Spread Of Cancer Research Articles

Potential VEGFR2 inhibitors for managing metastatic cervical cancer: insights from molecular dynamics and free energy landscape studies.

Metastatic cervical cancer, the advanced stage where the cancer spreads beyond the cervix to other parts of the body, poses significant treatment challenges and is associated with poor survival rates. Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), a critical angiogenic mediator, is upregulated in metastatic cervical cancer, driving the formation of new blood vessels that fuel tumor growth and spread, making it an attractive target for anti-angiogenic therapies aimed at halting metastasis. This study aims to determine the anti-angiogenic effects of natural compounds to identify new VEGFR2 inhibitors for managing metastatic cervical cancer. The potential effect of these compounds as VEGFR2 inhibitors at the structural level was assessed using various methods such as virtual screening, docking, MD simulations (1000ns), binding free energy calculations, and free energy landscape analysis. Four compounds, including IMPHY007574, IMPHY004129, IMPHY008783, and IMPHY004928, were found to be potential VEGFR2 inhibitors. Among the structures analyzed in the present work, IMPHY007574 revealed the highest binding stability with VEGFR2 and the most favorable interaction pattern, thus proving the possibility of its use as an effective anti-angiogenic compound. The other three compounds also demonstrated a reasonably good promise in VEGFR2 inhibition. These findings provide a foundation for developing novel therapeutic strategies for metastatic cervical cancer, potentially overcoming drug resistance and improving patient survival rates.

Exosomal miR-320d promotes angiogenesis and colorectal cancer metastasis via targeting GNAI1 to affect the JAK2/STAT3 signaling pathway

Colorectal cancer is a common malignant tumor, whose growth and metastasis are influenced by numerous factors. MicroRNAs have garnered increasing attention in recent years due to their involvement in tumor development. Exosomes are involved in intercellular signaling and influence tumor development by promoting tumor cell proliferation and metastasis through activation of angiogenesis and other mechanisms. This study aimed to investigate how the exosomes containing miR-320d from colorectal cancer (CRC) cells promote colorectal cancer metastasis by regulating angiogenesis. CRC-derived exosomes containing miR-320d can be transferred to vascular endothelial cells, facilitating their proliferation, invasion, migration, and angiogenesis. By targeting GNAI1, miR-320d in these exosomes reduces GNAI1 levels in endothelial cells, causing more JAK2/STAT3 activation and VEGFA production. This ultimately enhances the migration and angiogenic capacity of vascular endothelial cells. Moreover, CRC patients with high levels of miR-320d in their blood respond better to treatment with bevacizumab. In vivo experiments further proved the role of miR-320d from CRC exosomes in increasing tumor size, blood vessel formation, and the spread of cancer to the liver. In this study, we have demonstrated that exosomal miR-320d promotes cancer cell metastasis and enhances angiogenesis by downregulating GNAI1 expression and enhancing JAK2/STAT3.

Education and Training Needs of Health Care Professionals in the Philippines Encountering Patients with Lung Oligometastatic Cancers

This study aimed to examine the education and training needs of health care practitioners (HCPs) in the Philippines who encounter lung oligometastatic cancer patients. Lung oligometastatic disease is among the most common sites for cancer spread and has the most established practices for treating oligometastases. A modified version of the Hennessy–Hicks Training Needs Assessment Questionnaire was administered online to HCPs working in private and public centers in the Philippines. HCPs were recruited via purposive sampling. Twenty-seven HCPs completed the questionnaire (47% response rate). Respondents were mostly female (59%) and between the ages of 30 and 39 years (70%). Three-quarters (74%) were consultants, and most respondents were radiation oncologists (44%) or medical oncologists (30%). Medical oncologists rated Management/Supervisory Tasks (mean = 1.42) as their highest area of training need while radiation oncologists rated Clinical Tasks (mean = 1.30) as their highest training need. Pulmonologists (mean = 0.60) and other specialists (mean = 1.00) rated Administration tasks as their top area of training need. The clinical task-related category was rated the highest need among the continuing medical education topics. This study provides valuable insights for the implementation and advancement of a comprehensive curriculum in clinical oncology, specifically designed to enhance the administrative, clinical, and research capacities of oncologists who encounter oligometastatic lung disease in the Philippines.

Role of circulating tumor cells in breast cancer.

