Cancer Treatment Pathway Research Articles

Chitosan-based nanoarchitectures for siRNA delivery in cancer therapy: A review of pre-clinical and clinical importance.

The gene therapy has been developed into a new cancer treatment option. Now that we know which molecular components contribute to carcinogenesis, we may use gene therapy to target particular signalling pathways in cancer treatment. Problems with gene therapy include genetic tool degradation in blood, off-targeting features, and inadequate tumor site accumulation; new delivery mechanisms are needed to address these issues. A polysaccharide made from chitin, chitosan has found extensive use in the creation of nanoparticles. The delivery of genes in the treatment of illnesses, particularly cancer, has made use of nanostructures modified with chitosan. Topics covered in this review center on cancer treatment using chitosan-based polymers for siRNA delivery. This study aims to assess the potential of chitosan nanoparticles for the simultaneous administration of siRNA and anti-cancer medications. In cancer treatment, these nanoparticles can transport phytochemicals or chemotherapeutics together with siRNA. In addition, chitosan nanoparticles loaded with siRNA can inhibit the growth and spread of human malignancies by delivering siRNA that targets particular genes. Chitosan nanoparticles loaded with siRNA can heighten the responsiveness of cancer cells. Future therapeutic applications of chitosan nanoparticles may open the path for cancer treatment, thanks to their biocompatibility and biosafety.

The complex interplay between redox dysregulation and mTOR signaling pathway in cancer: A rationale for cancer treatment.

The mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that plays a critical role in regulating cellular processes such as growth, proliferation, and metabolism in healthy cells. Dysregulation of mTOR signaling and oxidative stress have been implicated in various diseases including cancer. This review aims to provide an overview of the current understanding of mTOR and its involvement in cell survival and the regulation of cancer cell metabolism as well as its complex interplay with reactive oxygen species (ROS). On the one hand, ROS can inhibit or activate mTOR pathway in cancer cells through various mechanisms. Conversely, mTOR signaling can induce oxidative stress in tumor cells notably due to the inhibition in the expression of antioxidant enzyme genes. Since mTOR is often activated and plays crucial role in cancer cell survival the use of mTOR inhibitors, which often induce ROS accumulation, could be an interesting approach for cancer treatment. This review will address the advantages, disadvantages, combination strategies, and limitations associated with therapeutic modulation of mTOR signaling pathway in cancer treatment.

Advances towards potential cancer therapeutics targeting Hippo signaling.

Decades of research into the Hippo signaling pathway have greatly advanced our understanding of its roles in organ growth, tissue regeneration, and tumorigenesis. The Hippo pathway is frequently dysregulated in human cancers and is recognized as a prominent cancer signaling pathway. Hence, the Hippo pathway represents an ideal molecular target for cancer therapies. This review will highlight recent advancements in targeting the Hippo pathway for cancer treatment and discuss the potential opportunities for developing new therapeutic modalities.

LATS2 and FAT4 as key candidate genes of hippo pathway associated with the risk and progression of breast cancer: an in-silico approach

BackgroundThe 2020 cancer report states that breast cancer remains a significant cause of death for females, despite the use of various strategies for early detection and treatment. However, there are still gaps in the fight against this disease. Researchers are exploring the hippo pathway, one of eight significant pathways involved in cancer progression, for potential biomarkers to use in personalized therapeutics.MethodsThe current study used bioinformatic tools such as DEGs analysis, Methsurv, Km Plotter to generate data that can predict molecular biomarkers associated with hippo pathway in breast cancer development and treatment. The protein-protein interaction pathway was generated using the STRING database to find associations of hippo pathway genes with other dysregulated genes in breast cancer datasets. A disease enrichment study was also done to explore the potential of the hippo pathway in various aspects.ResultsLATS2 and FAT4 genes of the hippo pathway have shown an interesting association with overall survival, hypermethylation, genetic alterations, and decreased expression levels in the breast cancer cohort. Our findings suggest that both of these genes are associated with breast cancer progression and diagnosis and can be utilized as predictive biomarkers by oncologists for personalized therapy in patients.

Thapsigargin and its prodrug derivatives: exploring novel approaches for targeted cancer therapy through calcium signaling disruption.

