Cancer Pathways Research Articles

Impact of pathways navigation status on approval rates and outcomes of oral lung cancer treatments.

415 Background: Oral targeted therapies in lung cancer represent a costly but critical component of care. Currently, the approval process for these treatments can sometimes take several weeks. Assessing the approval rates and efficacy of on-pathway treatment recommendations is an important step towards bringing clinicians and payors together to streamline the decision support and authorization process. Methods: We retrospectively analyzed authorization requests for oral anti-cancer agents for lung cancer. Eligible requests were filed between August 1, 2022, to March 1, 2024, and represented new treatment starts for that agent. In addition to collecting information about final authorization decisions, we determined whether the use case was consistent with Dana-Farber Pathways treatment recommendations in place at the time of the order. Furthermore, we measured survival from the start of oral therapy. Median survivals were calculated using the Kaplan-Meier method. These were assessed for the whole cohort and for each class of genomic aberrations. Results: There were a total of 214 eligible oral therapy claims filed between August 1, 2022, to March 1, 2024. 147 (69%) of these were considered on pathway, while 67 (31%) were off pathway. In total, 100% of the on-pathway navigations received payor approval, compared to 93% of the off-pathway navigations. The estimated 12-month survival was 86.5% for the on-pathway group, compared to 56.5% for the off-pathway group. Median overall survival has not yet been reached for either group. EGFR and ALK targeted therapies accounted for the majority of authorization requests, with 114 and 28, respectively. Conclusions: With the use of Dana-Farber Lung Cancer Pathways, the majority of requests for targeted therapies were consistent with pathway recommendations. This on-pathway cohort not only achieved a 100% payor authorization rate, but the 12-month survival was superior to that of off-pathway requests. These data provide a meaningful starting point for pathways vendors and healthcare payors to develop mutually agreed upon recommendations for use of these costly but impactful therapies.

Intratumoral microbiota as cancer therapeutic target.

Intratumoral microbiota, which affects the physiological and pathological processes of the host, has attracted increasing attention from researchers. Microbials have been found in normal as well as tumor tissues that were originally thought to be sterile. Intratumoral microbiota is considered to play a significant role in the development of tumors and the reduction of clinical benefits. In addition, intratumoral microbiota are heterogeneous, which have different distribution in various types of tumors, and can influence tumor development through different mechanisms, including genome mutations, inflammatory responses, activated cancer pathways, and immunosuppressive microenvironments. Therefore, eliminating the intratumoral microbiota is considered one of the most promising ways to slow down the tumor progression and improve therapeutic outcomes. In this review, we systematically categorized the intratumoral microbiota and elucidated its role in the pathogenesis and therapeutic response of cancer. We have also described the novel strategies to mitigate the impact of tumor progression. We hope this review will provide new insights for the anti-tumor treatment, particularly for the elderly population, where such insights could significantly enhance treatment outcomes.

Deciphering the PI3K-Akt pathway in lung cancer

This computational study explores the immune landscape of early-stage lung adenocarcinoma through single-cell RNA sequencing data analysis. By leveraging paired single-cell data, key insights were gained into the gene expression profiles of tumor samples, focusing on potential therapeutic targets and pathway interactions involved in cancer progression.Single-cell RNA sequencing data from non-lymphocytic immune cells isolated from stage IA lung adenocarcinoma and adjacent normal tissue were computationally processed. Data quality was assessed using sequence quality control tools, and reads were aligned to the hg38 reference genome. Differential gene expression analysis was conducted to identify upregulated and downregulated features. Reactome pathway analysis complemented with literature review was employed to scrutinize potential relationships and pathway interactions. Correlation analysis highlighted key genes involved in tumor progression, including Thrombospondin, HTR6 (5-hydroxytryptamine receptor 6), and LCK.Distinct gene expression patterns were identified in tumor samples, with strong positive correlations between Thrombospondin, HTR6, and LCK. These genes were found to interact within the PI3K-Akt pathway, suggesting their involvement in tumor proliferation and survival. Pathway analysis further revealed molecular crosstalk between these genes and other metabolic processes, offering potential avenues for therapeutic intervention.This computational analysis of single-cell RNA sequencing data identified key gene expression signatures and pathway interactions in early-stage lung adenocarcinoma. The findings, particularly the roles of Thrombospondin, HTR6, and LCK in the PI3K-Akt pathway, provide new insights into potential therapeutic targets for lung cancer treatment.

