Target In Cancer Research Articles

Merging Metabolic Modeling and Imaging for Screening Therapeutic Targets in Colorectal Cancer.

Cancer-associated fibroblasts (CAFs) play a key role in metabolic reprogramming and are well-established contributors to drug resistance in colorectal cancer (CRC). To exploit this metabolic crosstalk, we integrated a systems biology approach that identified key metabolic targets in a data-driven method and validated them experimentally. This process involved a novel machine learning-based method to computationally screen, in a high-throughput manner, the effects of enzyme perturbations predicted by a computational model of CRC metabolism. This approach reveals the network-wide effects of metabolic perturbations. Our results highlighted hexokinase (HK) as the crucial target, which subsequently became our focus for experimental validation using patient-derived tumor organoids (PDTOs). Through metabolic imaging and viability assays, we found that PDTOs cultured in CAF-conditioned media exhibited increased sensitivity to HK inhibition, confirming the model predictions. Our approach emphasizes the critical role of integrating computational and experimental techniques in exploring and exploiting CRC-CAF crosstalk.

Abstract C097: PVT1 exon 9-dependent overexpression of RSAD2 is a characteristic of prostate cancer in males of African ancestry

Abstract Aggressive prostate cancer (PCa), including castrate-resistant and neuroendocrine subtypes, is projected to increase in incidence 5% each year. Aggressive PCa disproportionally impacts African American men, has limited effective treatment options and high mortality rates. Although racial disparities are established in PCa development, attributed to multiple contributory factors including systemic racism, differences in socioeconomic status and distrust in the medical system, work is still needed to understand the contribution of biological factors. We found the exon 9 region of plasmacytoma variant translocation 1 (PVT1) overexpressed in aggressive PCa cell lines derived from African American (AA) men. We found PVT1 exon 9 overexpression induced phenotypic changes to normal prostate epithelial cells in vitro and led to tumor formation in vivo. RNA-sequencing analysis revealed 156 significantly differentially expressed genes influenced by PVT1 exon 9 overexpression and radical S-adenosyl methionine domain containing 2 (RSAD2) was the top significantly overexpressed gene (log2Fold change 1.71, p-value < 0.05). We utilized the GSE223405 publicly available dataset to identify whether our identified PVT1 exon 9 downstream genes were enriched in AA prostate cancer cells. RSAD2 was significantly overexpressed in AA prostate cancer cells compared to prostate cancer cells from men of European ancestry (moEA) (log2Fold change 6.18, p-value < 0.05). Comparing normal cells to prostate cancer cells between these groups, we found that normal AA prostate cells had significantly higher expression of RSAD2 (log2fold change 4.25, p-value < 0.001) whereas moEA samples did not (log2fold change 0.837, p-value=0.150). From analysis of data obtained from cBioPortal, we found RSAD2 alteration significantly correlates (p-value < 0.001) with self-identified race and copy number overexpression of RSAD2 was found to be enriched in AA patients (18.16% moEA versus 24% AA). Finally, we found 88.6% of the significantly differentially expressed genes within our PVT1 exon 9 RNA-sequencing dataset were significantly differentially expressed in GSE223405 AA samples and of those, 51.7% of genes exhibited a similar differential expression pattern suggesting that the PVT1 exon 9/RSAD2 dependent pathway may be more prominent in AA men. Mechanistically, we found two differing pathways of RSAD2 overexpression in aggressive prostate cancer cell models, one dependent and one independent of PVT1 exon 9 overexpression, with similar but differing biological functions related to epigenetic processes and metabolism. Ongoing work is investigating the RSAD2 and PVT1 exon 9 expression axis in a diverse set of human prostate cancer tissues and investigating their utilization as a therapeutic target in prostate cancer. Citation Format: Rachel E. Sexton-Bonacci1, Murtaza Barkarar1, Chindeum Udekwu1, Olorunseun O. Ogunwobi1. PVT1 exon 9-dependent overexpression of RSAD2 is a characteristic of prostate cancer in males of African ancestry [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 C097.

