Search Results (11,190)

Tumor angiogenesis, the formation of new blood vessels from pre-existing vasculature, is a crucial process in cancer growth and metastasis. Mathematical modeling through partial differential equations helps to understand this complex biological phenomenon. Here, we provide a conservation properties analysis in a tumor angiogenesis model describing the evolution of endothelial cells, proteases, inhibitors, and extracellular matrix. The adopted approach introduces a numerical framework that combines spatial and time discretization techniques. Here, we focus on maintaining solution accuracy while preserving physical quantities during the simulation process. The method achieved second-order accuracy in both space and time discretizations, with conservation errors showing consistent convergence as the mesh was refined. The numerical schema demonstrates stable wave propagation patterns, in agreement with experimental observations. Numerical experiments validate the approach and demonstrate its reliability for long-term angiogenesis simulations. Full article

Background/Objectives: This study aims to explore the risk factors associated with poor survival outcomes in geriatric female patients with breast cancer. Methods: This study utilized data from the METABRIC database to evaluate the risk factors associated with poor survival outcomes among geriatric breast cancer patients. A total of 2909 female patients, 766 of whom were geriatric, were included in the study. The effects of the type of surgery; breast cancer types; cellularity; Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status; molecular class; axillary lymph nodes; Nottingham prognostic index (NPI); status of receiving systemic chemotherapy (SCT), hormone therapy (HT), and radiotherapy (RT); tumor size and tumor on overall survival (OS); and progression-free status (PFS) of geriatric patients were investigated. Additionally, the disease-specific survival of geriatric patients was compared with other patients. Results: HER2 receptor positivity, advanced-stage tumors (T3–T4), a high NPI, and Luminal B subtypes were significant predictors of worse outcomes. Conversely, Luminal A tumors, associated with favorable hormonal responsiveness, demonstrated the best progression-free survival (PFS). HER2-positive patients exhibited a poorer PFS compared to their HER2-negative counterparts, underscoring the need for careful management of aggressive subtypes in older adults. Additionally, patients undergoing mastectomy were less likely to receive adjuvant therapies, contributing to inferior outcomes compared to breast-conserving surgery (BCS). Conclusions: Mastectomy, HER2 positivity, high NPI, advanced stages, and Luminal B tumors are significant prognostic factors in geriatric breast cancer patients. Full article

Patient-centered precision oncology strives to deliver individualized cancer care. In lung cancer, preclinical models and technological innovations have become critical in advancing this approach. Preclinical models enable deeper insights into tumor biology and enhance the selection of appropriate systemic therapies across chemotherapy, targeted therapies, immunotherapies, antibody–drug conjugates, and emerging investigational treatments. While traditional human lung cancer cell lines offer a basic framework for cancer research, they often lack the tumor heterogeneity and intricate tumor–stromal interactions necessary to accurately predict patient-specific clinical outcomes. Patient-derived xenografts (PDXs), however, retain the original tumor’s histopathology and genetic features, providing a more reliable model for predicting responses to systemic therapeutics, especially molecularly targeted therapies. For studying immunotherapies and antibody–drug conjugates, humanized PDX mouse models, syngeneic mouse models, and genetically engineered mouse models (GEMMs) are increasingly utilized. Despite their value, these in vivo models are costly, labor-intensive, and time-consuming. Recently, patient-derived lung cancer organoids (LCOs) have emerged as a promising in vitro tool for functional precision oncology studies. These LCOs demonstrate high success rates in growth and maintenance, accurately represent the histology and genomics of the original tumors and exhibit strong correlations with clinical treatment responses. Further supported by advancements in imaging, spatial and single-cell transcriptomics, proteomics, and artificial intelligence, these preclinical models are reshaping the landscape of drug development and functional precision lung cancer research. This integrated approach holds the potential to deliver increasingly accurate, personalized treatment strategies, ultimately enhancing patient outcomes in lung cancer. Full article