In silico and in vitro evaluation of compounds from Methanol whole extracts of Solanum aculeastrum Dunal berries against benign prostatic hyperplasia and prostate cancer

Background: This study evaluated anti-prostate potentials of compounds from methanol extract of Solanum aculeastrum Dunal berries (MESADB) against benign prostatic hyperplasia (BPH) and prostate cancer (PC). Methods: We used Swiss ADME and pKCSM tools to select drug-like candidates from MESADB. DisGeNET and related databases were used to identify targets for compounds of MESADB, BPH and PC. Molecular roles, biological processes, cellular components involved, and crucial pathways associated with biological processes of gene enrichment were obtained using Gene Ontology (GO) & Kyoto Encyclopedia of Genes and Genomes (KEGG), respectively. Docking was achieved using VINA tool. Antiproliferative and gene expression profiling were determined using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) bioassay, and RT-qPCR respectively, and data analyzed using Graph Pad Prism (version 8.4). Results: Three ideal drug-like candidates [Undecane; D-Arabinitol; and 9-Oxabicyclo [3.3.1] nonan-2-one,6-hydroxy-] were identified. Key targets included TLR4, PTGS2, STAT3, ESR1, MTOR, SRC, MMP9, HDAC1, AKT1 and EGFR. GO analysis revealed key targets were mainly enriched in 601 biological processes (BP), 53 molecular function (MF) and 24 cellular components (CC) terms (p < 0.05). KEGG analysis presented pathways for cancer, pathway of proteoglycans in cancer, amongst others. Docking revealed [D-Arabinitol; and 9-Oxabicyclo [3.3.1] nonan-2-one,6-hydroxy-] demonstrated high binding affinity with PTGS2 and EGFR. MESADB significantly (p < 0.0001) inhibited growth of DU-145 cells with IC50 value and selectivity index of 5.11μg/ml and 14.84, respectively, while sparing Vero CCL-81 cells. There were significant (p < 0.0001) downregulations of EGFR, PTGS2 and BCL-2, in treated DU-145 cells compared to control. Conclusion: MESADB possesses antiprostate potentials.

Recommendation of consensus definition of sea turtle fibropapillomatosis

AbstractSea turtle fibropapillomatosis (FP) is an emerging transboundary contagious disease that affected concomitantly two different marine hot spots in the Northern Atlantic Ocean and in the South China Sea at the beginning of the twentieth century. FP reached a panzootic status in the 1990s in green turtle (Chelonia mydas) populations, with increased risks of emergence and spread of the disease which have been correlated with climate induced terrestrial and oceanic physical and chemical changes. During 2023–2024, scientific experts performed a bibliographic review and recommend the consensus definition of sea turtle fibropapillomatosis. FP is an emerging transboundary viral terrestrial and aquatic contagious neoplastic syndrome involving cancerous molecular transmission pathways, which may affect all species of sea turtles at all life stages. The diagnosis of the most common verrucous form of FP is pathognomonic by visual examination of a sea turtle. We summarize the main clinical characteristics of FP, moderated by a degree of confidence of research findings adapted from the Intergovernmental Panel on Climate Change (IPCC) assessment reports. We recommend the implementation of a universal and transparent monitoring strategy of sea turtle fibropapillomatosis in sentinel bays, under the governance of the World Organisation for Animal Health.

Construction and validation of a pancreatic cancer prognostic model based on genes related to the hypoxic tumor microenvironment.

Pancreatic cancer is one of the most lethal malignancies, characterized by poor prognosis and low survival rates. Traditional prognostic factors for pancreatic cancer offer inadequate predictive accuracy, often failing to capture the complexity of the disease. The hypoxic tumor microenvironment has been recognized as a significant factor influencing cancer progression and resistance to treatment. This study aims to develop a prognostic model based on key hypoxia-related molecules to enhance prediction accuracy for patient outcomes and to guide more effective treatment strategies in pancreatic cancer. To develop and validate a prognostic model for predicting outcomes in patients with pancreatic cancer using key hypoxia-related molecules. This pancreatic cancer prognostic model was developed based on the expression levels of the hypoxia-associated genes CAPN2, PLAU, and CCNA2. The results were validated in an independent dataset. This study also examined the correlations between the model risk score and various clinical features, components of the immune microenvironment, chemotherapeutic drug sensitivity, and metabolism-related pathways. Real-time quantitative PCR verification was conducted to confirm the differential expression of the target genes in hypoxic and normal pancreatic cancer cell lines. The prognostic model demonstrated significant predictive value, with the risk score showing a strong correlation with clinical features: It was significantly associated with tumor grade (G) (b P < 0.01), moderately associated with tumor stage (T) (a P < 0.05), and significantly correlated with residual tumor (R) status (b P < 0.01). There was also a significant negative correlation between the risk score and the half-maximal inhibitory concentration of some chemotherapeutic drugs. Furthermore, the risk score was linked to the enrichment of metabolism-related pathways in pancreatic cancer. The prognostic model based on hypoxia-related genes effectively predicts pancreatic cancer outcomes with improved accuracy over traditional factors and can guide treatment selection based on risk assessment.