Abstract B011: FOXA1 as a pioneer factor in ERα-DNA interactions and its therapeutic potential in ER+ breast cancer: Insights from ChIP-seq and GWAS in Hispanic populations

Abstract Forkhead box A1 (FOXA1) acts as a pioneer factor for Estrogen Receptor alpha (ERα), playing a crucial role in determining where ERα binds to DNA and regulates gene expression in breast cancer cells. A pioneer factor is a class of transcription factors (TF) that is responsible for opening the chromatin to allow other TFs to attach and activate transcription of that gene. FOXA1 acts as a facilitator for ERα-DNA interactions. It binds to specific DNA regions, opening the chromatin for ERα to bind. It “pre-marks” these sites in the genome even in the absence of estrogen. In fact, FOXA1 is frequently overexpressed in ER+ breast cancers, suggesting it has a crucial role in driving tumor growth. As such, FOXA1 is an attractive therapeutic target that already serves as a great biomarker for many types of breast cancers. Inhibiting FOXA1 can potentially block ER activity and inhibit growth of ER+ breast cancer, especially in those resistant to anti-estrogen therapies, such as tamoxifen. In this project, we identified sites that FOXA1 opens and correlated them with SNP mutations commonly found in the Hispanic population. The presence of these SNPs portends a worse outcome in Hispanic patients. To assess which open chromatin regions are crucial for breast cancer pathogenesis, a ChIP-seq analysis was done on vehicle-treated and estrogen-treated samples to determine FOXA1 binding sites. After identifying gained, lost, and differentially expressed peaks set, these were compared to genome-wide association studies (GWAS) of Hispanic patients to develop an understanding of how much overlap is common between sites of mutations and open sections of chromatin due to FOXA1. Through our analysis, we uncovered a subset of FOXA1 binding sites that overlap with sites of inherited mutation in Hispanic patients. This informs on the subset of genes that are linked to breast cancer and potential therapeutic targets. Citation Format: Hemakshat Sharma, Alyssa Maria Arreola, Frances L. Heredia, Hector L. Franco, Julie Dutil. FOXA1 as a pioneer factor in ERα-DNA interactions and its therapeutic potential in ER+ breast cancer: Insights from ChIP-seq and GWAS in Hispanic populations [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 B011.

A selective dual-signal electrochemical paper-based device using imprinted sensors for voltammetric and impedance analysis of 4-NQO and carcinoembryonic antigen (CEA)

BackgroundCarcinoembryonic Antigen (CEA) and 4-nitroquinoline-N-oxide (4-NQO) are cancer markers that play a crucial role in tumor risk assessment and early cancer diagnosis. Therefore, it is in demand to develop a fast, accurate, simple, and cost-effective method to detect these cancer markers for quick and early stage-cancer diagnosis and treatment. ResultsHerein, we report a dual signaling approach for direct and indirect signal transduction of cancer biomarker binding on molecularly imprinted-electrodes integrated on an ePAD, enabling sensitive and selective quantitative analysis of 4-NQO and CEA. Multiple test zones on a single device based on artificial recognition sites using core-shell Cu-MOF@MIP were developed to create a selective “Dual-signal-ePAD”. An effective and facile imprinting method on a Cu-MOF surface based on the synthesized of 4-VPBA/MAA/TRIM polymer. It resulted in a novel MIP useable as a high-performance sensing tool for the ultrasensitive and specific quantification of the target cancer biomarkers. Multiple tests consisted of voltammetric analysis of 4-NQO via oxidation of the analyte on a WE1, and impedance analysis of CEA via the molecular interaction with the imprinted WE2. SignificanceThe proposed device provides enhanced electrochemical signal amplification due to its high conductivity, electrocatalytic activity, and the target-specific recognition sites for accurate determination of 4-NQO and CEA targets. The Dual-signal-ePAD exhibits good voltammetric and EIS response, oxidation currents of 4-NQO at −0.06 V and RCT of CEA, resulting in high selectivity and sensitivity with a linear response range covering the concentration range of clinical interest for both analytes. Dual-signal ePAD is a good candidate for clinical screening and POCT.