Thapsigargin, a sesquiterpene lactone derived from Thapsia garganica L., has demonstrated mixed potential as an anticancer agent due to its potent ability to disrupt calcium signaling and induce apoptosis. This review evaluates the chemopreventive and chemotherapeutic potential of thapsigargin, focusing on its molecular mechanisms and toxicity. An extensive literature review of studies published since 2015 was conducted using databases such as PubMed/MedLine and Science Direct. Findings indicate that thapsigargin's primary mechanism is the inhibition of sarco/endoplasmic reticulum calcium ATPase, leading to endoplasmic reticulum stress and cell death in various cancer types. Despite these effects, thapsigargin's non-specific cytotoxicity results in significant side effects, including organ damage and histamine-related reactions. Recent advances in targeted delivery, especially with the prodrug mipsagargin, initially suggested promise in minimizing these toxicities by selectively activating in cancer cells expressing prostate-specific membrane antigen (PSMA). However, the completion of clinical trials with no ongoing studies suggests that the viability of mipsagargin and other prodrugs remains uncertain, especially in light of the toxicities observed. While thapsigargin and its derivatives present a potential pathway in cancer treatment, their future role in oncology requires careful re-evaluation.

Targeting regulated cell death pathways in cancers for effective treatment: a comprehensive review.

Cancer is a complex disease characterized by specific "mission-critical" events that drive the uncontrolled growth and spread of tumor cells and their offspring. These events are essential for the advancement of the disease. One of the main contributors to these events is dysregulation of cell death pathways-such as apoptosis, necroptosis, ferroptosis, autophagy, pyroptosis, cuproptosis, parthanatos and-allows cancer cells to avoid programmed cell death and continue proliferating unabated. The different cell death pathways in cancers provide useful targets for cancer treatment. This review examines recent progresses in the preclinical and clinical development of targeting dysregulated cell death pathways for cancer treatment. To develop effective cancer therapies, it is essential to identify and target these mission-critical events that prevent tumor cells from timely death. By precisely targeting these crucial events, researchers can develop therapies with maximum impact and minimal side effects. A comprehensive understanding of the molecular and cellular mechanisms underlying these regulated cell death pathways will further the development of highly effective and personalized cancer treatments.

HPB O02 - On-site hepatobiliary surgery capability independently predicts treatment pathway completion in metastatic rectal cancer: A nationwide observational study of 15,727 patients

Abstract Background Stage IV rectal cancer carries a 10% 5-year survival rate (Jemal et al., 2005). Curative-intent management requires treatment of both the primary and metastatic disease. This study aimed to identify patterns in stage IV rectal cancer treatment pathway at population level across the UK, and to identify predictors of treatment pathway completion. Method Patient demographics and treatment data were extracted from the UK Colorectal Cancer Intelligence Hub’s CORECT-R repository, national chemotherapy (SACT), radiotherapy datasets (RTDS), and Hospital Episode Statistics (HES) data. Treatment pathway completion was defined as receipt of intervention to the primary tumour, in addition to metastasis-directed therapy, or the combination alongside chemotherapy. Multivariable logistic regression analysis was performed to identify independent predictors of treatment completion. Results A total of 15,727 patients with stage IV rectal cancer diagnosed between 2010-19 were identified. There was significant variation in proportion of patients with complete treatment between MDTs. Multivariable analyses showed that lack of on-site HPB surgery capability was the only predictor of failure to complete treatment (OR 1.22, 95%CI:1.07-1.38, p<0.01). Conclusion Across the UK, there is variation in Stage IV rectal cancer patients completing treatment for both their primary and metastatic disease. Further work is needed to determine whether differences in treatment pathways stem from variation in access to specialist services between cancer alliances or whether they are due to differences in MDT decision making.

New Horizons in Cancer Progression and Metastasis: Hippo Signaling Pathway.