The treatment of cancers with immunotherapies has yielded significant milestones in recent years. Amongst these immunotherapeutic strategies, the FDA has approved several checkpoint inhibitors (CPIs), primarily Anti-Programmed Death-1 (PD-1) and Programmed Death Ligand-1/2 (PDL-1/2) monoclonal antibodies, in the treatment of various cancers unresponsive to immune therapeutics. Such treatments resulted in significant clinical responses and the prolongation of survival in a subset of patients. However, not all patients responded to CPIs, due to various mechanisms of immune resistance. One such mechanism is that, in addition to PD-1 expression on CD8 T cells, other inhibitory receptors exist, such as Lymphocyte Activation Gene 3 (LAG-3), T cell Immunoglobulin Mucin 3 (TIM3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT). These inhibitory receptors might be active in the presence of the above approved CPIs. Clearly, it is clinically challenging to block all such inhibitory receptors simultaneously using conventional antibodies. To circumvent this difficulty, we sought to target a potential transcription factor that may be involved in the molecular regulation of more than one inhibitory receptor. The transcription factor Yin Yang1 (YY1) was found to regulate the expression of PD-1, LAG-3, and TIM3. Therefore, we hypothesized that targeting YY1 in CD8 T cells should inhibit the expression of these receptors and, thus, prevent the inactivation of the anti-tumor CD8 T cells by these receptors, by corresponding ligands to tumor cells. This strategy should result in the prevention of immune evasion, leading to the inhibition of tumor growth. In addition, this strategy will be particularly effective in a subset of cancer patients who were unresponsive to approved CPIs. In this review, we discuss the regulation of LAG-3 by YY1 as proof of principle for the potential use of targeting YY1 as an alternative therapeutic approach to preventing the immune evasion of cancer. We present findings on the molecular regulations of both YY1 and LAG-3 expressions, the direct regulation of LAG-3 by YY1, the various approaches to targeting YY1 to evade immune evasion, and their clinical challenges. We also present bioinformatic analyses demonstrating the overexpression of LAG-3, YY1, and PD-L1 in various cancers, their associations with immune infiltrates, and the fact that when LAG-3 is hypermethylated in its promoter region it correlates with a better overall survival. Hence, targeting YY1 in CD8 T cells will result in restoring the anti-tumor immune response and tumor regression. Notably, in addition to the beneficial effects of targeting YY1 in CD8 T cells to inhibit the expression of inhibitory receptors, we also suggest targeting YY1 overexpressed in the tumor cells, which will also inhibit PD-L1 expression and other YY1-associated pro-tumorigenic activities. Full article

Despite the popular belief in the anti-tumor properties of Vespa bicolor venom (VBV), there is limited scientific evidence to support this claim. This study is the first to examine the anti-tumor effects of VBV on liver cancer, both alone and in combination with cisplatin (DDP), through in vitro and in vivo experiments. In vitro experiments evaluated VBV and its combination with DDP on HepG2 cell proliferation, invasion, migration, and apoptosis. Animal studies examined the tumor-suppressive effects, safety (hepatotoxicity and nephrotoxicity), and immune impact of these treatments in tumor-bearing mice. VBV monotherapy significantly inhibited the growth of HepG2 cells by suppressing their proliferation and invasion and induced apoptosis in vitro. Notably, low VBV concentrations significantly promoted the proliferation of normal liver cells (L-02), suggesting a hepatoprotective effect. In vivo, VBV monotherapy enhanced immune function and exhibited tumor suppression comparable to DDP monotherapy but did not induce significant liver or kidney damage. In addition, VBV combined with DDP synergistically enhanced the anti-tumor effects of DDP, compensating for its limited apoptosis-inducing activity and insufficient enhancement of immune function. Initial studies have shown the strong potential of VBV as an anti-liver-tumor drug, highlighting its unique clinical value. Full article