Abstract C083: Meta-analysis reveals differences in somatic alterations by genetic ancestry across common cancers

Abstract Genetic similarity of populations (or genetic ancestry) contributes to cancer driving alterations. We performed a meta-analysis leveraging two real-world cohorts of targeted gene panel sequencing, comprising 275,605 tumor samples, to investigate ancestry-associated somatic alterations across 14 common cancers. We focused on five continental ancestries – European (EUR), African (AFR), East Asian (EAS), South Asian (SAS), and admixed American (AMR). Genetic ancestry was inferred using single nucleotide polymorphism markers from captured regions of gene panel sequencing in each cohort. The combined cohort from Memorial Sloan Kettering – Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) and Foundation Medicine (FMI) contains a substantial number (45,131) of non-EUR samples. Within each cohort, we performed multivariate logistic regression to test association of each cancer gene alteration with proportion of genetic ancestry as a continuous variable, controlling for relevant covariates (age, sex, gene panel version, and histological subtypes) for every combination of ancestry and cancer type. Our analysis focused on oncogenic or likely oncogenic alterations spanning mutations, copy number alterations, and structural rearrangements for each gene. We then aggregated the logistic regression results from the two cohorts using a fixed effects model of meta-analysis weighted by cohort sample size. We found 444 significant associations involving 116 unique genes with consistent logistic regression coefficients between cohorts and False Discovery Rate (FDR)-adjusted p-value < 0.1. These genes were involved in cancer-specific and cross-cancer associations. TP53, KRAS, and TERT were the top three recurrent ancestry-associated genes respectively. TERT promoter mutations were depleted in patients of AFR or EAS ancestry, but enriched in EUR ancestry in bladder urothelial carcinoma, glioblastoma, cutaneous melanoma, and hepatocellular carcinoma. Additionally, TP53 mutations were enriched in AFR and EAS ancestry across multiple cancers, consistent with previous reports, but depleted in prostate cancer in both AFR and EAS ancestries. Among the novel cancer-specific associations with FDA-approved targeted therapies, we found that CDK12 mutations in prostate adenocarcinoma were enriched in EAS ancestry while ERBB2 mutations in lung adenocarcinoma were enriched in AMR ancestry. We also found novel potential drug targets/biomarkers associated with AFR ancestry, such as enrichment of BAP1 mutations in head and neck squamous cell carcinoma and depletion of FGFR2 mutations in uterine endometrioid carcinoma. Overall, our work identified ancestry-associated somatic alteration differences of cancer genes in a combined cohort with a large number of non-European samples. This work underscores the value of studying under-represented populations to replicate or reveal new potential targets for precision oncology. Citation Format: Setor Amuzu, Amy Xie, Xuechun Bai, Kelly R. Pekala, David Ma, Tomin Perea-Chamblee, Kanika Aurora, Garrett Frampton, Michael Berger, Nikolaus Schultz, Justin Y. Newberg, Jian Carrot-Zhang. Meta-analysis reveals differences in somatic alterations by genetic ancestry across common cancers [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 C083.

Targeting cancer with small-molecule pan-KRAS degraders

Mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein are highly prevalent in cancer. However, small-molecule concepts that address oncogenic KRAS alleles remain elusive beyond replacing glycine at position 12 with cysteine (G12C), which is clinically drugged through covalent inhibitors. Guided by biophysical and structural studies of ternary complexes, we designed a heterobifunctional small molecule that potently degrades 13 out of 17 of the most prevalent oncogenic KRAS alleles. Compared with inhibition, KRAS degradation results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines, killing cancer cells while sparing models without genetic KRAS aberrations. Pharmacological degradation of oncogenic KRAS was tolerated and led to tumor regression in vivo. Together, these findings unveil a new path toward addressing KRAS-driven cancers with small-molecule degraders.

