Targeting stress induction of GRP78 by cardiac glycoside oleandrin dually suppresses cancer and COVID-19.

BACKGROUND: Despite recent therapeutic advances, combating cancer resistance remains a formidable challenge. The 78-kilodalton glucose-regulated protein (GRP78), a key stress-inducible endoplasmic reticulum (ER) chaperone, plays a crucial role in both cancer cell survival and stress adaptation. GRP78 is also upregulated during SARS-CoV-2 infection and acts as a critical host factor. Recently, we discovered cardiac glycosides (CGs) as novel suppressors of GRP78 stress induction through a high-throughput screen of clinically relevant compound libraries. This study aims to test the possibility that agents capable of blocking stress induction of GRP78 could dually suppress cancer and COVID-19. RESULTS: Here we report that oleandrin (OLN), is the most potent among the CGs in inhibiting acute stress induction of total GRP78, which also results in reduced cell surface and nuclear forms of GRP78 in stressed cells. The inhibition of stress induction of GRP78 is at the post-transcriptional level, independent of protein degradation and autophagy and may involve translational control as OLN blocks stress-induced loading of ribosomes onto GRP78 mRNAs. Moreover, the human Na+/K+-ATPase α3 isoform is critical for OLN suppression of GRP78 stress induction. OLN, in nanomolar range, enhances apoptosis, sensitizes colorectal cancer cells to chemotherapeutic agents, and reduces the viability of patient-derived colon cancer organoids. Likewise, OLN, suppresses GRP78 expression and impedes tumor growth in an orthotopic breast cancer xenograft model. Furthermore, OLN blocks infection by SARS-CoV-2 and its variants and enhances existing anti-viral therapies. Notably, GRP78 overexpression mitigates OLN-mediated cancer cell apoptotic onset and suppression of virus release. CONCLUSION: Our findings validate GRP78 as a target of OLN anti-cancer and anti-viral activities. These proof-of-principle studies support further investigation of OLN as a readily accessible compound to dually combat cancer and COVID-19.

Variability in Kidney Cancer Treatment and Survival in England: Results of a National Cohort Study.

AIMS: To establish whether there are geographic differences in treatments and outcomes for patients with kidney cancer (KC) in England which could potentially be improved by the creation of national guidelines. MATERIALS AND METHODS: A multidisciplinary group convened by the charity Kidney Cancer UK developed Quality Performance Indicators (QPIs) for the treatment of KC. Adherence to these QPIs was reported for all patients with a histological diagnosis of KC diagnosed in England between 2017 and 2018. Utilising data extracted from national datasets, logistic and linear probability models were used to estimate geographic variation in the delivery of surgery and systemic anti-cancer therapy at Cancer Alliance and NHS trust levels. Results were adjusted for a priori confounders, including age at diagnosis, area deprivation of residence, and Charlson Comorbidity Index. Differences in overall survival are reported. RESULTS: The cohort comprised 18,640 tumours in 18,421 patients. Of tumours diagnosed, median patient age was 68 (interquartile range 58-77) years and 63.4% were in males. When stratified by Cancer Alliance, the proportions of T1a/T1b/N0/M0 KC that had radical nephrectomy (RN), nephron sparing surgery or ablation ranged from 53.3% (95% CI [48.7, 57.8]) to 80.3% (95% CI [73.0, 86.0]). For stage T1b-3 cancers, the proportion that received RN ranged from 65.6% (95% CI [60.3, 70.5]) to 77.3% (95% CI [72.1, 81.7]). Patients with M0 (n = 12,365) and M1 KC (n = 3312) at diagnosis had 24-month survival of 87.5% and 25.1%, respectively. Of patients diagnosed with M1 KC, 50.3% received systemic anti-cancer therapy, ranging from 39.7% (95% CI [33.7, 46.1]) to 70.7% (95% CI [59.6, 79.8]) between Cancer Alliances. The six-month survival of these patients was 77.4% compared to 27.6% for those that did not receive SACT. CONCLUSION: These major geographical differences in surgical and systemic therapy practice have led to national guideline development.

Role of Mesenchymal Stem/Stromal Cells in Head and Neck Cancer-Regulatory Mechanisms of Tumorigenic and Immune Activity, Chemotherapy Resistance, and Therapeutic Benefits of Stromal Cell-Based Pharmacological Strategies.