Unveiling the impact of estrogen exposure on ovarian cancer: a comprehensive risk model and immune landscape analysis

This study examines the impact of estrogenic compounds like bisphenol A (BPA), estradiol (E2), and zearalenone (ZEA) on human ovarian cancer, focusing on constructing a risk model, conducting gene set variation analysis (GSVA), and evaluating immune infiltration. Differential gene expression analysis identified 980 shared differentially expressed genes (DEGs) in human ovarian cells exposed to BPA, E2, and ZEA, indicating disruptions in ribosome biogenesis and RNA processing. Using the cancer genome atlas ovarian cancer (TCGA-OV) dataset, a least absolute shrinkage and selection operator (LASSO)-based risk model was developed incorporating prognostic genes 4-hydroxyphenylpyruvate dioxygenase like (HPDL), Thy-1 cell surface antigen (THY1), and peptidase inhibitor 3 (PI3). This model effectively stratified ovarian cancer patients into high-risk and low-risk categories, showing significant differences in overall survival, disease-specific survival, and progression-free survival. GSVA analysis linked HPDL expression to pathways related to the cell cycle, DNA damage, and repair, while THY1 and PI3 were associated with apoptosis, hypoxia, and proliferation pathways. Immune infiltration analysis revealed distinct immune cell profiles for high and low-expression groups of HPDL, THY1, and PI3, indicating their influence on the tumor microenvironment. The findings demonstrate that estrogenic compounds significantly alter gene expression and oncogenic pathways in ovarian cancer. The risk model integrating HPDL, THY1, and PI3 offers a strong prognostic tool, with GSVA and immune infiltration analyses providing insights into the interplay between these genes and the tumor microenvironment, suggesting potential targets for personalized therapies.

B3GALT4 modulates tumor progression and autophagy by AKT/mTOR signaling pathway in breast cancer

Backgroundβ-1,3-Galactosyltransferase-4 (B3GALT4), a member of the β-1,3-galactosyltransferase gene family, is essential to the development of many malignancies. However, its biological function in breast cancer is still unknown.MethodPublically accessible datasets, as well as quantitative real-time PCR, western blot, and immunohistochemistry on our patient cohort were used to investigate the expression levels of B3GALT4 in breast cancer. The correlation of B3GALT4 expression with clinical histopathological data and mortality in breast cancer patients was investigated. The effects of B3GALT4 in breast cancer in vitro and in vivo were investigated. RNA-seq, western blot, autophagolysosomes, and the fluorescence intensity of LC3 were used to explore the effects of B3GALT4 on autophagy. Western blot and gene set enrichment analysis (GSEA) were used to identify the AKT/mTOR pathway.ResultsB3GALT4 was significantly overexpressed in breast cancer tissues and was positively correlated with some aspects of clinicopathological status and poor prognosis. B3GALT4 overexpression significantly promoted cell proliferation, migration, and invasion, both in vitro and in vivo. B3GALT4 inhibition suppressed breast cancer cell proliferation, migration, and invasion in vitro. Suppression of B3GALT4 triggered autophagy and hindered the AKT/mTOR signaling pathway.ConclusionAccording to the present research, B3GALT4 blocked autophagy via the AKT/mTOR pathway and accelerated the growth of breast cancer. B3GALT4 may be an effective target for patients with breast cancer.

Mechanisms of Action of the Herba Salviae Chinensis-Fructus Akebiae Pair in the Treatment of Non-small Cell Lung Cancer based on a Network Pharmacology Study