Rosmarinic acid attenuates glioblastoma cells and spheroids’ growth and EMT/stem-like state by PTEN/PI3K/AKT downregulation and ERK-induced apoptosis

BackgroundGlioblastoma (GB) is a highly malignant type of brain cancer with a poor prognosis. Therapeutic strategies for GB are still limited. Rosmarinic acid (RA), a polyphenolic compound, is a promising experimental anticancer agent, but its specific protein targets for GB remain unclear. PurposeThis study aimed to elucidate the anticancer effects of RA in 2D- and 3D-GB cells and the underlying mechanisms. Methods3D-tumor spheroids (mimics in vivo tumors) were obtained by the hanging-drop/agarose method. RA's anti-glioma activity on U-87MG (p53-wt/PTEN-mt) and LN229 (p53-mt/PTEN-wt) cells was evaluated through cell viability, colony-formation, migration/invasion/angiogenesis assays, fluorescence imaging, and spheroid growth analysis. The underlying mechanism of the anticancer effects of RA was investigated by Western blot and immunofluorescence analysis. The MEK inhibitor U0126 was used to block ERK phosphorylation. ResultsRA treatments exerted anti-proliferative and pro-apoptotic effects on human GB cells. RA dose-dependently reduced angiogenesis and intracellular ROS levels, suppressed glioma growth, and migration/invasion in 2D-culture and cancer stem cell (CSC)-like 3D-spheroid culture (SPC). Repeated therapy in SPC was more effective by leading to disrupted structure than a single treatment. Treatments in SPC also suppressed epithelial-mesenchymal transition (EMT) and CSC-like properties. Strikingly, RA downregulated the SIRT1/FOXO1/NF-κB axis independently of p53 or PTEN function in both gliomas. Immunofluorescence labeling revealed decreased SIRT1 and NF-κB-p65 and increased FOXO1 and GAPDH proteins in nuclear location (associated with apoptosis). Surprisingly, RA increased p-ERK1/2 levels, but priming with U0126 abolished RA-mediated p-ERK upregulation; thus, autophagy and apoptosis induction in GB cells were prevented, and the growth of GB spheroids accelerated. Specifically, RA also inhibited the PTEN/PI3K/AKT pathway in U-87MG cells. Due to genetic differences in cells, U-87MG cells were more sensitive to RA treatments than LN229 cells. Meanwhile, our positive control drug trial results with FDA-approved temozolomide (TMZ) used in GB treatment showed that our test compound rosmarinic acid exhibited higher therapeutic effects than TMZ at lower doses. ConclusionSuppression of EMT, downregulation of SIRT1/FOXO1/NF-κB axis, inhibition of PTEN/PI3K/AKT signaling pathway, and ERK-induced apoptosis and autophagy were determined to be involved in stopping glioma progression. Our findings for the first time, revealed that RA may have potential therapeutic use by having multiple targets in human brain cancer with further clinical studies.

In vivo CRISPR screens identify Mga as an immunotherapy target in triple-negative breast cancer

Immune evasion is not only critical for tumor initiation and progression, but also determines the efficacy of immunotherapies. Through iterative in vivo CRISPR screens with seven syngeneic tumor models, we identified core and context-dependent immune evasion pathways across cancer types. This valuable high-confidence dataset is available for the further understanding of tumor intrinsic immunomodulators, which may lead to the discovery of effective anticancer therapeutic targets. With a focus on triple-negative breast cancer (TNBC), we found that Mga knock-out significantly enhances antitumor immunity and inhibits tumor growth. Transcriptomics and single-cell RNA sequencing analyses revealed that Mga influences various immune-related pathways in the tumor microenvironment. Our findings suggest that Mga may play a role in modulating the tumor immune landscape, though the precise mechanisms require further investigation. Interestingly, we observed that low MGA expression in breast cancer patients correlates with a favorable prognosis, particularly in those with active interferon-γ signaling. These observations provide insights into tumor immune escape mechanisms and suggest that further exploration of MGA's function could potentially lead to effective therapeutic strategies in TNBC.