Head and neck cancer (HNC) entails a heterogenous neoplastic disease that arises from the mucosal epithelium of the upper respiratory system and the gastrointestinal tract. It is characterized by high morbidity and mortality, being the eighth most common cancer worldwide. It is believed that the mesenchymal/stem stromal cells (MSCs) present in the tumour milieu play a key role in the modulation of tumour initiation, development and patient outcomes; they also influence the resistance to cisplatin-based chemotherapy, the gold standard for advanced HNC. MSCs are multipotent, heterogeneous and mobile cells. Although no MSC-specific markers exist, they can be recognized based on several others, such as CD73, CD90 and CD105, while lacking the presence of CD45, CD34, CD14 or CD11b, CD79α, or CD19 and HLA-DR antigens; they share phenotypic similarity with stromal cells and their capacity to differentiate into other cell types. In the tumour niche, MSC populations are characterized by cell quiescence, self-renewal capacity, low reactive oxygen species production and the acquisition of epithelial-to-mesenchymal transition properties. They may play a key role in the process of acquiring drug resistance and thus in treatment failure. The present narrative review examines the links between MSCs and HNC, as well as the different mechanisms involved in the development of resistance to current chemo-radiotherapies in HNC. It also examines the possibilities of pharmacological targeting of stemness-related chemoresistance in HNSCC. It describes promising new strategies to optimize chemoradiotherapy, with the potential to personalize patient treatment approaches, and highlights future therapeutic perspectives in HNC.

Doxorubicin-loaded liposome-like particles embedded in chitosan/hyaluronic acid-based hydrogels as a controlled drug release model for local treatment of glioblastoma.

Glioblastoma (GBM) resection and medication treatment are limited, and local drug therapies are required. This study aims to create a hybrid system comprising liposome-like particles (LLP-DOX) encapsulated in chitosan/hyaluronic acid/polyethyleneimine (CHI/HA/PEI) hydrogels, enabling controlled local delivery of doxorubicin (DOX) into the resection cavity for treating GBM. CHI/HA/PEI hydrogels were characterized morphologically, physically, chemically, mechanically, and thermally. Findings revealed a high network and compact micro-network structure, along with enhanced physical and thermal stability compared to CHI/HA hydrogels. Simultaneously, drug release from CHI/HA/PEI/LLP-DOX hydrogels was assessed, revealing continuous and controlled release up to the 148th hour, with no significant burst release. Cell studies showed that CHI/HA/PEI hydrogels are biocompatible with low genotoxicity. Additionally, LLP-DOX-loaded CHI/HA/PEI hydrogels significantly decreased cell viability and gene expression levels compared to LLP-DOX alone. It was also observed that the viability of GBM spheroids decreased over time when interacting with CHI/HA/PEI/LLP-DOX hydrogels, accompanied by a reduction in total surface area and an increase in apoptotic tendencies. In this study, we hypothesized that creating a hybrid drug delivery system by encapsulating DOX-loaded LLPs within a CHI/HA/PEI hydrogel matrix could achieve sustained drug release, improve anticancer efficacy via localized treatment, and effectively mitigate GBM progression for 3D microtissues.

The Pivotal Role of Preclinical Animal Models in Anti-Cancer Drug Discovery and Personalized Cancer Therapy Strategies.

The establishment and utilization of preclinical animal models constitute a pivotal aspect across all facets of cancer research, indispensably contributing to the comprehension of disease initiation and progression mechanisms, as well as facilitating the development of innovative anti-cancer therapeutic approaches. These models have emerged as crucial bridges between basic and clinical research, offering multifaceted support to clinical investigations. This study initially focuses on the importance and benefits of establishing preclinical animal models, discussing the different types of preclinical animal models and recent advancements in cancer research. It then delves into cancer treatment, studying the characteristics of different stages of tumor development and the development of anti-cancer drugs. By integrating tumor hallmarks and preclinical research, we elaborate on the path of anti-cancer drug development and provide guidance on personalized cancer therapy strategies, including synthetic lethality approaches and novel drugs widely adopted in the field. Ultimately, we summarize a strategic framework for selecting preclinical safety experiments, tailored to experimental modalities and preclinical animal species, and present an outlook on the prospects and challenges associated with preclinical animal models. These models undoubtedly offer new avenues for cancer research, encompassing drug development and personalized anti-cancer protocols. Nevertheless, the road ahead continues to be lengthy and fraught with obstacles. Hence, we encourage researchers to persist in harnessing advanced technologies to refine preclinical animal models, thereby empowering these emerging paradigms to positively impact cancer patient outcomes.