Objective: To study the active ingredients and mechanism of action of "Herba Salviae Chinensis-Fructus Akebiae" drug pair in the treatment of non-small cell lung cancer (NSCLC) by using network pharmacology to provide theoretical basis for clinical application. Methods: The TCMSP (Traditional Chinese Medicine Systematic Pharmacology Database and Analysis Platform) was used to obtain the active ingredients and targets of "Herba Salviae Chinensis-Fructus Akebiae", and the results were analyzed by the Genecard (https://genecard, org/) database, the Online Mendelian Inheritance Network (OMI), the Genecard database, the Genecard database, and the Online Mendelian Inheritance Network. We searched the Genecard (https://genecard, org/) database and the Online Mendelian Inheritance in Man (OMIM) database (http://omim. org/) for non-small cell lung cancer (NSCLC) disease targets by selecting "NSCLC" as a keyword, and then obtained the results of the "Herba Salviae Chinensis-Fructus Akebiae" drug pair by using venn. We used venn to obtain the intersecting targets of the drug pair "Herba Salviae Chinensis-Fructus Akebiae" and NSCLC, and then used the STRING database and Cytoscape to construct a common target visualization network diagram. The gene (GO) enrichment analysis and KEGG enrichment analysis were realized with the help of metascape database and Microbiology platform. Results: Five active ingredients of Ishiminokan-Precipitant were obtained, and 3695 non-small cell lung cancer targets and 123 common targets were obtained. GO analysis showed that the process of GO enrichment was mainly related to the regulation of responses to inorganic substances, transcriptional regulatory complexes, cytokine receptor binding, etc. KEGG enrichment showed that the process of KEGG enrichment was mainly through Pathways in Cancer, ILRT, and cytokine receptor binding. KEGG enrichment showed that KEGG mainly exerted anti-cancer effects through pathways in cancer and IL-17 signaling pathway. Conclusion: Using the method of network pharmacology, it is proved that the drug pair "Herba Salviae Chinensis-Fructus Akebiae" can exert therapeutic effects on NSCLC through multi-components, multi-targets, and multi-pathways, and provides the theoretical basis for the clinical application.

Exosomal miR-502-5p suppresses the progression of gastric cancer by repressing angiogenesis through the Wnt/β-catenin pathway.

Gastric cancer (GC) is a significant global health concern, ranking as the fifth most common cancer and the third leading cause of cancer-related deaths. The role of miR-502-5p in various cancers has been studied, but its specific impact on gastric cancer through exosomes is not well understood. This study aimed to investigate the role and mechanism of exosome-derived miR-502-5p in gastric cancer. Differential expression of miR-502-5p in tissues or serum of GC patients was determined using qRT-PCR. The impact of miR-502-5p on cell proliferation, migration, and invasion was assessed through in vitro and in vivo experiments. The potential of exosome-miR-502-5p to inhibit metastatic ability was also explored by using vivo and vitro assay. Furthermore, the underlying mechanism of miR-502-5p in gastric cancer was investigated using western blotting. It was found that miR-502-5p suppressed the proliferation, migration, and invasion of gastric cancer cells. Exosome-miR-502-5p expression was negatively linked to metastatic ability and demonstrated inhibition of metastasis in vitro and in vivo. Additionally, miR-502-5p appeared to inhibit angiogenesis through the Wnt/β-catenin pathway in gastric cancer. Exosomal miR-502-5p acts as a suppressor in the development and progression of gastric cancer, suggesting its potential as a target for anti-cancer therapy or as a diagnostic biomarker.

Transcriptome Profiling Associated with CARD11 Overexpression in Colorectal Cancer Implicates a Potential Role for Tumor Immune Microenvironment and Cancer Pathways Modulation via NF-κB.

The immune system plays a critical role in inflammation by initiating responses to infections or tissue damage. The nuclear factor-κB (NF-κB) pathway plays a key role in inflammation and innate immunity, as well as other cellular activities. Dysregulation of this well-choreographed pathway has been implicated in various diseases, including cancer. CARD11 is a key molecule in the BCL10-MALT1 complex, which is involved in transducing the signal downstream of the NF-κB pathway. This study aims to elucidate how CARD11 overexpression exacerbates the prognosis of colorectal cancer (CRC). To identify the cellular pathways influenced by CARD11, transcriptomic analysis in both CRC cell lines and patients was carried out on CARD11- overexpressed HCT-116 and HT-29 CRC cell lines alongside empty vector-transfected cell lines. Furthermore, a comparison of transcriptomic data from adenoma and carcinoma CRC patients with low- (CARD11-) and high-(CARD11+) CARD11 expression was carried out. Whole transcriptomics and bioinformatics analysis results indicate that CARD11 appears to play a key role in CRC progression. Absolute GSEA (absGSEA) on HCT-116 transcriptomics data revealed that CARD11 overexpression promotes cell growth and tissue remodeling and enhances immune response. Key genes co-expressed with CARD11, such as EP300, KDM5A, HIF1A, NFKBIZ, and DUSP1, were identified as mediators of these processes. In the HT-29 cell line, CARD11 overexpression activated pathways involved in chemotaxis and extracellular matrix (ECM) organization, marked by IL1RN, MDK, SPP1, and chemokines like CXCL1, CXCL3, and CCL22, which were shown to contribute to the more invasive stage of CRC. In patient samples, adenoma patients exhibited increased expression of genes associated with the tumor immune microenvironment, such as IL6ST, collagen family members, and CRC transition markers, such as GLI3 and PIEZO2, in CARD11+ adenoma patients. Carcinoma patients showed a dramatic increase in the expression of MAPK8IP2 in CARD11+ carcinoma patients alongside other cancer-related genes, including EMB, EPHB6, and CPEB4.

