Colloidal chitosan-integrated functional nanoparticles for combination cancer therapy: Synergistic strategies in oncology via step-delivery of genes/proteins and small drugs

Over the past decade there have been remarkable advancements in the understanding of the molecular underpinnings of malignancy, leading to the development of a number of innovative and highly effective treatments. The success of these treatments can largely be attributed to an increased ability to deliver cancer therapies on a more individualized level based on the genetic makeup of patients’ tumours. Methods of testing such as fluorescent in situ hybridization, polymerase chain reaction and direct sequencing , which can identify the genetic architecture of tumours have improved to the point where there is an increased desire to incorporate the genomic information derived from such tests into treatment selection for cancer patients. There is, however, uncertainty with regards to the impact that genomic testing prior to treatment will have on not only health outcomes but also the costs it will incur. There is therefore a need to develop economic evidence to support the implementation of genomic testing and targeted treatment strategies in oncology to ensure the resources allocated to these approaches offer value for money. This thesis primarily investigates the most appropriate approaches to assessing the value of genomic medicine in oncology. First, factors that are important to consider when undertaking economic evaluations of genomic test and treat strategies are identified and a discussion is presented on how existing methods can be adapted to account for the unique aspects of genomic technologies. Second, one of the first model-based economic evaluations of genomic testing and targeted treatment is developed to provide initial evidence of cost-effectiveness in a metastatic lung adenocarcinoma population. Third, efforts to improve the translation of the economic evidence of genomic medicine in oncology are undertaken to ensure appropriate and timely access to these innovative and potentially beneficial technologies. Finally, the thesis addresses another important issue in the economic evaluation of oncology treatments; the estimation of health state utility values for use in cost-utility analyses. To limit bias in future evaluations, existing estimation approaches are compared and the most reliable approach is identified. The findings from this thesis suggest that a number of test-related characteristics are important to consider and can have large impacts on the results of economic evaluations of genomic approaches to treatment. More complex testing approaches are likely to make the application of traditional methods for assessing clinical and economic value more difficult, suggesting the need to adapt existing methods in the future. The results of the modelled economic evaluation highlight the difficulty in assessing the value of genomic testing when results dictate the use of high cost targeted therapies associated with only small improvements in clinical outcomes. Potential future advancements in testing, however, offer the opportunity for improvements in cost-effectiveness. To facilitate this, a greater understanding and flexibility from all stakeholders involved will be required. With respect to estimating health state utility values in oncology, response mapping is shown to result in the most accurate and reliable predictions and should therefore be used in future economic evaluations, where appropriate. To move the science forward, this program of research would suggest an iterative approach to the economic evaluation of genomic test and treat strategies in oncology. This will greatly improve our understanding of their impact on health outcomes and the overall health budget, thus informing evidence-based decision making.

Introduction The synergistic combination of histone deacetylase inhibitors and platinum-based medicines represents a promising therapeutic strategy to efficacy and overcome drug resistance in cancer therapy, necessitating a comprehensive understanding on their molecular interactions and clinical potential. Areas covered The objective of presented review is to investigate the molecular pathways of platinum medicines and HDAC inhibitors. A comprehensive literature review from 2011 to 2024 was conducted across multiple databases like MEDLINE, PubMed, Google Scholar, Science Direct, Scopus and official websites of ClinicalTrial.gov to explore publications on HDAC inhibitors, platinum drugs, and combination cancer therapies, revealing preliminary evidence of innovative treatment strategies involving HDAC inhibitors and platinum chemotherapeutics. Several new platinum (IV) complexes, with HDAC inhibitory moieties and better cytotoxicity profiles than conventional platinum drugs, are also reviewed here. Expert opinion The above combination has great potential in cancer treatment, however managing toxicity, dosage regimens, and patient selection biomarkers are problematic. More selective HDAC inhibitors and innovative delivery techniques are potential areas for future research. An adaptation toward changing cancer therapeutic landscapes, highlights combining HDAC inhibitors with platinum-based medicines serves as a new concept for personalized medicine, however, a deeper research is still needed at this time.

Treatment of malignant tumors has always been a worldwide challenge. The complexity, diversity, and heterogeneity of tumors have prompted the treatment strategies to gradually shift from monotherapy to combination therapy that can synergize multiple treatment modalities. With unique physical and chemical properties, nanomaterials have been widely used in different cancer therapies, including chemotherapy, immunotherapy, and phototherapy. Especially, the variability and integrity of nanomaterials make them ideal media for synergistic collaboration strategies. Here, we provide our perspective on the synergistic strategy of nanoplatform-mediated phototherapies and related combination therapies, specifically photochemotherapy, photoradiotherapy, and photoimmunotherapy. Besides, we provide an analysis and outlook on the current challenges faced by synergistic nanophototherapy.