Potential Consequences of the Use of Adipose-Derived Stem Cells in the Treatment of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) ranks as the most prevalent of primary liver cancers and stands as the third leading cause of cancer-related deaths. Early-stage HCC can be effectively managed with available treatment modalities ranging from invasive techniques, such as liver resection and thermoablation, to systemic therapies primarily employing tyrosine kinase inhibitors. Unfortunately, these interventions take a significant toll on the body, either through physical trauma or the adverse effects of pharmacotherapy. Consequently, there is an understandable drive to develop novel HCC therapies. Adipose-derived stem cells (ADSCs) are a promising therapeutic tool. Their facile extraction process, coupled with the distinctive immunomodulatory capabilities of their secretome, make them an intriguing subject for investigation in both oncology and regenerative medicine. The factors they produce are both enzymes affecting the extracellular matrix (specifically, metalloproteinases and their inhibitors) as well as cytokines and growth factors affecting cell proliferation and invasiveness. So far, the interactions observed with various cancer cell types have not led to clear conclusions. The evidence shows both inhibitory and stimulatory effects on tumor growth. Notably, these effects appear to be dependent on the tumor type, prompting speculation regarding their potential inhibitory impact on HCC. This review briefly synthesizes findings from preclinical and clinical studies examining the effects of ADSCs on cancers, with a specific focus on HCC, and emphasizes the need for further research.

Personalizing Therapy Outcomes through Mitogen-Activated Protein Kinase Pathway Inhibition in Non-Small Cell Lung Cancer.

Lung cancer (LC) is a highly invasive malignancy and the leading cause of cancer-related deaths, with non-small cell lung cancer (NSCLC) as its most prevalent histological subtype. Despite all breakthroughs achieved in drug development, the prognosis of NSCLC remains poor. The mitogen-activated protein kinase signaling cascade (MAPKC) is a complex network of interacting molecules that can drive oncogenesis, cancer progression, and drug resistance when dysregulated. Over the past decades, MAPKC components have been used to design MAPKC inhibitors (MAPKCIs), which have shown varying efficacy in treating NSCLC. Thus, recent studies support the potential clinical use of MAPKCIs, especially in combination with other therapeutic approaches. This article provides an overview of the MAPKC and its inhibitors in the clinical management of NSCLC. It addresses the gaps in the current literature on different combinations of selective inhibitors while suggesting two particular therapy approaches to be researched in NSCLC: parallel and aggregate targeting of the MAPKC. This work also provides suggestions that could serve as a potential guideline to aid future research in MAPKCIs to optimize clinical outcomes in NSCLC.

Bioengineered Mesenchymal Stem/Stromal Cells in Anti-Cancer Therapy: Current Trends and Future Prospects.

Mesenchymal stem/stromal cells (MSCs) are one of the most widely used cell types in advanced therapies due to their therapeutic potential in the regulation of tissue repair and homeostasis, and immune modulation. However, their use in cancer therapy is controversial: they can inhibit cancer cell proliferation, but also potentially promote tumour growth by supporting angiogenesis, modulation of the immune milieu and increasing cancer stem cell invasiveness. This opposite behaviour highlights the need for careful and nuanced use of MSCs in cancer treatment. To optimize their anti-cancer effects, diverse strategies have bioengineered MSCs to enhance their tumour targeting and therapeutic properties or to deliver anti-cancer drugs. In this review, we highlight the advanced uses of MSCs in cancer therapy, particularly as carriers of targeted treatments due to their natural tumour-homing capabilities. We also discuss the potential of MSC-derived extracellular vesicles to improve the efficiency of drug or molecule delivery to cancer cells. Ongoing clinical trials are evaluating the therapeutic potential of these cells and setting the stage for future advances in MSC-based cancer treatment. It is critical to identify the broad and potent applications of bioengineered MSCs in solid tumour targeting and anti-cancer agent delivery to position them as effective therapeutics in the evolving field of cancer therapy.

Combination of STING agonist with anti-vascular RGD-(KLAKLAK)2 peptide as a novel anti-tumor therapy.