Dual folate/biotin-decorated liposomes mediated delivery of methylnaphthazarin for anti-cancer activity

Chemotherapy is an effective strategy for mitigating the global challenge of cancer treatment, which often encounters drug resistance and negative side effects. Methylnaphthazarin (MNZ), a natural compound with promising anti-cancer properties, has been underexplored due to its poor aqueous solubility and low selectivity. This study introduces a novel approach to overcome these limitations by developing MNZ-encapsulating liposomes decorated with folate and biotin (F/B-LP-MNZ). This dual-targeting strategy aims to enhance the anti-cancer efficacy and specificity of MNZ delivery. Our innovative F/B-LP-MNZ formulation demonstrated excellent physicochemical properties, stability, and controlled drug release profiles. In vitro studies revealed that MNZ-loaded liposomes attenuate the toxicity associated with free MNZ while F/B-LP-MNZ significantly increased cytotoxicity against HeLa cells, which express high levels of folate and biotin receptors, compared to non-targeted liposomes. Enhanced cellular uptake and improved dynamic flow attachment further confirmed the superior specificity of F/B-LP in targeting cancer cells. Additionally, our results revealed that F/B-LP-MNZ effectively inhibits HeLa cell migration and adhesion through EMT suppression and apoptotic induction, indicating its potential to prevent cancer metastasis. These findings highlight the potential of dual folate and biotin receptors-targeting liposomes as an effective delivery system for MNZ, offering a promising new avenue for targeted cancer therapy.

TRMT10C-mediated m7G modification of circFAM126A inhibits lung cancer growth by regulating cellular glycolysis

The N7-methylguanosine (m7G) modification and circular RNAs (circRNAs) have been shown to play important roles in the development of lung cancer. However, the m7G modification of circRNAs has not been fully elucidated. This study revealed the presence of the m7G modification in circFAM126A. We propose the novel hypothesis that the methyltransferase TRMT10C mediates the m7G modification of circFAM126A and that the stability of m7G-modified circFAM126A is reduced. circFAM126A is downregulated in lung cancer and significantly inhibits lung cancer growth both in vitro and in vivo. The expression of circFAM126A correlates with the stage of lung cancer and with the tumour diameter, and circFAM126A can be used as a potential molecular target for lung cancer. The molecular mechanism by which circFAM126A increases HSP90 ubiquitination and suppresses AKT1 expression to regulate cellular glycolysis, ultimately inhibiting the progression of lung cancer, is elucidated. This study not only broadens the knowledge regarding the expression and regulatory mode of circRNAs but also provides new insights into the molecular mechanisms that regulate tumour cell metabolism and affect tumour cell fate from an epigenetic perspective. These findings will facilitate the development of new strategies for lung cancer prevention and treatment.Graphical Graphical Headlights• circRNA can undergo m7G modification. The methyltransferase TRMT10C mediates circFAM126A m7G modification, thereby enhancing circFAM126A stability.• m7G-modified circFAM126A can perform a biological function in inhibiting lung cancer progression by regulating cellular glycolysis.• circFAM126A increases ubiquitination of HSP90 and inhibits AKT1 expression to regulate cellular glycolysis.

Emerging Targets in Non-Small Cell Lung Cancer.