The Hippo pathway is highly evolved to maintain tissue homeostasis in diverse species by regulating cell proliferation, differentiation, and apoptosis. In tumor biology, the Hippo pathway is a prime example of signaling molecules involved in cancer progression and metastasis. Hippo core elements LATS1, LATS2, MST1, YAP, and TAZ have critical roles in the maintenance of traditional tissue architecture and cell homeostasis. However, in cancer development, dysregulation of Hippo signaling results in tumor progression and the formation secondary cancers. Hippo components not only transmit biochemical signals but also act as mediators of mechanotransduction pathways during malignant neoplasm development and metastatic disease. This review confers knowledge of Hippo pathway core components and their role in cancer progression and metastasis and highlights the clinical role of Hippo pathway in cancer treatment. The Hippo signaling pathway and its unresolved mechanisms hold great promise as potential therapeutic targets in the emerging field of metastatic cancer research.

Carbon dot-based nanomaterials with enzyme-like activity for fluorescence imaging and potential combination withtherapy of cancer.

Carbon dot-based nanomaterials (o-CDs@Mn) were fabricated by assembling fluorescent o-CDs with enzyme-like activity and Mn nanoparticles with photothermal properties for realizing fluorescence imaging and combined therapy of cancer. Due to the inherent optical properties of o-CDs, o-CDs@Mn can be effectively used for bioimaging. In addition, o-CDs@Mn possess peroxidase-like (POD-like) and glutathione (GSH) degradation capabilities, which can effectively deplete excessive H2O2 and GSH in the tumor microenvironment (TME), generating ·OH and reduced GSSH for regulating the TME and triggering ROS-mediated apoptosis in cancer cells. More importantly, it is synergistically supplemented with fluorescence imaging and photothermal therapy (PTT), which realizes the integration of monitoring and combined treatment, providing a promising potential pathway for accurate and efficient cancer treatment.

Inhibitors of the mTOR signaling pathway can play an important role in breast cancer immunopathogenesis.

This study explores the critical role of inhibitors targeting the mammalian target of rapamycin (mTOR) signaling pathway in breast cancer research and treatment. The mTOR pathway, a central regulator of cellular processes, has been identified as a crucial factor in the development and progression of breast cancer. The essay explains the complex molecular mechanisms through which mTOR inhibitors, such as rapamycin and its analogs, exert their anticancer effects. These inhibitors can stop cell growth, proliferation, and survival in breast cancer cells by blocking critical signaling pathways within the mTOR pathway. Furthermore, the essay discusses the implications of using mTOR inhibitors as a comprehensive therapeutic strategy. It emphasizes the potential benefits of combining mTOR inhibitors with other treatment approaches to enhance the effectiveness of breast cancer treatment. The evolving landscape of breast cancer research underscores the significance of mTOR as a therapeutic target and highlights ongoing efforts to improve and optimize mTOR inhibitors for clinical use. In conclusion, the essay asserts that inhibitors of the mTOR signaling pathway offer a promising approach in the fight against breast cancer. These inhibitors provide a focused and effective intervention targeting specific dysregulations within the mTOR pathway. As research advances, the integration of mTOR inhibitors into customized combination therapies holds excellent potential for shaping a more effective and personalized approach to breast cancer treatment, ultimately leading to improved outcomes for individuals affected by this complex and diverse disease.

Advances in CRISPR-Cas9 Technology for Tumor Therapy

Genome editing technology is an emerging toolbox that can specifically target genes. At present, the existing gene editing technologies include ZFN, TALEN, and CRISPR system editing technology with clusters of regularly spaced short palindromic repeats. However, ZFN and TALEN are no longer the preferred tools for gene editing due to some of their problems, and their complex protein design, high cost, and high difficulty are the main reasons that limit their use. The CRISPR system, on the other hand, is able to achieve specific binding by base complementary pairing of sgRNA to the target sequence. Traditional cancer treatment methods have limited efficacy and high recurrence rates, and the disease can be fundamentally treated by inactivating oncogenes or activating tumor suppressor genes through gene editing technology and then changing downstream signaling pathways for cancer treatment. With CRISPR-Cas9 technology, it is possible to have gene knockouts, insertions, and mutations. Here, we will investigate and explore the feasibility of the CRISPR system for tumor treatment, including the following three topics: oncogene knockout, augmentation of tumor suppressor gene expression, and enhancement of engineered T cell viability for effective tumor Through these methods, the CRISPR system is of great help and promising tumor therapy.