Circulating tumor cells (CTCs) are tumor cells that shed from the primary tumor or metastatic loci, intravasate, and circulate in the bloodstream. CTCs have been suggested to play a major role in the metastatic spread of cancer, constantly shedding from tumors during proliferation or as a result of mechanical insults. Breast cancer (BC) is one of the most representative tumors in CTC research, with several studies conducted on its clinical validity and utility in both early and advanced BC (EBC and ABC, respectively). The assessment of the number and molecular profiles of CTCs is expected to provide a more tailored therapy for patients with BC. The detection of CTCs is usually dependent on molecular markers, and epithelial cell adhesion molecules are widely used. Although the CellSearch® technology has been widely utilized for CTC detection, recent advances have led to the development of novel detection methods, facilitating further molecular analysis. In this review, we discuss the clinical applications of CTCs, current status of research, and efforts to incorporate CTC analysis into clinical practice. Additionally, we discuss potential challenges and future directions for integrating CTC analysis into clinical practice.

Role of transcription factors in metastasis of breast cancer

Metastasis causes a majority of deaths in breast cancer patients. Metastasis is the spread of cancer to distant sites in the body away from the primary tumor, creating secondary tumors, or metastases. A tumor metastasizes when cancer cells strategically regulate genes that play a role in angiogenesis, epithelial-mesenchymal transition (EMT), migration, invasion, and regulation of the cell cycle to bypass apoptosis and increase proliferation and stemness. Several transcription factors have also been identified to play a role in metastatic breast cancer, as they enable invasion, intravasation, transport, extravasation, and colonization of metastasis through other processes such as angiogenesis and EMT, making them a prime target for cancer treatment. Understanding how transcription factors play a role in breast cancer metastasis will enable the development of targeted therapeutics for breast cancer. This paper reviews the roles of E2Fs, hypoxia-inducible factors (HIFs), EMT master regulators, sex determining region Y (SRY)-related high-mobility group (HMG) box (SOX), E26 transformation-specific (ETS), Yin Yang 1 (YY1), forkhead box M1 (FoxM1), BTB domain and CNC homology 1 (Bach1), sineoculis homeobox homolog (SIX), runt-related transcription factor 2 (RUNX2), myelocytomatosis (MYC), Kruppel-like factors (KLFs), and c-Jun in breast cancer metastasis.

An eXplainable machine learning framework for predicting the impact of pesticide exposure in lung cancer prognosis

Lung cancer, the second most prevalent and lethal cancer, is caused by aberrant and uncontrolled cell division in the lungs. Once lung cancer spreads to surrounding tissues or organs, the likelihood of recovery declines; hence, early illness detection is vital. Machine learning has shown significant potential in several healthcare applications. Examining various factors and trends in the data, the machine learning model can predict lung cancer menace by pinpointing those more susceptible to the illness. Among the various causes of lung cancer, pesticide is a major contributor. ‘Pesticide’ refers to any chemical used in agriculture to manage pests like weeds and insects. Numerous health hazards, including the possibility of developing cancer, have been linked to exposure to specific pesticides. Our objective is to obtain the trust of medical professionals and patients depending on how interpretable machine learning models are in healthcare. This paper deals with implementing the proposed study by utilizing a public dataset from a Thai case study to predict the risk of lung cancer caused by pesticide exposure. Since the dataset was highly imbalanced, a hybrid normalization technique was utilized, combining the Synthetic Minority Oversampling Technique (SMOTE) and Edited Nearest Neighbor (ENN). We applied a two-stage feature selection technique combined with Extra Tree Classifier and Principal Component Analysis. An eXplainable XGBoost Classifier is developed to predict lung cancer risk based on pesticide exposure. The robustness of the model is reflected in the results, with accuracy, sensitivity, and F1-Score as 99.00%, 98.87%, and 98.57%, respectively. Two public datasets were utilized to generalize the model, and the model performed well on both datasets. The model achieved accuracy, sensitivity, and F1-Score of 99.00%, 99.00%, and 99.33% on the ‘Lung Cancer Prediction’ dataset. The model is trained and tested on the ‘survey lung cancer’ dataset and obtained an accuracy, sensitivity, and F1-Score of 99.00%, 99.00%, 99.00%, respectively. The proposed model outperformed existing state-of-the-art methodologies regarding quality metrics. An illustration is done on the XAI (eXplainable Artificial Intelligence) model by utilizing SHapley Additive exPlanations (SHAP), thereby identifying the most relevant features contributing to the lung cancer menace.