Analysis of Modular Hub Genes and Therapeutic Targets across Stages of Non-Small Cell Lung Cancer Transcriptome.

Non-small cell lung cancer (NSCLC), representing 85% of lung cancer cases, is characterized by its heterogeneity and progression through distinct stages. This study applied Weighted Gene Co-expression Network Analysis (WGCNA) to explore the molecular mechanisms of NSCLC and identify potential therapeutic targets. Gene expression data from the GEO database were analyzed across four NSCLC stages (NSCLC1, NSCLC2, NSCLC3, and NSCLC4), with the NSCLC2 dataset selected as the reference for module preservation analysis. WGCNA identified eight highly preserved modules-Cyan, Yellow, Red, Dark Turquoise, Turquoise, White, Purple, and Royal Blue-across datasets, which were enriched in key pathways such as "Cell cycle" and "Pathways in cancer", involving processes like cell division and inflammatory responses. Hub genes, including PLK1, CDK1, and EGFR, emerged as critical regulators of tumor proliferation and immune responses. Estrogen receptor ESR1 was also highlighted, correlating with improved survival outcomes, suggesting its potential as a prognostic marker. Signature-based drug repurposing analysis identified promising therapeutic candidates, including GW-5074, which inhibits RAF and disrupts the EGFR-RAS-RAF-MEK-ERK signaling cascade, and olomoucine, a CDK1 inhibitor. Additional candidates like pinocembrin, which reduces NSCLC cell invasion by modulating epithelial-mesenchymal transition, and citalopram, an SSRI with anti-carcinogenic properties, were also identified. These findings provide valuable insights into the molecular underpinnings of NSCLC and suggest new directions for therapeutic strategies through drug repurposing.

Exploring the Mechanism of Comfrey in Lung Cancer Based on Network Pharmacology and Molecular Docking

Network pharmacology was used to investigate the active ingredients and mechanism of action of the Chinese medicine comfrey in lung cancer. Comfrey constituents and their targets were collected by searching the TCMSP and PubChem databases. The Gene Cards database was searched to extract target information for lung cancer. Based on the STRING database, Cytoscape 3.9.1 software was used to construct the PPI network of common targets of comfrey in lung cancer. We searched for common targets and performed GO and KEGG pathway enrichment analyses to build a 'network diagram' of TCM active ingredient-disease targets. The results of the pharmacological network analysis showed that after the screening, 12 compounds and 904 drug targets were obtained, and 147 drug-disease common targets were obtained, with AKT1, EGFR, TNF, and CASP3 as the core targets. After enrichment analysis of the above key targets, it was found that cancer pathways, prostate cancer, PI3K-Akt signaling pathway, endocrine resistance, and cancer proteoglycans were involved in the treatment of comfrey. The molecular docking results also showed that the comfrey compounds had good binding activities with the key targets, proving the accuracy of the network pharmacological prediction results. The results of this experiment provisionally verified the basic pharmacological effects of comfrey and its mechanism of action against lung cancer and provided directions for further research.

Effects of fumonisin B1 on gene-specific DNA methylation related to cancer pathways of p53 signalling and PI3K/Akt signalling in human kidney cells

Abstract Fumonisin B1 (FB1), which is emerged by contamination of corn and similar products with Fusarium species, causes a high risk for human and animal health. FB1 shows hepatotoxic, nephrotoxic, neurotoxic, immunotoxic and teratogenic effects. FB1 has also been linked to carcinogenesis processes that are unrelated to genotoxic pathways. Our goal was to investigate the role of gene-specific DNA methylation and expression of tumour suppressor genes in the toxicity of FB1 in human kidney (HK-2) cells. Using array panels, effects of FB1 exposure (10-100 μM) for 24 h on methylation levels of tumour suppressor genes were investigated. ToppGene Suite (Toppfun) portal was used to perform gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) and Reactome enrichment studies. The most of the genes were hypermethylated significantly at 100 μM concentrations of FB1. These results are consistent with the expression results which downregulate the selected genes of CD44, CDKN1A, CDKN2B, CTNNB1, MYC and p16. Functional enrichment analysis further elucidated the molecular mechanisms of FB1 in cancer-related pathways especially p53 signalling and PI3K/Akt signaling. It has been expected that the present study could contribute to the studies on the mechanisms that play a role in FB1 induced carcinogenesis.