Lung cancer is responsible for a high burden of disease globally. Over the last two decades, the discovery of targetable oncogenic genomic alterations has revolutionized the treatment landscape for early-stage and advanced non-small cell lung cancer (NSCLC). New molecular drivers continue to emerge as promising therapeutic targets, including KRAS non-G12C, RAF/MEK, HER3, Nectin-4, folate receptor alpha, ITGB6, and PRMT5. In this review, we summarize the emerging molecular targets with a potential clinical impact in advanced NSCLC, elaborating on their clinical characteristics and specific mechanisms and molecular pathways for which targeted treatments are currently available. Additionally, we present an aggregate of ongoing clinical trials investigating the available treatment options targeting such alterations, in addition to their current recruitment status and preliminary efficacy data. These advancements may guide further research endeavors and inform future treatment strategies to improve the management of and transform outcomes for patients with advanced NSCLC.

Advances in targeting cancer epigenetics using CRISPR-dCas9 technology: A comprehensive review and future prospects.

Cancer, a complex and multifaceted group of diseases, continues to challenge the boundaries of medical science and healthcare. Its relentless impact on global health, both in terms of prevalence and mortality, underscores the urgent need for a comprehensive understanding of its underlying mechanisms and innovative therapeutic approaches. In recent years, significant progress has been achieved in identifying the genetic and epigenetic mechanisms that cause cancer development and treatment resistance. Researchers are currently investigating the possibility of epigenetic editing such as CRISPR-dCas9 (Clustered Regularly Interspaced Short Palindromic Repeats/deactivated CRISPR-associated protein 9) technologies, for targeting and modifying cancer related epigenetic alterations. A revolutionary form of precision cancer treatment called CRISPR-dCas9 is derived from the bacterial CRISPR-Cas (CRISPR-associated nuclease) system. CRISPR-dCas9 can be combined with epigenetic effectors (EE) to alter malignant epigenetic characteristics associated with cancer. The purpose of this review article is to provide a thorough analysis of recent advancements in utilizing CRISPR-dCas9 technology to target and modify epigenetic changes associated with cancer. This review aims to summarize the latest research developments, evaluate the effectiveness and limitations of CRISPR-dCas9 applications in cancer therapy, identify key challenges such as delivery methods and explore future directions for improving and expanding these technologies. Here, we address the various obstacles that may arise in clinical applications while showcasing the latest advancements and potential future uses of CRISPR-Cas9 in cancer therapy.

A biocompatible nanoformulation of curcumin analogue and curd exosomes targeting EphA2 signalling cascade in head and neck cancer

BackgroundMajor therapeutic developments have been made in the prevention of head and neck cancer (HNC), and crucial measures have been implemented for the survival of patients. The advent of cancer nano-theranostic as an effective approach targets cancer by allowing drug aggregation at the tumour site, its proper bioaccessibility, and tumour cell death. Curd exosomes are the cellular interactive nanovesicles, considered a convenient conveyance medium for cargoes still unexplored. Curcumin analogue alanine is primarily recognised for its superior radical scavenging activity and anti-mutagen properties compared with curcumin.MethodsThe current study focussed on the isolation and characterisation of curd exosomes, followed by their interaction with cancer cells to deliver their content conveniently. Herein, we developed a nanoformulation of curd exosomes loaded with curcumin alanine to determine its bioaccessibility and anti-proliferative effect compared with curcumin alanine free drug. In addition, the influence of curcumin alanine and its nanoformulation on cell morphology, nucleus structures, colony formation potential, and tumour cell death was observed. The expression of EphA2 and its associated molecules was determined using western blot and PCR to explore the mechanism at the cellular level.ResultsThe recent investigation revealed the encapsulation of curcumin analogue alanine in curd exosomes enhanced the bioaccessibility in contrast with curcumin alanine. Then, we focussed on the curcumin alanine effect on HNC cells to monitor morphological alterations, a reduction in cell multiplication, and triggering apoptosis. Particularly, we found considerable suppression of EphA2 influencing mitochondrial dynamics with the strengthening of mitochondrial fusion MFN1 and MFN2, whereas fission-associated protein DRP1 was down-regulated by the treatment of curcumin alanine nanoformulation. Furthermore, curcumin alanine nanoformulation activates the apoptotic marker caspase-7 and suppresses the anti-apoptotic marker Bcl-xL.ConclusionHence, these findings have drawn attention to curd exosomes loaded curcumin alanine nanoformulation impairing cell multiplication and mitochondrial fission, leading to apoptotic cell death, as one of the effective approaches for the treatment of HNC.Graphical