Modified Lateral Surgical Approach to the Pterygopalatine Fossa for Safe Preservation of the Peripheral Branch of the Marginal Mandibular Nerve

In cases where oral cancer spreads toward the maxillary tubercle, surgery may extend to the pterygopalatine fossa. There are 2 main extraoral approaches: anterior and lateral. Previously, we introduced a modified lateral approach with a mouth corner incision from the lower lip, that preserves the mental and marginal mandibular nerves. Now, we present a further modification that allows safer preservation of the peripheral branches of the marginal mandibular nerve around the mouth. The procedure has 2 key points. The first is to follow the course of the marginal mandibular nerve from the submandibular incision. The second is to begin the mouth corner incision from the upper lip. Deploying the cheek flap ensured the marginal mandibular nerve was contained within a preserved platysma band. The postoperative contours and unremarkable scar on the face were acceptable to the patient. Paralysis of the facial and mental nerves was almost nonexistent. In conclusion, this newly modified lateral approach is useful in fully exposing the pterygopalatine fossa while preserving the mental nerve and not only the main trunks of the marginal mandibular nerves but also the peripheral branches around the mouth.

Abstract PR014: DNA associated with EVs is uniquely chromatinized and prevents metastasis by enhancing anti-tumor immunity

Abstract Cells release extracellular vesicles (EVs) loaded with functional biomolecules that facilitate intercellular communication in health and disease. These EVs contain DNA (EV-DNA), mirroring the mutational profile of parental cells, yet the mechanism of DNA packaging onto EVs and its role in diseases like cancer remain unclear. Using advanced imaging and biochemical techniques, we discovered that EV-DNA predominantly resides on the vesicle surface, bound to modified histones. Through genome-wide CRISPR knockout screens in cancer cell lines, we identified immune-related pathways and genes crucial for EV-DNA loading, such as APAF1 and NCF1. In several cancer models, loss of APAF1 reduced EV-DNA packaging, and enhancing metastasis, thus implicating EV-DNA in immune surveillance against cancer spread. We demonstrated that EV-DNA uptake by liver macrophages triggers DNA damage response, altering cytokine production and promoting immune activation in pre-metastatic sites. Moreover, quantifying EV-DNA in colorectal cancer biopsies revealed its potential as a predictive metastatic risk biomarker. Our findings shed light on EV-DNA packaging mechanisms and its significance, suggesting that elevated levels of tumor-derived EV-DNA bolster anti-tumor immunity and inhibit metastasis. Citation Format: Inbal Wortzel, Han-Sang Kim, David C. Lyden. DNA associated with EVs is uniquely chromatinized and prevents metastasis by enhancing anti-tumor immunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR014.

Abstract A009: PIEZO1 driven tumor aggressiveness in an organ-on-chip model of colorectal cancer

Abstract Mechanical forces have long been known to affect the progression of cancer, however exact study of the specific consequences of these forces has been hampered by currently available model systems. Traditional cell culture models often lack the ability to incorporate physiologically relevant mechanical forces, and animal models offer too much complexity to be able to effectively isolate and study the mechanical forces. Organ-on-chip (OOC) technology allows for the integration of human relevant physiological forces in a setting conducive to their study. Here, we explore how the early metastatic spread of colorectal cancer (CRC) can be influenced by physiological mechanical forces. Specifically, we investigated the ability of peristaltic motions, responsible for natural bowel motility, to enhance the invasive capability of colon tumor cells. Our microfluidic OOC model comprises of an epithelial channel and endothelial channel separated by a porous membrane allowing for biological and chemical crosstalk between them. Vacuum channels spanning the length of the structure allow force to applied in a cyclic manner mimicking peristaltic contraction and relaxation. Our OOC model supports the addition of tumor microenvironment (TME) components in a piece-wise manner to better understand how specific factors influence the behavior of tumor cells. Analyzing gene and protein expression levels, we have found that peristaltic-like motions induce changes in the Hippo signaling and epithelial-to-mesenchymal (EMT) pathways resulting in greater invasion of tumor cells into the endothelial compartment as observed by on-chip confocal imaging. Moreover, knock down studies have demonstrated that the response to peristaltic-like stretch is driven through a PIEZO1-mediated mechanism. Furthermore, to increase the physiological relevance of our model, we administered peripheral blood mononuclear cells (PBMCs) to the endothelial channel to simulate aspects of the immune TME. Preliminary studies revealed that the recruitment of PBMCs can be altered by the presence of peristaltic-like stretch. Our findings demonstrate that mechanical forces in the CRC TME can dramatically alter tumor behavior as shown in our CRC-OOC model. Citation Format: Curran A. Shah, Carly R. Strelez, Aaron Schatz, Hannah Jiang, Rachel Perez, Shannon M. Mumenthaler. PIEZO1 driven tumor aggressiveness in an organ-on-chip model of colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A009.