Covariance Assisted Multivariate Penalized Additive Regression (CoMPAdRe)

We propose a new method for the simultaneous selection and estimation of multivariate sparse additive models with correlated errors. Our method called Covariance Assisted Multivariate Penalized Additive Regression (CoMPAdRe) simultaneously selects among null, linear, and smooth non-linear effects for each predictor while incorporating joint estimation of the sparse residual structure among responses, with the motivation that accounting for inter-response correlation structure can lead to improved accuracy in variable selection and estimation efficiency. CoMPAdRe is constructed in a computationally efficient way that allows the selection and estimation of linear and non-linear covariates to be conducted in parallel across responses. Compared to single-response approaches that marginally select linear and non-linear covariate effects, we demonstrate in simulation studies that the joint multivariate modeling leads to gains in both estimation efficiency and selection accuracy, of greater magnitude in settings where signal is moderate relative to the level of noise. We apply our approach to protein-mRNA expression levels from multiple breast cancer pathways obtained from The Cancer Proteome Atlas and characterize both mRNA-protein associations and protein-protein subnetworks for each pathway. We find non-linear mRNA-protein associations for the Core Reactive, EMT, PIK-AKT, and RTK pathways. Supplementary Materials are available online.

Abstract C111: Characterization of kisspeptin receptor signaling pathways in cervical cancer: Unveiling novel mechanisms and therapeutic potentials

Abstract Introduction: This study delves into the complex signaling mechanisms of the kisspeptin system in cervical cancer, aiming to unravel the intricate interactions between kisspeptin and its receptor, as well as their roles in modulating cancer progression. Given the emerging significance of the kisspeptin system in tumor biology, our research seeks to illuminate how kisspeptin signaling influences cellular behaviors critical to cancer development, such as proliferation and migration. By exploring the nuanced effects of kisspeptin receptor activation, this study contributes to a deeper understanding of its therapeutic potential and underscores the importance of kisspeptin pathways in the broader context of cancer research. Methods: Was employed Bioluminiscence Resonance Energy Transfer (BRET) assays to explore the activation of the kisspeptin receptor in cervical cancer cell lines, using synthesized analogs of kisspeptin-10 for detailed signaling analysis. Functional effects were assessed through proliferation and migration assays. Additionally, we evaluated the activation or reduction in phosphorylation of specific kinases involved in tumoral processes, providing a nuanced understanding of the signaling mechanisms at play. Results: Our data demonstrate that activation of the kisspeptin receptor substantially modulates cellular proliferation and motility in cervical cancer cell lines. We uncovered novel activation of the Gz protein by kisspeptin-10, which is integral to the kisspeptin receptor function, and identified an upregulation of signaling pathways critical for cell survival and metastasis. Importantly, we observed activation of kinases such as Chk2, c-Jun, p70 S6 kinase, and RSK 1/2/3, as well as members of the STAT family, following kisspeptin-10 stimulation. This kinase activation underscores the multifaceted role of kisspeptin in tumor progression, suggesting its involvement in both pro-oncogenic and tumor-suppressive pathways, and provides direct insights into the mechanistic underpinnings of kisspeptin effect on cancer cell behavior. Conclusion: In conclusion, our study elucidates the complex role of kisspeptin-10 in cervical cancer, demonstrating its ability to modulate cellular proliferation and motility through activation of the kisspeptin receptor. The novel activation of the Gz protein and subsequent upregulation of signaling pathways associated with cell survival and metastasis highlight the intricate involvement of kisspeptin in cancer progression. Furthermore, the activation of key kinases such as Chk2, c-Jun, p70 S6 kinase, RSK 1/2/3, and STAT family members upon kisspeptin-10 stimulation reveals a dual-faceted influence on tumor dynamics, promoting both pro-oncogenic and tumor-suppressive mechanisms. These findings provide significant insights into the molecular actions of kisspeptin in cervical cancer, offering potential targets for therapeutic intervention and a deeper understanding of its role in tumor biology. Citation Format: Deisy Y. Rodríguez-Sarmiento, Pedro H. Scarpelli-Pereira, Michel Bouvier. Characterization of kisspeptin receptor signaling pathways in cervical cancer: Unveiling novel mechanisms and therapeutic potentials [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C111.