Immunotherapy is one of the most promising anti-cancer treatment. It involves activating the host's own immune system to eliminate cancer cells. Activation of cGAS-STING pathway is promising therapeutic approach for cancer immunotherapy. However, in human clinical trials, targeting cGAS-STING pathway results in insufficient or unsustainable anti-tumor response. To enhance its effectiveness, combination with other anti-cancer therapies seems essential to achieve synergistic systemic anti-tumor response.The aim of this study was to evaluate whether the combination of STING agonist-cGAMP with anti-vascular RGD-(KLAKLAK)2 peptide results in a better anti-tumor response in poorly immunogenic tumors with various STING protein and αvß3 integrin status.Combination therapy inhibited growth of murine breast carcinoma more effectively than melanoma. In melanoma, the administration of STING agonist alone was sufficient to obtain a satisfactory therapeutic effect. In both tumor models we have noted stimulation of innate immune response following cGAMP administration alone or in combination. The largest population of immune cells infiltrating the TME after therapy were activated NK cells. Increased infiltration of cytotoxic CD8+ T lymphocytes within the TME was only observed in melanoma tumors. However, they also expressed the "exhaustion" PD-1 receptor. In contrast, in breast carcinoma tumors each therapy caused the drop in the number of infiltrating CD8+ T cells.The obtained results indicate an additional therapeutic benefit from combining STING agonist with an anti-vascular agent. However, this effect depends on the type of tumor, the status of its microenvironment and the expression of specific proteins such as STING and αvß3 family integrin.

Stem cell-based targeted therapy in pancreatic cancer: Current approaches and future prospects.

Despite recent improvements in oncology, diagnosis, and therapy, pancreatic cancer remains extremely difficult to cure due to its aggressive growth pattern with early invasion and distant metastases, chemoresistance, and a lack of effective screening modalities for early detection. Here, novel therapeutic approaches for treating pancreatic cancer are urgently needed. Recently, stem cells have drawn a lot of interest as a possible treatment for pancreatic cancer due to their ability to locate tumors. Though research over the last few decades has revealed some very exciting and promising new treatment approaches, the clinical success of these stem-cell based anti-cancer medicines has been quite limited. The most effective stem cell-mediated therapeutic options will only be available with a deeper understanding of the intricate molecular biology underlying pancreatic cancer and the subsequent identification of cancer stem cells as a novel target that promotes the growth of the cancer and resistance to chemotherapy. This review will highlight the stem cell based anti-cancer therapy targeting pancreatic cancer stem cells and different molecular signaling pathways. A particular focus will be on the therapeutic potential of naïve Stem cells, anti-cancer drug loaded stem cells, genetically engineered stem cells and exosomal miRNA released by stem cells in pancreatic cancer treatment. Similarly, the role of nanotechnology in stem cell based anticancer therapy will be further discussed to better implementation of these cell-based cancer therapy.

Longitudinal Comparative Analysis of Circulating Tumor DNA and Matched Tumor Tissue DNA in Patients with Metastatic Colorectal Cancer Receiving Palliative First-Line Systemic Anti-Cancer Therapy.

Purpose: This study aimed to compare tumor tissue DNA (ttDNA) and circulating tumor DNA (ctDNA) to explore the clinical applicability of ctDNA and to better understand clonal evolution in patients with metastatic colorectal cancer undergoing palliative first-line systemic therapy. Materials and Methods: We performed targeted sequencing analysis of 88 cancer-associated genes using germline DNA, ctDNA at baseline (baseline-ctDNA), and ctDNA at progressive disease (PD-ctDNA). The results were compared with ttDNA data. Results: Among 208 consecutively enrolled patients, we selected 84 (41 males; median age 59, range 35 to 90) with all four sample types available. A total of 202 driver mutations were found in 34 genes. ttDNA exhibited the highest mutation frequency (n=232), followed by baseline-ctDNA (n=155) and PD-ctDNA (n=117). Sequencing ctDNA alongside ttDNA revealed additional mutations in 40 patients (47.6%). PD-ctDNA detected 13 novel mutations in 10 patients (11.9%) compared to ttDNA and baseline-ctDNA. Notably, 7 mutations in 5 patients (6.0%) were missense or nonsense mutations in APC, TP53, SMAD4, and CDH1 genes. In baseline-ctDNA, higher maximal variant allele frequency (VAF) values (p=0.010) and higher VAF values of APC (p=0.012), TP53 (p=0.012), and KRAS (p=0.005) mutations were significantly associated with worse overall survival. Conclusion: While ttDNA remains more sensitive than ctDNA, our ctDNA platform demonstrated validity and potential value when ttDNA was unavailable. Post-treatment analysis of PD-ctDNA unveiled new pathogenic mutations, signifying cancer's clonal evolution. Additionally, baseline-ctDNA's VAF values were prognostic after treatment.