Microwave and ultrasound-assisted green protocols for 5-methylthiazole induced Betti bases: molecular docking, in-silico pharmacokinetics, and anticancer activity studies

ABSTRACT Herein, we describe an efficient one-pot three-component microwave and ultrasound-endorsed approaches for synthesizing distinct 5-methylthiazole induced Betti bases (5-methyl-thiazol-2-ylamino-aryl-benzylnapthols) employing silica sulfuric acid (SSA, silica-OSO3H) as an active heterogeneous acid catalyst. The title compounds produced in good yields (86–95%) from naphthalen-2-ol, 5-methylthiazol-2-amine, and assorted aryl aldehydes; and structurally characterized by spectral and elemental analyses. A comprehensive comparative study of conventional, ultrasonic, and microwave-irradiated synthetic routes has been achieved by optimizing various reaction parameters. These new protocols provide several advantages, including the use of an inexpensive, non-toxic, and reusable catalyst. Additionally, they benefit from mild reaction conditions, short reaction times, and simple workup and purification procedures, thereby increasing their practicality. Furthermore, the synthesized compounds were evaluated for their anticancer potency against A-549 (lung cancer) and A-498 (kidney cancer) cell lines, with scaffold IVa demonstrating excellent (GI50 < 10 µg/mL) inhibitory activity against A-549. Additionally, molecular docking was performed to investigate potential binding interactions between ligands and proteins. Scaffold IVa exhibited the best docking with cancerous target proteins 1M17 (−8.9 kcal/mol) and 1M14 (−7.2 kcal/mol), thereby supporting our bio-activity studies.

Dendrobine Suppresses Tumor Growth by Regulating the PD-1/PD-L1 Checkpoint Pathway in Lung Cancer

Background: Dendrobine is a bioactive alkaloid isolated from Dendrobium nobile. Studies have evaluated the anti-tumor effect of dendrobine in cancers, including lung cancer. However, the mechanism of dendrobine inhibiting tumors requires further study. Methods: Bioinformatics was performed to screen the potential targets of dendrobine. The in-tersection of dendrobine and lung cancer targets was performed for KEGG analysis. CCK-8 was used to detect cell viability after dendrobine treatment. A xenograft mouse model was es-tablished to explore the effect of dendrobine on lung cancer. The percentages of PD-L1+, CD4+, CD8+, CD11b+, CD25+FOXP3+ cells, the expression of Ki-67 and caspase-3, the ex-pression of pathway-related proteins, the levels of IL-2, IFN-γ, and TGF-β, and the changes of indicators of liver and renal function were measured. Results: Dendrobine regulated the PD1/PD-L1 checkpoint signaling pathway and affected the occurrence and development of lung cancer. Dendrobine decreased the cell viability of lung cancer. Dendrobine and anti-PD-L1 decreased tumor growth, increased caspase-3 expression, and reduced Ki-67 expression in tumor tissues. Dendrobine and anti-PD-L1 suppressed pro-tein expression of PD-L1, p-JAK1/JAK1, and p-JAK2/JAK2 in tumor tissues. Greatly, den-drobine and anti-PD-L1 decreased the percentages of PD-L1+, CD11b+, and CD25+FOXP3+ cells, increased the percentages of CD4+ and CD8+cells, and enhanced the levels of IL-2, IFN-γ, and TGF-β in tumor tissues. Dendrobine demonstrated no hepatorenal toxicity to the tumor mice. The combination of dendrobine and anti-PD-L1 greatly strengthened the effects of dendrobine on tumors. Conclusion: Dendrobine inhibited tumor immune escape by suppressing the PD-1/PD-L1 checkpoint pathway, thus restricting tumor growth of lung cancer. conclusion: Dendrobiine inhibited tumor immune escape by suppressing PD-1/PD-L1 checkpoint pathway, thus restricting tumor growth of lung cancer. other: N/A

LKB1 suppresses KSHV reactivation and promotes primary effusion lymphoma progression.