Abstract C103: Exploring ethnicity-specific molecular mechanism of cholesterol and fatty acid synthesis pathway in Hispanic colorectal cancer

Abstract Colorectal cancer (CRC) is the most prevalent gastrointestinal cancer, the third most common malignancy and the second leading cause of cancer-related mortality worldwide. The American Cancer Society (ACS) estimates 152,810 new cases of colorectal cancer, with an estimated 53,010 deaths in 2024. Typically diagnosed in older adults, CRC incidence is rising among younger individuals, particularly in Hispanics (16.5%) compared to non-Hispanic whites (8.7%). Due to the lack of timely screenings in this ethnic group, further research is crucial to identify novel biomarkers and therapeutic targets for improved early detection and intervention. To accomplish this goal, we performed RNA-sequencing of Hispanic and non-Hispanic White (NHW) CRC tissues. The transcriptomic analysis revealed differential gene expression patterns in Hispanic and NHW populations when compared to respective normal adjacent tissues (NATs). We identified 3577 differentially expressed genes (DEGs) in Hispanic CRC samples and 2971 DEGs in NHW CRC samples, of which 1831 DEGs were unique to Hispanic. Based on the preliminary analysis we hypothesized that unique DEGs from the Hispanic population could help identify potential pathways contributing to CRC progression. Among these 1831 unique DEGs, many of the genes are associated with cholesterol and fatty acid synthesis pathway. The cholesterol biosynthesis pathway is a highly diverse and interconnected signaling pathway, playing essential roles in cellular function and systemic homeostasis. Its complexity and regulatory mechanisms make it a critical area of study in cancer. Studies indicate that Hispanics and African Americans with high cholesterol tend to have higher Body mass index (BMI) levels compared to Whites which has an increased risk of colorectal cancer. However, the role of cholesterol metabolism and fatty acid metabolism in CRC have not been studied from the Hispanic health disparities perspective. From the 1831 DEGs, we selected those in the cholesterol and fatty acid synthesis pathways with significant log2 fold changes (≤ -2 or ≥ +2) and adjusted p-values (FDR ≤ 0.05). Our bioinformatics analysis identified four key DEGs: LCN2, DHCR7, PCSK9 and SQLE. The expression levels of these genes were examined in Hispanic CRC vs. NHW CRC tissue samples using qRT-PCR. Elevated expression of LCN2 and SQLE was observed in late-stage Hispanic CRC tissues compared to NHW CRC tissues, while DHCR7 exhibited high expression in early-stage Hispanic CRC. On the other hand, PCSK9 showed low expression in both early and late stages of Hispanic CRC, suggesting potential ethnicity-specific molecular signatures in CRC progression. Moving forward, protein level studies and functional analysis of these DEGs in Hispanic CRC tissues and organoids will enhance our understanding of the role of cholesterol and fatty acid synthesis pathway proteins. Thus, elucidating novel molecular mechanisms underlying CRC progression could lead to identification of potential Hispanic specific biomarkers and therapeutic targets for early diagnosis and intervention. Citation Format: Somrita Roy, Soumya Nair, MD Zahirul Islam Khan, Sourav Roy. Exploring ethnicity-specific molecular mechanism of cholesterol and fatty acid synthesis pathway in Hispanic colorectal cancer [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C103.

Abstract C100: Defining the role of Hedgehog, Notch, and Wnt signaling pathways in aggressive lethal prostate cancer of Hispanic men