Patient-derived tumoroids and proteomic signatures: tools for early drug discovery.

Onco-virotherapy is an emergent treatment for cancer based on viral vectors. The therapeutic activity is based on two different mechanisms including tumor-specific oncolysis and immunostimulatory properties. In this study, we evaluated onco-virotherapy in vitro responses on immunocompetent non-small cell lung cancer (NSCLC) patient-derived tumoroids (PDTs) and healthy organoids. PDTs are accurate tools to predict patient's clinical responses at the in vitro stage. We showed that onco-virotherapy could exert specific antitumoral effects by producing a higher number of viral particles in PDTs than in healthy organoids. In the present work, we used multiplex protein screening, based on proximity extension assay to highlight different response profiles. Our results pointed to the increase of proteins implied in T cell activation, such as IFN-γ following onco-virotherapy treatment. Based on our observation, oncolytic viruses-based therapy responders are dependent on several factors: a high PD-L1 expression, which is a biomarker of greater immune response under immunotherapies, and the number of viral particles present in tumor tissue, which is dependent to the metabolic state of tumoral cells. Herein, we highlight the use of PDTs as an alternative in vitro model to assess patient-specific responses to onco-virotherapy at the early stage of the preclinical phases.

Evaluation of patient satisfaction of receiving Systemic Anti-Cancer Therapy prescribed by nurse Non-Medical Prescribers.

PURPOSE: To evaluate patient satisfaction of patients receiving Systemic Anti-Cancer Treatment prescribed by nurse Non-Medical Prescribers as a new model of care at a Cancer Unit in Northern Ireland, United Kingdom. METHODS: A cross-sectional survey design, with a convenience sample of patients from five tumour groups who received Systemic Anti-Cancer Therapy by nurse Non-Medical Prescribers, across a 3-month period in 2022 was employed. Anonymised data were collected via postal survey, which incorporated a minimally modified version of the 45-item Leeds Satisfaction Questionnaire (LSQ). RESULTS: One-hundred and sixteen surveys were returned, yielding a 36% response rate. Overall patients' satisfaction levels with nurse non-medical prescribing of systemic anti-cancer therapy were high across all six subscales of the modified LSQ corroborated by qualitative free-text comments. Eighty-five percent of participants indicated they were happy to continue being prescribed systemic anti-cancer therapy by the nurse non-medical prescribers. CONCLUSION: Overall patient satisfaction of Systemic Anti-Cancer Treatment prescribed by nurse Non-Medical Prescribers was positively rated; with high standards of compassionate, person-centred care reported, demonstrating an acceptable transformation in care delivery from a consultant-led model. Nonetheless, there was scope for improved health literacy to enhance patients' understanding and compliance with treatment.

Risk factors of using late-autophagy inhibitors: Aspects to consider when combined with anticancer therapies.

Cancer resistance to therapy is still an unsolved scientific and clinical problem. In 2022, the hallmarks of cancer have been expanded to include four new features, including cellular senescence. Therapy-induced senescence (TIS) is a stressor-based response to conventional treatment methods, e.g. chemo- and radiotherapy, but also to non-conventional targeted therapies. Since TIS reinforces resistance in cancers, new strategies for sensitizing cancer cells to therapy are being adopted. These include macroautophagy as a potential target for inhibition due to its potential cytoprotective role in many cancers. The mechanism of late-stage autophagy inhibitors is based on blockage of autophagolysosome formation or an increase in lysosomal pH, resulting in disrupted cargo degradation. Such inhibitors are relevant candidates for increasing anticancer therapy effectiveness. In particular, 4-aminoquoline derivatives: chloroquine/hydroxychloroquine (CQ/HCQ) have been tested in multiple clinical trials in combination with senescence-inducing anti-cancer drugs. In this review, we summarize the properties of selected late-autophagy inhibitors and their role in the regulation of autophagy and senescent cell phenotype in vitro and in vivo models of cancer as well as treatment response in clinical trials on oncological patients. Additionally, we point out that, although these compounds increase the effectiveness of treatment in some cases, their practical usage might be hindered due to systemic toxicity, hypoxic environment, dose- ant time-dependent inhibitory effects, as well as a possible contribution to escaping from TIS.