BackgroundWith the discovery that more than half of human cancers harbor mutations in chromatin proteins, deregulation of epigenetic mechanisms has been recognized a hallmark of malignant transformation. Post-translational modifications (PTMs) of histone proteins, as main components of epigenetic regulatory machinery, are also broadly accepted as therapeutic target. Current “epigenetic” therapies target predominantly writers, erasers and readers of histone acetylation and (to a lesser extent) methylation, leaving other types of PTMs largely unexplored. One of them is the phosphorylation of serine 10 on histone H3 (H3S10ph).Main bodyH3S10ph is emerging as an important player in the initiation and propagation of cancer, as it facilitates cellular malignant transformation and participates in fundamental cellular functions. In normal cells this histone mark dictates the hierarchy of additional histone modifications involved in the formation of protein binding scaffolds, transcriptional regulation, blocking repressive epigenetic information and shielding gene regions from heterochromatin spreading. During cell division, this mark is essential for chromosome condensation and segregation. It is also involved in the function of specific DNA–RNA hybrids, called R-loops, which modulate transcription and facilitate chromosomal instability. Increase in H3S10ph is observed in numerous cancer types and its abundance has been associated with inferior prognosis. Many H3S10-kinases, including MSK1/2, PIM1, CDK8 and AURORA kinases, have been long considered targets in cancer therapy. However, since these proteins also participate in other critical processes, including signal transduction, apoptotic signaling, metabolic fitness and transcription, their chromatin functions are often neglected.ConclusionsH3S10ph and enzymes responsible for deposition of this histone modification are important for chromatin activity and oncogenesis. Epigenetic-drugs targeting this axis of modifications, potentially in combination with conventional or targeted therapy, provide a promising angle in search for knowledge-driven therapeutic strategies in oncology.

DNA methylation is a fundamental modification characterized by the addition of a methyl group to the cytosine bases of DNA and plays an important role in regulating gene expression, maintaining genome stability, and influencing cellular differentiation. Since the identification of abnormal DNA methylation in primary human tumors, comprehensive research has been conducted and strongly demonstrates that distorted DNA methylation patterns in cancer can lead to the silencing of inhibitory genes and the activation of oncogenes, thereby promoting tumorigenesis, progression, and resistance to treatment. These alterations in the methylation landscape present both challenges and opportunities for cancer treatment: it cannot only serve as hallmark features of cancer for early detection and monitoring treatment response, but also offer unique insights into potential therapeutic targets and new treatment strategies. The exploration of the molecular mechanisms underlying the changes in DNA methylation levels highlights the intricate relationship between DNA methylation, gene regulation, and cancer pathophysiology, allowing researchers to identify potential therapeutic targets that can effectively and safely inhibit the growth of cancer cells. This research topic aims to explore the complexity of DNA methylation in cancer therapy, highlighting its significance as a biomarker for diagnosis and prognosis, as well as a promising avenue for innovative treatment strategies.Zhang et al., attempted to develop a prognostic model for hepatocellular carcinoma (HCC) based on the expression of DNA methylation-related genes to identify potential therapeutic targets and predict overall survival. The researchers analyzed the transcriptomic, clinical, and DNA methylation data from The Cancer Genome Atlas Liver Hepatocellular Carcinoma database and the GSE54236 liver cancer dataset. They identified three methylation-related differential genes-GLS, MEX3B, and GNA14and established a risk score model to predict patient prognosis. The model was validated using an independent dataset, and its accuracy was further confirmed through qRT-PCR and immunohistochemistry. The study concluded that the gene signature could provide reliable predictions for clinical applications and enhance the understanding of the mechanisms behind the occurrence and progression of HCC.Liu et al., investigated the correlation between TERT promoter methylation and its expression levels in papillary thyroid cancer (PTC). By analyzing 571 PTC samples from The Cancer Genome Atlas (TCGA), the researchers found that patients with TERT hypermethylation had significantly higher expression level and poorer clinical outcomes compared to those with TERT hypomethylation. Additionally, the study demonstrated that treatment with the demethylating agent decitabine reduced TERT expression and cell viability in PTC cell lines. The findings suggest that TERT promoter methylation can serve as a prognostic marker for PTC risk stratification. The research enhances our understanding of the epigenetic mechanisms underlying the progression of PTC and provides a potential target for therapeutic intervention.Peng et al., explored the role of DNA methylation in hepatocellular carcinoma (HCC), focusing on how methylation modifications influence the tumor microenvironment (TME) and the efficacy of immunotherapy. Through a comprehensive analysis of DNA methylation regulators and TME profiles in HCC, the researchers identified three distinct methylation patterns, each with unique TME characteristics. They developed a DNA methylation score (DMscore) to evaluate individual methylation levels, which could predict patient subtype, TME infiltration, and prognosis. A low DMscore, indicative of an inflamed TME with high tumor mutation burden (TMB) and viral infection, was associated with poor survival outcomes. This study suggests that the DMscore can serve as a valuable biomarker for survival and immunotherapy response in HCC patients, potentially aiding in the optimization of immunotherapy approaches.Li et al., investigates the association between MGMT promoter methylation, CD47, and TIGIT expression levels and their impact on patient prognosis in adult diffuse gliomas (ADG). This study reclassified ADG into astrocytoma, oligodendroglioma, and glioblastoma (GBM) based on the 2021 WHO classification system. The findings revealed that higher CD47 and TIGIT expression levels in tumor tissues are associated with poorer overall survival rates. Notably, MGMT unmethylation is linked to a poor prognosis in astrocytoma patients. The study suggests that patients with elevated CD47 and TIGIT expression may benefit from anti-CD47 and TIGIT immunotherapy, highlighting the potential of these markers for therapeutic intervention in ADG. However, due to the unbalanced sample size of ADG subtypes and the lack of treated patients, this study acknowledges limitations which precludes definitive conclusions regarding the efficacy of immunotherapy.In conclusion, this Research Topic of articles highlights the critical role of DNA methylation in cancer development. These findings emphasize the potential of DNA methylation as a valuable biomarker for diagnosis, prognosis, and treatment strategies in oncology.