Abstract C001: Cytomegalovirus infection modulates distinct immune cell dynamics across tumor-immune microenvironments and systemic macroenvironment during metastasis

Abstract Cytomegalovirus (CMV) is ubiquitously present worldwide and has been implicated in the modulation of cancer development and spread. Notably, CMV proteins have been detected in approximately 90% of lymph node and brain metastases in breast cancer, suggesting its potential influencing tumor invasiveness and metastases. This study investigates the effects of CMV infection on the tumor microenvironment and macroenvironment during metastatic progression in triple-negative breast cancer (TNBC). We employed a syngeneic TNBC mouse model designed to develop spontaneous metastases following primary tumor resection. Using multi-omics sequencing and comprehensive analysis tools, we characterized the tumor-immune landscape across multiple organs relevant to CMV infection and tumor metastasis, including blood, bone marrow, spleen, lungs, brain, and lymph nodes. Our results demonstrate that CMV infection systematically activated the immune response, suppressing primary tumor growth and subsequent metastasis. At the primary tumor site, prior to metastasis, CMV-infected mice exhibited significantly lower proportions of macrophages and plasma cells compared to uninfected counterparts, while CD8+ T cells were significantly enriched. In contrast, the proportions of neutrophils and dendritic cells did not significantly differ between the groups. Distinct patterns of immune cell dynamics were observed at metastatic sites. In the spleen of CMV-infected mice, a notable reduction in macrophages and elevated neutrophil levels were detected. Lung tissues displayed a marked increase in macrophages, CD8+ T cells, and dendritic cells in CMV-infected mice. Interestingly, in the blood, we noted a decreased proportion of natural killer cells in CMV-infected mice. However, no significant difference in plasma cell percentages was observed between CMV-infected and uninfected mice in metastatic lung tissues. The cell-cell interaction analysis further showed a complex crosstalk network between immune cells as well as tumor and immune cells. These findings highlight the profound impact of CMV infection on remodeling the immune landscape at both primary tumors and metastatic sites. The distinct immune cell dynamics orchestrated by CMV infection underscore the virus's role in modifying tumor-immune microenvironments and macroenvironments. Our study offers novel perspectives for developing targeted cancer therapies that consider the complex interactions between viral infections and the tumor immune axis. Further research is warranted to elucidate the mechanisms underlying CMV-mediated immune modulation at molecular level and its potential therapeutic implications in TNBC and other cancer types. Citation Format: Wenjuan Dong, Jianting Sheng, Shan Xu, Matthew Vasquez, Hong Zhao, Stephen T.C Wong. Cytomegalovirus infection modulates distinct immune cell dynamics across tumor-immune microenvironments and systemic macroenvironment during metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C001.

Mendelian randomization analysis to explore the relationship between cathepsins and malignant ovarian tumors.

Cysteine cathepsins are a family of lysosomal proteases that are often overexpressed in several human malignancies and haves been linked to cellular genomic alterations, disturbances in genomic stability, and the onset and spread of cancer. Recent studies have shown alterations in cysteine cathepsins in malignant ovarian tumors. However, it remains unclear whether there is a causal relationship between ovarian cancer, and its subtypes, and the cathepsin family. This study utilized two-sample Mendelian randomization (MR) analysis to examine this potential causal relationship. Genetic instruments derived from publicly available genetic summary data were used for the analyses. For MR analysis, the inverse-variance weighted method, weighted median method, and MR-Egger regression were employed. Multivariate MR analysis was performed concurrently. Univariate MR analysis indicated a strong correlation between decreased incidence of low-grade serous ovarian cancer and elevated levels of cathepsin L2 (odds ratio = 0.803, 95% confidence interval = 0.685-0.942, P = .007), whereas clear cell ovarian cancer showed a strong correlation with elevated levels of cathepsin H (odds ratio = 1.149, 95% confidence interval = 1.036-1.274, P = .008). Multivariate analysis, adjusted for 9 different cathepsins as covariates, confirmed the genetic relationships between cathepsin L2 and low-grade serous ovarian cancer and between cathepsin H and clear cell ovarian cancer. Our results suggest a causal relationship between cathepsins and ovarian malignancy and its subtypes. Cathepsin L2 has a protective effect on low-grade serous ovarian cancer, whereas cathepsin H is an adverse risk factor for clear cell ovarian cancer.