Pancreatic cancer is the third leading cause of cancer-related mortality in the United States, with rising incidence and mortality. The receptor for advanced glycation end products (RAGE) and its ligands significantly contribute to pancreatic cancer progression by enhancing cell proliferation, fostering treatment resistance, and promoting a pro-tumor microenvironment via activation of the nuclear factor-kappa B (NF-κB) signaling pathways. This study validated pathway activation in human pancreatic cancer and evaluated the therapeutic efficacy of TTP488 (Azeliragon), a small-molecule RAGE inhibitor, alone and in combination with radiation therapy (RT) in preclinical models of pancreatic cancer. Human (Panc1) and murine (Pan02) pancreatic cancer cell lines exhibited elevated levels of RAGE and its ligands compared to normal pancreatic tissue. In vitro, Azeliragon inhibited RAGE-mediated NF-κB activation and ligand-mediated cell proliferation in pancreatic cancer cell lines. Target engagement of Azeliragon was confirmed in vivo, as determined by decreased NF-κB activation. Azeliragon demonstrated significant growth delay in mouse models of pancreatic cancer and additive effects when combined with RT. Additionally, Azeliragon modulated the immune suppressive tumor microenvironment in pancreatic cancer by reducing immunosuppressive cells, including M2 macrophages, regulatory T cells, and myeloid-derived suppressor cells, while enhancing CD8+ T cell infiltration. These findings suggest that Azeliragon, by inhibiting RAGE-mediated signaling and modulating immune response, may serve as an effective anti-cancer agent in pancreatic cancer. Full article

Mutations of the von Hippel–Lindau (VHL) tumor suppressor gene occur frequently in clear cell renal cell carcinoma (RCC), the predominant histology of kidney cancer, and have been associated with its pathogenesis and progression. Alterations of VHL lead to impaired degradation of hypoxia-inducible factor 1α (HIF1α) and HIF2α promoting neoangiogenesis, which is pivotal for cancer growth. As such, targeting the VHL-HIF axis holds relevant potential for therapeutic purposes. Belzutifan, an HIF-2α inhibitor, has been recently indicated for metastatic RCC and other antiangiogenic drugs directed against HIF-2α are currently under investigation. Further, clinical and preclinical studies of combination approaches for metastatic RCC including belzutifan with cyclin-dependent kinase 4–6 inhibitors, tyrosine kinase inhibitors, or immune checkpoint inhibitors achieved promising results or are ongoing. This review aims to summarize the existing evidence regarding the VHL/HIF pathway, and the approved and emerging treatment strategies that target this pivotal molecular axis and their mechanisms of resistance. Full article

Background: Alpha radionuclide therapy has emerged as a promising novel strategy for cancer treatment; however, the therapeutic potential of ²²⁵Ac-labeled peptides in pancreatic cancer remains uninvestigated. Methods: In the cytotoxicity study, tumor cells were incubated with ²²⁵Ac-DOTA-RGD₂. DNA damage responses (γH2AX and 53BP1) were detected using flowcytometry or immunohistochemistry analysis. Biodistribution and therapeutic studies were carried out in BxPC-3-bearing mice. Results: ²²⁵Ac-DOTA-RGD₂ demonstrated potent cytotoxicity against cells expressing α_vβ₃ or α_vβ₆ integrins and induced G2/M arrest and γH2AX expression as a marker of double-stranded DNA breaks. ²²⁵Ac-DOTA-RGD₂ (20, 40, 65, or 90 kBq) showed favorable pharmacokinetics and remarkable tumor growth inhibition without severe side effects in the BxPC-3 mouse model. In vitro studies revealed that 5 and 10 kBq/mL of ²²⁵Ac-DOTA-RGD₂ swiftly induced G2/M arrest and elevated γH2AX expression. Furthermore, to clarify the mechanism of successful tumor growth inhibition for a long duration in vivo, we investigated whether short-term high radiation exposure enhances radiation sensitivity. Initially, a 4 h induction treatment with 5 and 10 kBq/mL of ²²⁵Ac-DOTA-RGD₂ enhanced both cytotoxicity and γH2AX expression with 0.5 kBq/mL of ²²⁵Ac-DOTA-RGD₂ compared to a treatment with only 0.5 kBq/mL of ²²⁵Ac-DOTA-RGD₂. Meanwhile, the γH2AX expression induced by 5 or 10 kBq/mL of ²²⁵Ac-DOTA-RGD₂ alone decreased over time. Conclusions: These findings highlight the potential of using ²²⁵Ac-DOTA-RGD₂ in the treatment of intractable pancreatic cancers, as its ability to induce G2/M cell cycle arrest enhances radiosensitization, resulting in notable growth inhibition. Full article