Endocrine therapy of metastatic breast cancer has been established for more than a century. Following the discovery of the beneficial effects of oophorectomy by Beatson in 1896 and the identification of the first estrogen receptor (ER- ) by E. Jensen 70 years later (1967), antihormonal treatment of breast cancer represented not only the first systemic treatment strategy in oncology but also the first for which a clear scientific rationale has been established. While early treatment options (either surgical or additive drug treatment) were associated with significant side effects, the partial estrogen receptor antagonist tamoxifen established modern endocrine drug therapy of metastatic breast cancer. The compound became the most widely used drug in breast cancer therapy until now. Recently, the role of tamoxifen has been challenged following development of other novel, highly potent, and selective drugs. The most important improvement has certainly been made with the implementation of the third generation of aromatase inhibitors (anastrozole, letrozole, and exemestane). These compounds are now in general used as first-line therapy in metastatic breast cancer in postmenopausal women not exposed to the compounds in the adjuvant setting for those relapsing after adjuvant therapy with an aromatase inhibitor. In addition, SERDs (selective estrogen receptor downregulators) like fulvestrant have shown clinical efficacy and have been introduced in standard care as well. The present publication provides an overview about endocrine treatment options of metastatic breast cancer and discusses possible treatment algorithms for both pre-and postmenopausal breast cancer patients.

Although conventional modalities such as chemotherapy and radiotherapy have markedly reduced cancer incidence, they are frequently accompanied by profound adverse effects, including systemic toxicity and the emergence of multidrug resistance. While advances in immunotherapy and targeted therapy have addressed certain limitations, such as the need for precision drug delivery, cancer treatment continues to face major challenges, particularly in overcoming tumor biological barriers to enhance therapeutic efficacy and prevent acquired resistance. With the rapid advent of novel biomaterials, polymer-based nanoparticles are reshaping traditional drug delivery paradigms and accelerating the evolution of precision oncology and intelligent drug delivery platforms. Nevertheless, comprehensive and systematic investigations remain limited regarding how polymer nanoparticles can overcome the inherent drawbacks of conventional delivery strategies in oncology. This review aims to systematically synthesize recent advances in the application of polymer nanoparticles for cancer therapy. We highlight how the intrinsic properties of polymeric nanomaterials - such as chemical tunability, stimuli-responsive mechanisms, surface engineering, and multifunctional integration - enable breakthroughs in drug synergy, tumor barrier penetration, and spatiotemporally controlled delivery. Furthermore, we delineate the major challenges and future directions in this rapidly evolving field, with the aim of providing a conceptual framework and potential roadmap for the next generation of cancer therapeutics.