Abstract B030: Advancing precision management in retinoblastoma via aqueous humor liquid biopsy: A case of TP53 and MDM4 alterations

Abstract Background: Precision medicine has revolutionized cancer treatment, but its application in retinoblastoma (RB) has been limited due to the risks associated with traditional tumor biopsies, which can lead to the spread of cancer outside the eye. Blood plasma has not been effective in intraocular RB management because the blood-brain barrier (BBB) prevents tumor-derived material from entering the bloodstream, and in cases of bilateral RB—occurring in over 40% of patients—each eye may harbor distinct genomic alterations, complicating the use of blood-based biomarkers. Given these challenges, the discovery of tumor-derived genomic material in the aqueous humor (AH) offers a promising and safer alternative—a liquid biopsy that provides localized and specific insights into the tumor's genetic makeup. Although AH liquid biopsies have been valuable in identifying genomic changes in RB, they have yet to guide treatment decisions. This is primarily due to the rarity of the disease, the heterogeneity of treatment modalities, and the unclear definition of in vivo RB subtype classifications. Consequently, translating these genomic insights into actionable, personalized treatment strategies has been challenging. Now, we present the first application of AH-monitored treatment in a 35-month-old male with unilateral RB, characterized by TP53 alteration and ecDNA-MDM4 amplification, highlighting a significant advancement in the precision management of RB. Methods: AH samples were obtained via clear corneal paracentesis and analyzed for copy number alterations and somatic variants using shallow whole-genome sequencing and targeted sequencing. The patient initially received systematic CEV, followed with intravitreal melphalan (IVM) monotherapy. Due to resistance, treatment was escalated to a combination of intravitreal melphalan and topotecan (IVM+IVT), monitored by the AH liquid biopsy genomic findings. Results:The patient initially showed resistance to monotherapy with intravitreal melphalan (IVM), but dual therapy with melphalan and topotecan (IVM+IVT) significantly reduced tumor fraction (TFx) from 81.61% to 26.63% and decreased tumor size. Continued dual therapy and subsequent topotecan monotherapy resulted in complete regression of vitreous seeds and stabilization of the disease, as indicated by a final AH TFx of 0%. At our institution, Children's Hospital Los Angeles (CHLA), the majority of RB cases are treated using IAC or IVM, with dual chemotherapy regimens rarely employed. Conclusions: This case underscores the importance of tailoring treatment protocols to genetic profiles identified through AH liquid biopsy in managing aggressive RB. The successful combination of genomic profiling and personalized therapy has potential to significantly improve clinical outcomes, marking a critical step toward real precision management of RB. Further clinical collaboration is essential to validate and refine protocols for TP53-altered and ecDNA-MDM4-driven RB. Citation Format: Liya Xu, Elaine Huang, Jesse Lee Berry. Advancing precision management in retinoblastoma via aqueous humor liquid biopsy: A case of TP53 and MDM4 alterations [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B030.

Phytochemicals as Novel Therapeutics for Triple-Negative Breast Cancer: A Comprehensive Review of Current Knowledge.