Influence of tumor microenvironment on the different breast cancer subtypes and applied therapies.

Despite the significant improvements made in breast cancer therapy during the last decades, this disease still has increasing incidence and mortality rates. Different targets involved in general processes, like cell proliferation and survival, have become alternative therapeutic options for this disease, with some of them already used in clinic, like the CDK4/6 inhibitors for luminal A tumors treatment. Nevertheless, there is a demand for novel therapeutic strategies focused not only on tumor cells, but also on their microenvironment. Tumor microenvironment (TME) is a very complex and dynamic system that, more than surrounding and supporting tumor cells, actively participates in tumor development and progression. During the last decades, it has become clear that the cellular and acellular components of TME differ between the various breast cancer subtypes and shape the differences regarding their severity and prognosis. The pivotal role of the TME in controlling tumor growth and influencing responses to therapy represents a potential source for novel targets and therapeutic strategies. In this review, we present a description of the multiple therapeutic options used for different breast cancer subtypes, as well as the influence that the TME may exert on the development of the disease and on the response to the distinct therapies, which in some cases may explain their failure by the occurrence of relapses and resistance. Furthermore, the ongoing studies focused on the use of TME components for developing potential cancer treatments are described.

The Role of Natural Killer Cells in the Tumor Immune Microenvironment of EBV-Associated Nasopharyngeal Carcinoma.

Endemic nasopharyngeal carcinoma (NPC) is closely associated with the Epstein-Barr virus (EBV), which contributes to tumor development and influences the tumor immune microenvironment (TIME) in NPC. Natural killer (NK) cells, as part of the innate immune system, play a crucial role in responding to viral infections and malignant cell transformations. Notably, NK cells possess a unique ability to target tumor cells independent of major histocompatibility complex class I (MHC I) expression. This means that MHC I-deficient tumor cells, which can escape from effective T cell attack, are susceptible to NK-cell-mediated killing. The activation of NK cells is determined by the signals generated through inhibitory and activating receptors expressed on their surface. Understanding the role of NK cells in the complex TIME of EBV+ NPC is of utmost importance. In this review, we provide a comprehensive summary of the current understanding of NK cells in NPC, focusing on their subpopulations, interactions, and cytotoxicity within the TIME. Moreover, we discuss the potential translational therapeutic applications of NK cells in NPC. This review aims to enhance our knowledge of the role of NK cells in NPC and provide valuable insights for future investigations.

Targeting focal adhesion kinase (FAK) for cancer therapy: FAK inhibitors, FAK-based dual-target inhibitors and PROTAC degraders.

Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, plays an essential role in regulating cell proliferation, migration and invasion through both kinase-dependent enzymatic function and kinase-independent scaffolding function. The overexpression and activation of FAK is commonly observed in various cancers and some drug-resistant settings. Therefore, targeted disruption of FAK has been identified as an attractive strategy for cancer treatment. To date, numerous structurally diverse inhibitors targeting distinct domains of FAK have been developed, encompassing kinase domain inhibitors, FERM domain inhibitors, and FAT domain inhibitors, with several FAK inhibitors advanced to clinical trials. Moreover, given the critical role of FAK scaffolding function in signal transduction, FAK-targeted PROTACs have also been developed. Although no current FAK-targeted therapeutics have been approved for the market, the combination of FAK inhibitors with other anticancer drugs has shown considerable promise in the clinic. This review provides an overview of current drug discovery strategies targeting FAK, including the development of FAK inhibitors, FAK-based dual-target inhibitors and proteolysis-targeting chimeras (PROTACs) in both literature and patent applications. Accordingly, their design and optimization process, mechanisms of action and biological activities are discussed to offer insights into future directions of FAK-targeting drug discovery in cancer therapy.

Targeting nicotinamide N-methyltransferase decreased aggressiveness of osteosarcoma cells.