Cancer persists as one of the most formidable global public health crises and socioeconomic burdens of our era, compelling the scientific community to develop innovative and diversified therapeutic modalities to revolutionize clinical management and enhance patient outcomes. The recent seminal discovery by Swamynathan et al. has unveiled menadione, a vitamin K precursor, as a potent inducer of triaptosis—a novel regulated cell death pathway mediated through the oxidative modulation of phosphatidylinositol 3-kinase PIK3C3/VPS34. This mechanistically distinct cell death paradigm, characterized by its intimate association with endosomal dysfunction and oxidative stress-induced cellular catastrophe, has demonstrated remarkable therapeutic efficacy in preclinical prostate cancer models, outperforming conventional therapeutic regimens and emerging as a potential paradigm-shifting strategy in oncology. This comprehensive review provides a critical synthesis of the triaptosis discovery landscape, elucidating its molecular intricacies and pathophysiological implications. We systematically examine the multifaceted roles of endosomal biology in oncogenesis and tumor progression, while offering a nuanced perspective on redox homeostasis in malignant cells and the therapeutic potential of oxidative stress modulation. Furthermore, we address the inherent dichotomy of oxidative stress induction in cancer therapy, balancing its therapeutic promise against potential adverse effects. Looking toward the horizon of cancer research, we explore transformative therapeutic strategies leveraging triaptosis induction and its potential applications beyond oncology, aiming to catalyze a new era of precision medicine that ultimately enhances patient survival and quality of life.

Introduction Pancreatic cancer is one of the most aggressive cancers. It occurs in men more often than women. The primary therapy for these cancers is surgery; chemotherapy, radiation therapy, hormone therapy, or immunotherapy are also used. More and better treatments are being sought for this disease. The use of PARP inhibitors in the treatment of pancreatic cancer has shown good results, so in this article we have done a review of the results of various studies on this topic. In this review, the results of studies on the use of various PARP inhibitors in pancreatic cancer of different hormonal status are presented. Purpose This article aims to give you an overview of the trials that have looked at the effects of different PARP inhibitors in the treatment of pancreatic cancer. PARP inhibitors are a relatively new cancer therapy with good results, so it is important to pay attention. State of Knowledge In this article, I used the PubMed database and considered papers from the last 10 years, but most of the information in this review comes from papers published after 2020. I have also taken into account the recommendations of the FDA and the European Medicines Agency on the use of PARP inhibitors. Conclusions PARP inhibitors have shown significant effects on pancreatic cancer outcomes. The differences in outcomes depending on the type of cancer, the PARP inhibitor used, and the previous therapies used in a given patient tell us how important it is to individualize therapy in oncology. The findings of the studies presented in this review also point to the need for further research that could focus on identifying patients who may best benefit from treatment with PARP inhibitors, as well as studying synergistic effects in combination with other forms of therapy, such as immunotherapy or chemotherapy. The changes in treatment outcomes that these drugs can bring underscore the importance of exploring new therapeutic strategies in oncology.

Recent advancements in photodynamic therapy and cancer biosensor using natural products

Molecular targeting strategies for cancer therapy are distinct from conventional chemotherapy and radiotherapy in their potential to provide increased tumor specificity. One particular molecular target of high promise in oncology is the epidermal growth factor receptor (EGFR). The EGFR is overexpressed, dysregulated or mutated in many epithelial malignancies, and EGFR activation appears important in tumor growth and progression. Advances in signal transduction biology continue to sharpen our understanding regarding specific contributions of EGFR signaling networks to cancer behavior. Two predominant classes of EGFR inhibitors have been developed including monoclonal antibodies (mAbs) that target the extracellular domain of EGFR, such as cetuximab (Erbitux), and small molecule tyrosine kinase inhibitors (TKIs) that target the receptor catalytic domain of EGFR, such as gefitinib (Iressa) and erlotinib (Tarceva). Mechanisms of action for EGFR inhibitors have been investigated in preclinical model systems. Safety, activity, pharmacokinetics and pharmacodynamics have been assessed in clinical trials. The anti-EGFR mAbs and TKIs have partially overlapping toxicity profiles, but distinct routes of administration, serum half-lives and therefore dosing schedules. Both classes of agents show clear antitumor activity, and cetuximab and gefitinib have been recently FDA approved for colorectal and lung cancer indications respectively. However, the absence of survival benefit for EGFR TKIs in combination with chemotherapy in large-scale phase III lung cancer trials in 2003 underscores a major challenge in anti-EGFR oncology therapeutics; namely to identify those tumors and patients that will respond predictably to EGFR inhibitor approaches. Newly identified mutations in the EGFR catalytic domain that appear to confer sensitivity to EGFR TKIs promise to open new doors of investigation regarding response prediction. Advances will also require enhanced molecular understanding of the overall EGFR signaling network, and improved methods to gauge the dependence of individual tumors on EGFR signaling pathways for growth advantage. Results from newly reported phase III trials in 2004 now confirm a survival advantage for the use of EGFR inhibitors in combination with high-dose radiation in head and neck cancer, and in refractory lung cancer respectively. It appears likely that EGFR inhibitors (and other rationally designed molecular growth inhibitors) will play a meaningful role in cancer therapy in the years to come.