Triple-negative breast cancer is a characteristic subtype of breast cancer that lacks the estrogen receptor, human epidermal growth factor receptor 2, and progesterone receptor. Because of its highly diverse subtypes, increased metastasis capability, and poor prognosis, the risk of mortality for people with triple-negative breast cancers is high as compared with other cancers. Chemotherapy is currently playing a major role in treating triple-negative breast cancer patients; however, poor prognosis due to drug resistance is causing serious concern. Recent studies on several phytochemicals derived from various plants being used in Traditional Chinese Medicine, Traditional Korean Medicine, Ayurveda (Traditional Indian Medicine), and so on, have demonstrated to be a promising agent as a viable therapy against triple-negative breast cancer. Phytochemicals categorized as alkaloids, polyphenols, terpenoids, phytosterols, and organosulfur compounds have been demonstrated to reduce cancer cell proliferation and metastasis by activating various molecular pathways, thereby reducing the spread of triple-negative breast cancer. This review analyzes the molecular mechanisms by which various phytochemicals fight triple-negative breast cancer and offers a perspective on the difficulties and potential prospects for treating triple-negative breast cancer with various phytochemicals.

Optimal hyperthermic intraperitoneal chemotherapy regimen for advanced and peritoneal metastatic gastric cancer: a systematic review and Bayesian network meta-analysis.

Peritoneal metastasis is one of the most common modes of spread of gastric cancer. Currently, surgical treatment combined with hyperthermic intraperitoneal chemotherapy (HIPEC) and systemic chemotherapy has demonstrated promising outcomes in both the treatment and prevention of peritoneal metastasis in gastric cancer. However, various HIPEC drug regimens are in clinical use, and their efficacy remains unclear. This study aims to evaluate the effectiveness of different HIPEC drug regimens in patients with advanced gastric cancer to determine the optimal therapeutic approach. This study conducted a systematic review and Bayesian network meta-analysis. Patients in the experimental group underwent surgery combined with HIPEC and chemotherapy. The search period covered literature from database inception to June 1, 2024. Hazard ratios (HRs) with 95% confidence intervals (CIs) were used to evaluate overall survival (OS) as the primary outcome. Odds ratios (ORs) with 95% CIs were used to assess overall disease recurrence, peritoneal recurrence, and postoperative morbidity as secondary outcomes. To ensure scientific rigor and transparency, this study has been registered with PROSPERO (CRD42024533948). A total of 11 randomized controlled trials (RCTs) involving 1092 patients were included. Compared to surgery combined with chemotherapy, the regimens of cisplatin (HRs = 0.52, 95% CI: 0.38-0.73), mitomycin C (HRs = 0.99, 95% CI: 0.55-1.79), cisplatin plus fluorouracil (HRs = 0.60, 95% CI: 0.38-0.95), and oxaliplatin plus 5-fluorouracil (HRs = 0.53, 95% CI: 0.36-0.78) all demonstrated benefits in OS. The cisplatin (ORs = 0.16, 95% CI: 0.03-0.60) and mitomycin C (ORs = 0.03, 95% CI: 0-0.71) regimens also showed advantages in reducing peritoneal recurrence, with no impact on postoperative morbidity. Importantly, the cisplatin regimen was superior to other regimens in terms of OS and overall disease recurrence, achieving a balance between efficacy and safety. Compared to chemotherapy alone, HIPEC treatment shows significant benefits in OS without a notable disadvantage in postoperative morbidity. Although no single HIPEC regimen demonstrated clear benefits across all outcomes, the cisplatin regimen performed well in multiple aspects, indicating its potential for further research and clinical application. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=533948, identifier CRD42024533948.

TMET-34. PYROPTOSIS IS AN ACQUIRED VULNERABILITY OF BRAIN METASTASES

Abstract Metastasis, the spread of cancer cells from one part of the body to another, is a leading cause of death among cancer patients. Three particularly dangerous forms of metastases are the spread of lung, skin, and breast cancers to the brain. On average survival time of all brain metastasis (BM) patients is around 4 months, which is accompanied by a failing and undefined standard of care. We have strived to bridge the gap between novel safe therapeutics and brain metastasis patients by discovering and targeting metabolic vulnerabilities in brain metastases. Here, we conducted comparative metabolomic screening in patient-derived BM lines versus normal brain cells to identify dihydroorotate dehydrogenase (DHODH) as a cancer-selective targetable vulnerability. DHODH is an essential enzyme that is located within the inner membrane of the mitochondria which has a primary role in producing pyrimidine metabolites through the de novo uridine synthesis pathway and also contributes to the proper functioning of the electron transport chain. Through this, DHODH has been implicated in the essential functioning of energy metabolism, DNA and RNA synthesis, and most recently in the modulation of the immune system. In our studies we have elucidated the significant effect DHODH inhibitors and the induction of DHODH CRISPR knock-out has against the cell viability, sphere formation, and proliferation of patient derived BM samples in vitro and in vivo. Furthermore, through metabolomics we have discovered that following DHODH perturbation, there is a significant increase in a signaling lipid (D-ethryo-Dihydrosphingosine) that specifically inhibits Protein Kinase C (PKC) and initiates Gasdermin E (GSDME) mediated pyroptosis. By uncovering this mechanism we have discovered GSDME mediated pyroptosis is an aquired vulnerability of brain metastases. Overall, this study highlights the translational potential of DHODH inhibitors in BM and elucidates novel mechanistic underpinnings of nucleotide deprivation within the context of cell death.