Abstract Background: Hispanic American (HA) men with prostate cancer (PC) are more likely to have more aggressive and advanced diseases and greater mortality rates compared to non-Hispanic white (NHW) men. Resistance to the current anticancer therapy is the major hurdle that leads to poor clinical outcomes. Hedgehog, Notch, and Wnt signaling pathways play a crucial role in development, progression, and resistance to the various anticancer therapies. Here, we characterized the enrichment of Hedgehog, Notch, and Wnt signaling pathways and molecular tumors differences between HA and NHW patients. Methods: Our data consist of 88 PC tumors samples (HA=34, NHW=54) obtained from treatment-naive metastatic hormone-sensitive prostate cancer (mHSPC) that were analyzed by next-generation sequencing (592, NextSeq; Whole Exome Sequencing, NovaSeq) and Whole Transcriptome Sequencing (WTS; NovaSeq) (Caris Life Sciences, Phoenix, AZ). Pathway enrichment was determined by Gene Set Enrichment Analysis (GSEA, Broad Institute) by measurable TPM (transcripts per kilobase million). The medical records were reviewed in a deidentified fashion for clinical features. Statistical significance was determined using chi-square and Mann-Whitney U (p&amp;lt;0.05). Results: HA PC had enrichment of Hedgehog signaling (NES: 1.45, FDR=0.04), Notch signaling (NES: 1.41, FDR=0.07), and Wnt/β-catenin signaling (NES: 1.38, FDR=0.11) pathways compared to NHW tumors. HA tumors had higher expression of genes (HES1, Notch1, WNT1, WNT2; FC:1.1-2.5) associated with crosstalk between Hedgehog, Notch, and Wnt/β- catenin signaling pathways (all p&amp;lt;0.05). Moreover, HA tumors had higher expression of stemness (ALDH1A2, ALDH1A1, PROM1; FC: 1.7-3.0), drug efflux (ABCC1, ABCB1; FC: 1.1- 1.5), epithelial to mesenchymal transition (EMT) (TWIST1, MMP2; FC: 1.1-1.5), cell cycle (CCND2; FC: 1.2), inhibition of apoptosis (BIRC2, XIAP; FC: 1.1) and epigenetic (EP300, TET1, TET2; FC: 1.3-1.4) related genes compared to NHW tumors (all p&amp;lt;0.05). HA PC had higher frequency of Hedgehog and Wnt/β-catenin associated SPOP (16% vs 6.6%, p=0.2) and CTNNB1 (12% vs 2.2%, p=0.1) mutation compared to NHW PC. Conclusion: These results demonstrate that tumors from HA patients had enrichment of oncogenic Hedgehog, Notch, and Wnt/β-catenin signaling pathways, higher expression of stemness, drug efflux, EMT, cell cycle, inhibition of apoptosis and epigenetic-related genes, and mutations directly involved in activating the Hedgehog and Wnt/β-catenin signaling pathways. Together, these findings suggest that tumors from HA patients are enriched for gene signatures that promote cancer progression and therapy resistance. Additional research on collaboration and crosstalk between Hedgehog, Notch, and Wnt/β-catenin signaling pathways may help in designing better therapeutic strategies for HA men with mHSPC. Citation Format: Alejandro Recio-Boiles, Sachin Kumar Deshmukh, Ricardo J. Estrada-Mendizabal, Kenneth Barker, Sharon Wu, Joanne Xiu, Milan Radovich, Elisabeth I. Heath, Rana McKay, Juan Chipollini, Cynthia K. Miranti. Defining the role of Hedgehog, Notch, and Wnt signaling pathways in aggressive lethal prostate cancer of Hispanic men [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C100.

Lagerstroemin from Lagerstroemia speciosa as Antibreast Cancer Candidate Targeting AURKA, EGFR and SRC Protein: A Comprehensive Computational Study

Breast cancer is a type of cancer that has a high rate of diagnosis and mortality in the world. Lagerestroemia speciosa is a herb that has anticancer activity. This study aims to analyze the compounds in L. speciosa that most act as anticancer of the breast. The compounds in L. speciosa were selected based on drug-likeness, physicochemical properties, ability to penetrate the lipid bilayer and toxicity. The Lagerstroemin target related to Lagestroemin breast cancer was predicted using DisGeNET, SWISS Target Prediction and cBioportal. Molecular docking between Lagerstroemin and AURKA, EGFR and SRC was performed using AutoDock Vina. The interaction stability of each complex was analyzed by molecular dynamic simulation using YASARA with parameters of RMSD protein, RMSD ligand, number of hydrogen bonds and molecular dynamic binding energy. Of the 22 compounds, Quercetin, Caffeic acid, Lagerstroemin and Dypirone were predicted to have good ADME properties and can easily penetrate lipid membranes. Therefore, Quercetin, Caffeic acid and Lagerstroemin were predicted to have anti-breast cancer bioactivity. Of the 3 compounds, Lagerstroemin had the lowest toxicity. Lagerstroemin was predicted to interact with breast cancer-related proteins AURKA, EGFR and SRC. Molecular docking and dynamics showed that Lagerestroemin interacted stably at the ATP binding site of the 3 proteins, so it was very potential as an inhibitor of these 3 proteins. Therefore, Lagerstroemin was predicted to be the compound in L. speciosa with the most potential breast anticancer agent by targeting AURKA, EGFR and SRC. HIGHLIGHTS Quercetin, Caffeic acid and Lagerstroemin from Lagerstroemia speciosa show promising anticancer properties for breast cancer treatment. Lagerstroemin stands out with low toxicity and potent anticancer activity, suggesting its safety and effectiveness as a therapeutic agent. Lagerstroemin interacts stably with breast cancer-related proteins AURKA, EGFR and SRC, indicating its potential as a powerful inhibitor targeting key pathways in breast cancer. GRAPHICAL ABSTRACT

Exploring angiogenic pathways in breast cancer: Clinicopathologic correlations and prognostic implications based on gene expression profiles from a large-scale genomic dataset

Exploring angiogenic pathways in breast cancer: Clinicopathologic correlations and prognostic implications based on gene expression profiles from a large-scale genomic dataset