Cancer remains a significant global health burden despite advances in diagnosis and treatment. In recent years, drug repurposing has emerged as a promising strategy in oncology, offering reduced costs and shorter development timelines compared with de novo drug discovery. Among repurposed agents, the antifungal drug itraconazole has demonstrated anticancer activity across multiple tumor types, particularly when used in combination with other therapeutic modalities. In this review, we summarize current preclinical and clinical evidence supporting the use of itraconazole in cancer therapy, with a specific focus on its combination with chemotherapeutic agents and programmed cell death protein 1 (PD-1) immune checkpoint inhibitors. We highlight proposed mechanisms underlying this synergy, including modulation of tumor metabolism, angiogenesis, and immune signaling pathways. Additionally, we discuss key challenges and limitations, such as drug-drug interactions and toxicity considerations, that must be addressed to optimize clinical translation. Overall, the combination of itraconazole with chemotherapy or anti-PD-1 therapy represents a promising therapeutic strategy warranting further investigation in well-designed trials.

Cancer is predominantly considered as an environmental disease caused by genetic or epigenetic alterations induced by exposure to extrinsic (e.g., carcinogens, pollutants, radiation) or intrinsic (e.g., metabolic, immune or genetic deficiencies). Over-exposure to antibiotics, which is favored by unregulated access as well as inappropriate prescriptions by physicians, is known to have led to serious health problems such as the rise of antibiotic resistance, in particular in poorly developed countries. In this review, the attention is focused on evaluating the effects of antibiotic exposure on cancer risk and on the outcome of cancer therapeutic protocols, either directly acting as extrinsic promoters, or indirectly, through interactions with the human gut microbiota. The preponderant evidence derived from information reported over the last 10 years confirms that antibiotic exposure tends to increase cancer risk and, unfortunately, that it reduces the efficacy of various forms of cancer therapy (e.g., chemo-, radio-, and immunotherapy alone or in combination). Alternatives to the current patterns of antibiotic use, such as introducing new antibiotics, bacteriophages or enzybiotics, and implementing dysbiosis-reducing microbiota modulatory strategies in oncology, are discussed. The information is in the end considered from the perspective of the most recent findings on the tumor-specific and intracellular location of the tumor microbiota, and of the most recent theories proposed to explain cancer etiology on the notion of regression of the eukaryotic cells and systems to stages characterized for a lack of coordination among their components of prokaryotic origin, which is promoted by injuries caused by environmental insults.

A growing area of research is focused on cancer therapy, and new therapeutic approaches are welcomed. Mesenchymal stem cell (MSC)-based gene therapy is a promising strategy in oncology. Intrinsic tropism and migration to tumor microenvironment with off lights are attractive features of this type of cell carrier. In this way, suicide genes have also found a good platform for better performance and have shown a stronger anti-tumor mechanism by riding on mesenchymal cells. In this study, we investigated the anti-tumor activity of intratumoral injected MSCs transduced with a lentivector expressing the HSV/TK in a mouse cervical cancer model. Following the injection of MSCs transduced with lentivector carrying TK, MSCs alone or PBS into the mice tumor, ganciclovir was administered intraperitoneally during 14 days, and tumor size, survival time, natural killer (NK) cells and cytotoxic T lymphocyte (CTL) activities were assessed. We demonstrated that combination of suicide therapy and cell therapy leading m,to successful tumor inhibition. Significant reduction in tumor size was detected in test group in comparison with controls. Also, potent antitumor NK and CTL activity was seen in treatment group in comparison with controls. Our data demonstrated that the mesenchymal cells expressing TK had inhibitory effect on cervical cancer model.

Glutathione-Triggered catalytic response of Copper-Iron mixed oxide Nanoparticles. Leveraging tumor microenvironment conditions for chemodynamic therapy