The src-homology 2 domain-containing phosphatase 2 (SHP2) is a human cytoplasmic protein tyrosine phosphatase that plays a crucial role in cellular signal transduction. Aberrant activation and mutations of SHP2 are associated with tumor growth and immune suppression, thus making it a potential target for cancer therapy. Initially, researchers sought to develop inhibitors targeting SHP2’s catalytic site (protein tyrosine phosphatase domain, PTP). Due to limitations such as conservativeness and poor membrane permeability, SHP2 was once considered a challenging drug target. Nevertheless, with the in-depth investigations into the conformational switch mechanism from SHP2’s inactive to active state and the emergence of various SHP2 allosteric inhibitors, new hope has been brought to this target. In this study, we investigated the interaction models of various allosteric inhibitors with SHP2 using molecular dynamics simulations. Meanwhile, we explored the free energy landscape of SHP2 activation using enhanced sampling technique (meta-dynamics simulations), which provides insights into its conformational changes and activation mechanism. Furthermore, to biophysically interpret high-dimensional simulation trajectories, we employed interpretable machine learning methods, specifically extreme gradient boosting (XGBoost) with Shapley additive explanations (SHAP), to comprehensively analyze the simulation data. This approach allowed us to identify and highlight key structural features driving SHP2 conformational dynamics and regulating the activity of the allosteric inhibitor. These studies not only enhance our understanding of SHP2’s conformational switch mechanism but also offer crucial insights for designing potent allosteric SHP2 inhibitors and addressing drug resistance issues. Full article

4-pyridone-3-carboxamide-1-β-D-ribonucleoside (4PYR) is a nicotinamide derivative, considered a new oncometabolite. 4PYR formation induced a cytotoxic effect on the endothelium. Elevated blood 4PYR concentration was observed in patients with cancer. Still, little is known about the metabolic and functional effects of 4PYR in this pathology. The study aimed to investigate whether this toxic accumulation of 4PYR may affect the activity of anticancer therapy with cyclophosphamide in the orthotropic model of breast cancer. Female Balb/c mice were injected with 4T1 breast cancer cells and assigned into three groups: treated with PBS (Control), cyclophosphamide-treated (+CP), 4PYR-treated (+4PYR), and mice treated with both 4PYR and CP(+4PYR+CP) for 28 days. Afterward, blood and serum samples, liver, muscle, spleen, heart, lungs, aortas, and tumor tissue were collected for analysis of concentrations of nucleotides, nicotinamide metabolites, and 4PYR with its metabolites, as well as the liver level of cytochrome P450 enzymes. 4PYR treatment caused elevation of blood 4PYR, its monophosphate and a nicotinamide adenine dinucleotide (NAD+) analog—4PYRAD. Blood 4PYRAD concentration in the +4PYR+CP was reduced in comparison to +4PYR. Tumor growth and final tumor mass were significantly decreased in +CP and did not differ in +4PYR in comparison to Control. However, we observed a substantial increase in these parameters in +4PYR+CP as compared to +CP. The extracellular adenosine deamination rate was measured to assess vascular inflammation, and it was higher in +4PYR than the Control. Treatment with 4PYR and CP caused the highest vascular ATP hydrolysis and adenosine deamination rate. 4PYR administration caused significant elevation of CYP2C9 and reduction in CYP3A4 liver concentrations in both +4PYR and +4PYR+CP as compared to Control and +CP. In additional experiments, we compared healthy mice without cancer, treated with 4PYR (4PYR w/o cancer) and PBS (Control w/o cancer), where 4PYR treatment caused an increase in the serum proinflammatory cytokine expression as compared to Control w/o cancer. 4PYR accumulation in the blood interferes with cyclophosphamide anticancer activity and induces a pro-inflammatory shift of endothelial extracellular enzymes, probably by affecting its metabolism by cytochrome P450 enzymes. This observation may have crucial implications for the activity of various anticancer drugs metabolized by cytochrome P450. Full article

The vascular endothelial growth factor (VEGF) family includes key mediators of vasculogenesis and angiogenesis. VEGFs are secreted by various cells of epithelial and mesenchymal origin and by some immune cells in response to physiological and pathological stimuli. In addition, immune cells express VEGF receptors and/or co-receptors and can respond to VEGFs in an autocrine or paracrine manner. This immunological role of VEGFs has opened the possibility of using the VEGF inhibitors already developed to inhibit tumor angiogenesis also in combination approaches with different immunotherapies to enhance the action of effector T lymphocytes against tumor cells. This review pursues to examine the current understanding of the interplay between VEGFs and the immune system, while identifying key areas that require further evaluation. Full article