Methodological insights into severity distribution of non-fatal cancer burden in Belgium using a microsimulation model (2004-2019)

Abstract This study leverages a registry-based microsimulation model to analyze the non-fatal burden of cancer in Belgium from 2004 to 2019, emphasizing the methodology for severity distribution. Utilizing incidence- and prevalence-based approaches, we estimated Years Lived with Disability (YLD) through detailed national cancer registry data coupled with tailored disease models. The microsimulation model employed enabled nuanced translation of cancer incidence into prevalence estimates, incorporating the longitudinal impacts of disease severity influenced by treatment. Methodologically, the model integrated expert elicitation to adjust for treatment-related disabilities, such as surgical aftereffects, enhancing the accuracy of disability weight assignment across different cancer stages. This approach allowed for a dynamic assessment of disease burden, reflecting real-world complexities of cancer prognosis and treatment pathways. Significant findings include a substantial increase in the age-standardized non-fatal burden for non-melanoma skin cancer, highlighting the model’s capability to detect shifts in disease impact over time. By focusing on the microsimulation’s capacity to delineate severity distributions within the cancer burden landscape, this analysis underscores the model’s utility in refining health policy decisions and resource allocation. Ultimately, this study presents a robust framework for national burden of disease studies, facilitating detailed evaluations of health interventions and their longitudinal effectiveness.

The SUMO Family: Mechanisms and Implications in Thyroid Cancer Pathogenesis and Therapy.

(1) Background: Small ubiquitin-like modifiers (SUMOs) are pivotal in post-translational modifications, influencing various cellular processes, such as protein localization, stability, and genome integrity. (2) Methods: This review explores the SUMO family, including its isoforms and catalytic cycle, highlighting their significance in regulating key biological functions in thyroid cancer. We discuss the multifaceted roles of SUMOylation in DNA repair mechanisms, protein stability, and the modulation of receptor activities, particularly in the context of thyroid cancer. (3) Results: The aberrant SUMOylation machinery contributes to tumorigenesis through altered gene expression and immune evasion mechanisms. Furthermore, we examine the therapeutic potential of targeting SUMOylation pathways in thyroid cancer treatment, emphasizing the need for further research to develop effective SUMOylation inhibitors. (4) Conclusions: By understanding the intricate roles of SUMOylation in cancer biology, we can pave the way for innovative therapeutic strategies to improve outcomes for patients with advanced tumors.

Network pharmacology-based strategy to reveal the mechanism of pinocembrin against ovarian cancer.

Ovarian cancer stands as the foremost cause of mortality among gynaecological diseases globally, characterized by high morbidity and mortality. Pinocembrin, a flavonoid from natural plant sources, exhibits diverse pharmacological properties. Despite its known pharmacological activities, its specific role in ovarian cancer treatment remains scarcely reported, and its precise molecular mechanism remains elusive. This study integrates network pharmacology and molecular docking techniques to explore pinocembrin's potential mechanism in ovarian cancer treatment. The targets of pinocembrin were compiled from the several online databases. Ovarian cancer targets were identified using the GeneCards database, with common target genes determined by data aggregation. Protein-protein interactions were analysed using the STRING platform. Subsequent Gene Ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed. Molecular docking assessed the binding affinity between potential targets and active compounds. Finally, target validity was verified through in vitro experiments. We identified 163 potential pinocembrin targets for ovarian cancer treatment. GO and KEGG analyses revealed pinocembrin's involvement in protein kinase activity, protein phosphorylation, protein kinase complexes and cancer pathways in ovarian cancer treatment. Molecular docking demonstrated strong binding affinity between pinocembrin and most potential target active sites. In vitro experiments suggested pinocembrin's potential to induce apoptosis in ovarian cancer cells through the AKT1-mTOR signalling pathway. This study comprehensively elucidates pinocembrin's potential targets and mechanisms against ovarian cancer, aiming to provide promising candidates for developing novel and effective alternative and/or complementary nutritional supplements for the clinical treatment of ovarian cancer.

