

Viewed by 1304

Abstract

Ovarian cancer remains one of the most lethal gynecologic malignancies and requires more effective and targeted treatment strategies. Luteinizing hormone-releasing hormone (LHRH), or gonadotropin-releasing hormone (GnRH), receptors are expressed in approximately 80% of ovarian tumors, representing a promising target for targeted drug delivery. This narrative review aimed to explore the development and advancements of LHRH-receptor targeted therapies in ovarian cancer. A bibliographic search was performed using PubMed, Scopus, Google Scholar, and Web of Science. The search strategy included studies on LHRH-peptide drug delivery systems and LHRH-conjugate nanosystems. Literature search covered in vitro studies, preclinical models, and ongoing clinical trials from 2000 to 2025. A total of 19 studies were included for peptide-drug delivery, and 30 studies were included for LHRH-conjugated nanosystems. Overall findings demonstrated enhanced preclinical efficacy, achieving ~50–80% tumor-growth inhibition and 2–4-fold higher cellular uptake, alongside reduced systemic toxicity. Early clinical studies, although limited, reported an overall response/disease-control rate of approximately 50%, supporting improved tumor accumulation of drugs, small interfering RNA (siRNA), and diagnostic agents. Ovarian cancer-specific therapy, targeting LHRH receptors, represents a promising strategy to enhance therapeutic outcomes. Further efforts in preclinical and clinical research are essential to refine personalized treatments and integrate them with a combination of therapies. Full article

(This article belongs to the Special Issue Current Research on Cancer Biology and Therapeutics: Fourth Edition)

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