In-silico and In-vitro Investigation of Flavonoids and Alkaloids from Artocarpus heterophyllus, Tinospora cordifolia, and Glycosmis pentaphylla as Potential NF-κB Inhibitors in Oral Cancer.

Oral cancer is a global health concern, particularly because of its aggressive tissue invasion and metastases, holding 16th position on occurrence among all carcinoma worldwide. The aberrated transcription factor NF-κB1 influences development and spread of oral cancer, making it a potential therapeutic target. This study investigated the therapeutic potential of a few natural compounds from Artocarpus heterophyllus, Tinospora cordifolia, and Glycosmis pentaphylla in the treatment of oral cancer. Two FDA-approved drugs (5-fluorouracil, Docetaxel) and 16 natural compounds, including Artocarpin, Artocarpanone, Cycloartocarpin from Artocarpus heterophyllus; Berberine, Hydrastine, Magnoflorine, Palmatine Chloride, Tetrahydropalmatine from Tinospora cordifolia; and 5-Hydroxyarborinine, 5-Hydroxynoracronycine, 1-Hydroxy-3-methoxy-10-methyl-9-acridone, Des-N-methylacronycine, Des-N-methylnoracronycine, Kokusagenine, Noracronycin, Skimmianine from Glycosmis pentaphylla were examined using in-silico techniques. Among the 16 natural compounds studied, Hydrastine shown the highest binding energy (-6.87 kcal/mol) against NF-κB1, surpassing all other drugs, including the standards 5-fluorouracil (-4.04 kcal/mol) and docetaxel (-2.4 kcal/mol). Further molecular dynamics simulations and in-vitro experiments verified Hydrastine's exceptional anti-cancer activity. The results of in-vitro were well-aligned with the findings of in-silico, revealing considerable cytotoxicity, apoptosis induction, and cell cycle arrest. The findings revealed natural compounds' potential as safer, more effective alternatives to current cancer therapeutics, opening up new avenues for oral cancer treatment.

LncRNAs'p potential roles in the pathogenesis of cancer via interacting with signaling pathways; special focus on lncRNA-mediated signaling dysregulation in lung cancer.

Lung cancer ranks among the most lethal types of cancer globally, with a high occurrence and fatality rate. The spread of cancer to other parts of the body, known as metastasis, is the primary cause of treatment failure and death in lung cancer cases. Current approaches for treating advanced lung cancer typically involve a combination of chemotherapy and targeted therapy. However, the majority of patients ultimately develop resistance to these treatments, leading to a worsened prognosis. In recent years, cancer biology research has predominantly focused on the role of protein-encoding genes in cancer development. Long non-coding RNAs (lncRNAs) are transcripts over 200 nucleotides in length that do not encode proteins but are crucial RNA molecules involved in numerous biological functions. While many functions of lncRNAs remain unknown, some have been linked to human diseases, including cancer. Studies have demonstrated that lncRNAs interact with other large molecules in the cell, such as proteins, DNA, and RNA, influencing various critical aspects of cancer. LncRNAs play a significant role in regulating gene expression and have a crucial function in the transcriptional regulation of cancer cells. They mediate various biological and clinical processes such as invasion, metastasis, apoptosis, and cell proliferation. Dysregulation of lncRNAs has been found to impact the process of carcinogenesis through advanced technologies like RNA sequencing and microarrays. Collectively, these long non-coding RNAs hold promise as potential biomarkers and therapeutic targets for human cancers. In this segment, we provide a comprehensive summary of the literature on the characteristics and formation of lncRNAs, along with an overview of their current known roles in lung cancer.

The Role of Anesthetic Management in Lung Cancer Recurrence and Metastasis: A Comprehensive Review.