BACKGROUND: Osteosarcoma (OS) is a primary bone malignancy that mostly affects young people, characterized by high metastatic potential, and a marked chemoresistance that is responsible for disease relapse in most patients. Therefore, it is necessary to identify novel molecules to setup targeted strategies to improve the clinical outcome. The enzyme nicotinamide N-methyltransferase (NNMT) catalyses the N-methylation of nicotinamide and other analogs, playing a crucial role in the biotransformation of drugs and xenobiotics. NNMT overexpression was reported in a wide variety of cancers, and several studies demonstrated that is able to promote cell proliferation, migration and resistance to chemotherapy. The aim of this study was to explore the potential involvement of NNMT in OS. METHODS: Immunohistochemical analyses have been performed to evaluate NNMT expression in selected OS and healthy bone tissue samples. Subsequently, OS cell lines have been transfected with vectors targeting NNMT mRNA (shRNAs) and the impact of this downregulation on migration, cell proliferation, and response to chemotherapeutic treatment was also analysed by wound healing, MTT, SRB and Trypan blue assays, respectively. RESULTS: Results showed that OS samples display a significantly higher NNMT expression compared with healthy tissue. Preliminary results suggest that NNMT silencing in OS cell lines is associated to a decrease of cell proliferation and migration, as well as to enhanced sensitivity to chemotherapy. Data obtained showed that NNMT may represent an interesting marker for OS detection and a promising target for effective anti-cancer therapy.

Anticancer Drugs-Related Hypogonadism in Male Patients with Advanced Cancers on Active Treatment: A Systematic Review.

BACKGROUND: In male patients with cancer treated with antineoplastic drug, hypogonadism is a neglected cause of diminished quality of life. This condition may be cancer related as well as toxicity related. The role of antineoplastic drug in causing hypogonadism is poorly understood. The aim of this systematic review was to establish the prevalence, nature (primary/secondary), and impact of hypogonadism on quality of life in male patients with cancer on antineoplastic therapy. METHODS: The search strategy used PubMed, Embase, and Cochrane databases to select articles in English language that described hypogonadism in male patients with cancer. The search period was from January 1, 1945 to February 28, 2023. We included observational studies, case reports or case series and excluded studies concerning hematological malignancies, prostate cancer, female patients, and survivors. FINDINGS: Of 4488 records identified, 28 studies met inclusion criteria (17 observational studies, 11 case reports or case series). Anti-angiogenic drugs and crizotinib were found to have a role in the development of hypogonadism. Patients treated with immune checkpoint-inhibitors developed secondary hypogonadism due to immune-related hypophysitis or orchitis. As for active chemotherapy, platinum salts were often associated with hypogonadism, followed by antimetabolites and taxanes. Selected studies were heterogeneous for populations, interventions, and outcomes assessments. Thus, a generalization is difficult. Moreover, the role of concurrent etiologies cannot be excluded in most studies. CONCLUSION: Our research emphasizes the importance of evaluating the gonadal axis before treatment in patients considered at risk and testing it at regular intervals or in case of clinical suspicion.

Biomaterials in Drug Delivery: Advancements in Cancer and Diverse Therapies-Review.

Nano-sized biomaterials are innovative drug carriers with nanometric dimensions. Designed with biocompatibility in mind, they enable precise drug delivery while minimizing side effects. Controlled release of therapeutic substances enhances efficacy, opening new possibilities for treating neurological and oncological diseases. Integrated diagnostic-therapeutic nanosystems allow real-time monitoring of treatment effectiveness, which is crucial for therapy personalization. Utilizing biomaterials as nano-sized carriers in conjunction with drugs represents a promising direction that could revolutionize the field of pharmaceutical therapy. Such carriers represent groundbreaking drug delivery systems on a nanometric scale, designed with biocompatibility in mind, enabling precise drug delivery while minimizing side effects. Using biomaterials in synergy with drugs demonstrates significant potential for a revolutionary impact on pharmaceutical therapy. Conclusions drawn from the review indicate that nano-sized biomaterials constitute an innovative tool that can significantly improve therapy effectiveness and safety, especially in treating neurological and oncological diseases. These findings should guide researchers towards further studies to refine nano-sized biomaterials, assess their effectiveness under various pathological conditions, and explore diagnostic-therapeutic applications. Ultimately, these results underscore the promising nature of nano-sized biomaterials as advanced drug carriers, ushering in a new era in nanomedical therapy.