COVID-19 pandemic impact on gynecologic cancer treatment pathways in a Finnish tertiary center.

COVID-19 and new guidelines during the pandemic affected the gynecologic cancer treatment pathways, resulting in recorded delays and modifications in the treatment protocols. The aim of this study was to determine the impact of the COVID-19 pandemic in one of the major gynecologic cancer care centers in Finland, Tampere University Hospital. Our retrospective register study included 909 patients that were new gynecologic cancer cases (uterine, cervical, vulvar, vaginal, or ovarian) referred to the Tampere University Hospital Gynecologic Oncology Outpatient Clinic between March 17th, 2018, and March 15th, 2022. The patients were divided into two separate groups depending on their time of referral: time before COVID (March 17th, 2018, to March 15th, 2020), and during COVID (March 16th, 2020, to March 15th, 2022). These groups were compared in terms of patient characteristics, different cancer types and stages, symptoms, and treatment methods. During the COVID-19 pandemic, patients generally suffered from cancer symptoms longer (p < 0.003) and were more likely to be overweight (p = 0.035). The improved multidisciplinary team meeting gave the patients a faster route to their first intervention during COVID (p < 0.05). An insignificant shift toward nonsurgical first interventions and non-curative intent was seen during COVID, but the multidisciplinary team treatment plans were mostly implemented accordingly on both eras. No decrease was seen in the number of new gynecologic cancer cases, and the one-year overall survival remained the same in both groups. Overall, the COVID-19 pandemic did not significantly alter treatment pathways in gynecologic cancer care at Tampere University Hospital. The number of new patients and given treatments remained relatively stable. During COVID, access from referral to cancer treatment was significantly accelerated, which is likely confounded by changes to the multidisciplinary team protocol made in early 2021.

Breast cancer: do the current policies mean anything?

Aim Breast cancer remains one of the most prevalent malignancies globally with a high mortality rate. South Africa has a number of policies in place designed to ensure that minimum delays are experienced by patients from first symptom to initial treatment. This study was initiated to determine where the longest delays occurred during the patient’s journey, from the first symptom to the first treatment. This information, combined with the existing policy, identifies shortfalls in the breast cancer diagnostic and treatment pathways that must be addressed. Methods A cross-sectional study was undertaken in the Department of Medical Oncology, University of Pretoria/Steve Biko Academic Hospital between April 2020 and August 2021, analysing six timelines from first symptom to first treatment in patients with newly diagnosed breast cancer. Data was obtained by the researchers from the patients on their first visit relating to the delays experienced from first symptom to final biopsy. Clinical information was obtained from the patients’ source records once a treatment decision had been reached and treatment started where applicable. Results The longest delays experienced were between the patients’ first visit to any medical facility to date of diagnostic biopsy. Delays due to COVID-19 were in the minority with 13/79 (16.4%) patients reporting having experienced COVID-19 related delays. Key Area 2 of the Breast Cancer Prevention and Control Policy makes provision for patients to be referred directly to a regional/tertiary/quaternary medical facility for further screening, diagnosis and treatment within 21-60 days from the first visit. In the study’s cohort, a mean of four months from first visit to diagnostic biopsy was recorded. Overall delays of longer than 12 months due to non-representative biopsies (range 1-3) were recorded in three patients. Twenty-nine patients (36.7%) presented to three medical facilities prior to diagnostic biopsy with 10/79 (12.6%) and 1/79 (1.2%) presenting to four and five institutions, respectively, before the diagnostic biopsy. Conclusions The delays patients experienced highlights the lack of knowledge about the urgency and correct referral of suspected malignancy cases. Despite the number of promulgated policies relating to fast track systems via specialist breast units, fiscal and human capital deficiencies negatively impact the attempts to diagnose and treat patients timeously and increase survival.