Lung cancer remains a leading cause of cancer-related mortality worldwide. Although surgical treatment is a primary approach, residual cancer cells and surgery-induced pathophysiological changes may promote cancer recurrence and metastasis. Anesthetic agents and techniques have recently been shown to potentially impact these processes by modulating surgical stress responses, immune function, inflammatory pathways, and the tumor microenvironment. Anesthetics can influence immune-modulating cytokines, induce pro-inflammatory factors such as HIF-1α, and alter natural-killer cell activity, affecting cancer cell survival and spread. Preclinical studies suggest volatile anesthetics may promote tumor progression by triggering pro-inflammatory signaling, while propofol shows potential antitumor properties through immune-preserving effects and reductions in IL-6 and other inflammatory markers. Additionally, opioids are known to suppress immune responses and stimulate pathways that may support cancer cell proliferation, whereas regional anesthesia may reduce these risks by decreasing the need for systemic opioids and volatile agents. Despite these findings, clinical data remain inconclusive, with studies showing mixed outcomes across patient populations. Current clinical trials, including comparisons of volatile agents with propofol-based total intravenous anesthesia, aim to provide clarity but highlight the need for further investigation. Large-scale, well-designed studies are essential to validate the true impact of anesthetic choice on cancer recurrence and to optimize perioperative strategies that support long-term oncologic outcomes for lung cancer patients.

Representing ECM composition and EMT pathways in gastric cancer using a new metastatic gene signature.

Gastric cancer (GC) is an aggressive and heterogeneous malignancy marked by cellular and molecular diversity. In GC, cancer cells invade locally in the stomach at stage I and can progress to metastasis in distant organs by stage IV, where it often becomes fatal. We analyzed gene expression profiles from 719 stage I and stage IV GC patients across seven public datasets, conducting functional enrichment analysis to identify a gene signature linked to disease progression. Additionally, we developed an in vitro model of a simplified extracellular matrix (ECM) for cell-based assays. Our analysis identified a progression-associated gene signature (APOD, COL1A2, FSTL1, GEM, LUM, and SPARC) that characterizes stage IV GC. This signature is associated with ECM organization and epithelial-to-mesenchymal transition (EMT), both of which influence the tumor microenvironment by promoting cell invasion and triggering EMT. This gene signature may help identify stage I GC patients at higher risk, offering potential utility in early-stage patient management. Furthermore, our experimental ECM model may serve as a platform for investigating molecular mechanisms underlying metastatic spread in gastric cancer.

Possibilities of radiological methods of diagnosis of metastatic castration-resistant prostate cancer (Review Article).

Abstract Metastatic castration-resistant prostate cancer (mCRPC) is characterized by the progression of the tumor process when it becomes unresponsive to androgen-deprivation therapy. The incidence of bone metastases in these patients reaches up to 90%. Imaging modalities play a pivotal role in the diagnosis of this oncological condition. Computed tomography (CT) and magnetic resonance imaging (MRI) offer advantages in anatomical visualization; however, they face limitations in assessing the efficacy of prostate cancer treatment. Scintigraphy is applicable in screening for skeletal bone metastatic involvement but has limitations in assessing disease progression. Positron emission tomography combined with computed tomography (PET/CT) and single-photon emission computed tomography (SPECT/CT) are utilized for early detection of local or systemic spread of prostate cancer. The assessment of quantitative data on radiopharmaceutical uptake using PSMA PET imaging is used for predicting the efficacy of antitumor therapy. With the introduction of the radiopharmaceutical 177Lu-PSMA into clinical practice, the perspective of conducting radionuclide therapy with simultaneous efficacy evaluation through hybrid imaging methods has emerged. The capabilities of imaging modalities in assessing bone metastases present a particular interest for research and systematization of the data obtained to develop optimal parameters for conducting radioligand therapy and evaluating its efficacy. Aims: To explore the capabilities of imaging modalities in diagnosing metastatic castration-resistant prostate cancer. Conclusions: The analyzed literature data indicate that imaging methods for diagnosing mCRPC vary in sensitivity and specificity, have their advantages and disadvantages, which underscores the necessity for a comprehensive approach in their utilization. The development and advancement of methods for quantitative assessment of treatment efficacy, identification of prognostic markers can influence a more informed choice of treatment tactics and radiopharmaceutical selection, potentially leading to an increase in overall survival.