Gastric cancer remains a significant global health challenge, driving the need for innovative therapeutic approaches. Natural polyphenolic compounds such as resveratrol, piceatannol, curcumin, and quercetin currently show promising results in the prevention and treatment of various cancers, due to their diverse biological activities. This review presents the effects of natural compounds on important processes related to cancer, such as apoptosis, proliferation, migration, invasion, angiogenesis, and autophagy. Resveratrol, naturally found in red grapes, has been shown to induce apoptosis and inhibit the proliferation, migration, and invasion of gastric cancer cells. Piceatannol, a metabolite of resveratrol, shares similar anticancer properties, particularly in modulating autophagy. Curcumin, derived from turmeric, is known for its anti-inflammatory and antioxidant properties, and its ability to inhibit tumor growth and metastasis. Quercetin, a flavonoid found in various fruits and vegetables, induces cell cycle arrest and apoptosis while enhancing the efficacy of conventional therapies. Despite their potential, challenges such as low bioavailability limit their clinical application, necessitating further research into novel delivery systems. Collectively, these compounds represent a promising avenue for enhancing gastric cancer treatment and improving patient outcomes through their multifaceted biological effects. Full article

Colorectal cancer (CRC) is often associated with metastasis and recurrence and is the leading cause of cancer-related mortality. In the progression of CRC, recent studies have highlighted the critical role of neutrophils, particularly tumor-associated neutrophils (TANs). TANs have both tumor-promoting and tumor-suppressing activities, contributing to metastasis, immunosuppression, angiogenesis, and epithelial-to-mesenchymal transition. Tumor-promoting TANs promote tumor growth by releasing proteases, reactive oxygen species, and cytokines, whereas tumor-suppressing TANs enhance immune responses by activating T cells and natural killer cells. Understanding the mechanisms underlying TAN mobilization, plasticity, and their role in the tumor microenvironment has revealed potential therapeutic targets. This review provides a comprehensive overview of TAN biology in CRC and discusses both the tumor-promoting and tumor-suppressing functions of neutrophils. Novel therapeutic approaches targeting TANs, such as chemokine receptor antagonists, aim to modulate neutrophil reprogramming and offer promising avenues for improving treatment outcomes of CRC. Full article

Background: Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare and aggressive cancer with a poor prognosis and limited treatment options. Current chemotherapy regimens are predominantly platinum-based; however, the development of platinum resistance during treatment significantly worsens patient outcomes. Everolimus, an mTOR inhibitor, has been widely used in combination cancer therapies and has successfully enhanced the efficacy of platinum-based treatments. Method: In this study, we investigated the combined effects of everolimus and cisplatin on SCCOHT through both in vitro and in vivo experiments, complemented by RNA sequencing (RNA-seq) analyses to further elucidate the therapeutic impact. Result: Our findings revealed that everolimus significantly inhibits the proliferation of SCCOHT cells, induces cell cycle arrest, and accelerates apoptosis. When combined with cisplatin, everolimus notably enhances the therapeutic efficacy without increasing the toxicity typically associated with platinum-based drugs. RNA-seq analysis uncovered alterations in the expression of apoptosis-related genes, suggesting that the underlying mechanism involves autophagy regulation. Conclusions: Despite the current challenges in treating SCCOHT and the suboptimal efficacy of platinum-based therapies, the addition of everolimus significantly suppresses tumor growth. This indicates that everolimus enhances cisplatin efficacy by disrupting survival-promoting signaling cascades and inducing cell cycle arrest. Furthermore, it points to potential biomarkers for predicting therapeutic response. Full article

Cell-penetrating peptides (CPPs) offer a unique and efficient mechanism for delivering therapeutic agents directly into cancer cells. These peptides can traverse cellular membranes, overcoming one of the critical barriers in drug delivery systems. In this review, we explore recent advancements in the application of CPPs for cancer treatment, focusing on mechanisms, delivery strategies, and clinical potential. The review highlights the use of CPP-drug conjugates, CPP-based vaccines, and their role in targeting and inhibiting tumor growth. Full article