Piperine, a black pepper compound, induces autophagy and cellular senescence mediated by NF-κB and IL-6 in acute leukemia

Acute leukemia is characterized by abnormal white blood cell proliferation with rapid onset and severe complications. Natural compounds, which are alternative treatments, are widely used in cancer treatment. Piperine, an alkaloid compound from black pepper, exerts anticancer effects through the cell death signaling pathway. Autophagy and senescence signaling pathways are considered target signaling pathways for cancer treatment. In this study, we investigated the effects of piperine via autophagy and senescence signaling pathways in NB4 and MOLT-4 cells. The MTT assay results demonstrated that piperine significantly decreased the viability of NB4 and MOLT-4 cells. Piperine induced autophagy by increasing LC3, Beclin-1 and ULK1 and decreasing mTOR and NF-κB1 expression in NB4 and MOLT-4 cells. In addition, piperine increased senescence-associated beta-galactosidase fluorescence intensity by increasing p21 and IL-6 expression while decreasing CDK2 expression in NB4 and MOLT-4 cells. In conclusion, our study provides additional information about the induction of autophagy and senescence by piperine in acute leukemia.

Unlocking the potential of LHPP: Inhibiting glioma growth and cell cycle via the MDM2/p53 pathway

The recurrence of glioma after treatment has remained an intractable problem for many years. Recently, numerous studies have explored the pivotal role of the mouse double minute 2 (MDM2)/p53 pathway in cancer treatment. Lysine phosphate phosphohistidine inorganic pyrophosphate phosphatase (LHPP), a newly discovered tumor suppressor, has been confirmed in numerous studies on tumors, but its role in glioma remains poorly understood. Expression matrices in The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases were analyzed using gene set enrichment analysis (GSEA), revealing significant alterations in the p53 pathway among glioma patients with high LHPP expression. The overexpression of LHPP in glioma cells resulted in a reduction in cell proliferation, migration, and invasive ability, as well as an increase in apoptosis and alterations to the cell cycle. The present study has identified a novel inhibitory mechanism of LHPP against glioma, both in vivo and in vitro. The results demonstrate that LHPP exerts anti-glioma effects via the MDM2/p53 pathway. These findings may offer a new perspective for the treatment of glioma in the clinic.

Metabolomics and proteomics reveal the inhibitory effect of Lactobacillus crispatus on cervical cancer

Cervical cancer remains a significant global health issue due to its high morbidity and mortality rates. Recently, Lactobacillus crispatus has been recognized for its crucial role in maintaining cervical health. While some studies have explored the use of L. crispatus to mitigate cervical cancer, the underlying mechanisms remain largely unknown. In this study, we employed non-targeted proteomics and metabolomics to investigate how L. crispatus affects the growth of cervical cancer cells (SiHa) and normal cervical cells (Ect1/E6E7). Our findings indicated that the inhibitory effect of L. crispatus on SiHa cells was associated with various biological processes, notably the ferroptosis pathway. Specifically, L. crispatus was found to regulate the expression of proteins such as HMOX1, SLC39A14, VDAC2, ACSL4, and LPCAT3 by SiHa cells, which are closely related to ferroptosis. Additionally, it activated the tricarboxylic acid (TCA) cycle in SiHa cells, leading to increased levels of reactive oxygen species (ROS) and lipid peroxides (LPO). These results revealed the therapeutic potential of L. crispatus in targeting the ferroptosis pathway for cervical cancer treatment, opening new avenues for research and therapy in cervical cancer.

The implications of the TNFα-TNFR2 immune checkpoint signaling pathway in cancer treatment: From immunoregulation to angiogenesis.

Despite the tremendous advances that have been made in biomedical research, cancer remains one of the leading causes of death worldwide. Several therapeutic approaches have been suggested and applied to treat cancer with impressive results. Immunotherapy based on targeting immune checkpoint signaling pathways proved to be one of the most efficient. In this review article, we will focus on the recently discovered TNFα-TNFR2 signaling pathway, which controls the immunological and pro-angiogenic properties of many immunoregulatory and pro-angiogenic cells such as endothelial progenitor cells (EPCs), mesenchymal stem cells (MSCs), and regulatory T cells (Tregs). Due to their biological properties, these cells can play a major role in cancer progression and metastasis. Therefore, we will discuss the advantages and disadvantages of an anti-TNFR2 treatment that could carry two faces under one hood. It interrupts the immunosuppressive and pro-angiogenic behaviors of the above-mentioned cells and interferes with tumor growth and survival.