Viruses normally reprogram the host cell metabolic pathways as well as metabolic sensors to facilitate their persistence. The serine-threonine liver kinase B1 (LKB1) is a master upstream kinase of 5'-AMP-activated protein kinase (AMPK) that senses the energy status and therefore regulates the intracellular metabolic homeostasis. Previous studies showed that AMPK restricts Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication in endothelial cells during primary infection and promotes primary effusion lymphoma (PEL) cell survival. However, the role of LKB1 in KSHV lytic reactivation and KSHV-associated malignancies is unclear. In this study, we found that LKB1 is phosphorylated or activated in KSHV-positive PEL cells. Mechanistically, KSHV-encoded vCyclin mediated LKB1 activation in PEL cells, as vCyclin knockout ablated, while vCyclin overexpression enhanced LKB1 activation. Furthermore, knockdown of LKB1 inactivated AMPK and induced KSHV reactivation, as indicated by the increased expression of viral lytic genes and the increased virions in supernatants. Accordingly, AMPK inhibition by functional knockdown or a pharmacologic inhibitor, Compound C, promoted KSHV reactivation in PEL cells. Furthermore, inhibition of either LKB1 or AMPKα1 efficiently induced cell death by apoptosis of PEL cells both in vitro and in vivo. Together, these results identify LKB1 as a vulnerable target for PEL, which could be potentially exploited for treating other virus-associated diseases.IMPORTANCEKaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus associated with several human cancers, such as primary effusion lymphoma (PEL). Here, we showed that serine-threonine liver kinase B1 (LKB1), upstream of 5' AMP-activated protein kinase (AMPK), is activated by KSHV-encoded vCyclin and maintains KSHV latency in PEL cells. Inhibition of either LKB1 or AMPK enhances KSHV lytic replication from latency, which at least partially accounts for PEL cell death by apoptosis. Compound C, a potent AMPK inhibitor, induced KSHV reactivation and efficiently inhibited PEL progression in vivo. Thus, our work revealed that LKB1 is a potential therapeutic target for KSHV-associated cancers.

Evaluation of circulating plasma proteins in prostate cancer using mendelian randomization

BackgroundThe proteome is an important resource for exploring potential diagnostic and therapeutic targets for cancer. This study aimed to investigate the causal associations between plasma proteins and prostate cancer (PCa), and to explore the downstream phenotypes that plasma proteins may influence and potential upstream intervening factors.MethodsProteome-wide Mendelian randomization was used to investigate the causal effects of plasma proteins on PCa. Colocalization analysis examined the common causal variants between plasma proteins and PCa. Summary-statistics-based Mendelian Randomization (SMR) analyses identified associations between the expression of protein-coding genes and PCa. Phenome-wide association study was performed to explore the effect of target proteins on downstream phenotypes. Finally, a systematic Mendelian randomization analysis between lifestyle factors and plasma proteins was performed to assess upstream intervening factors for plasma proteins.ResultsThe findings revealed a positive genetic association between the predicted plasma levels of nine proteins and an elevated risk of PCa, while four proteins exhibited an inverse association with PCa risk. SMR analyses revealed ZG16B, PEX14 in blood and ZG16B, NAPG in prostate tissue were potential drug targets for PCa. The genetic association of PEX14 with PCa was further supported by colocalization analysis. Further Phenome-wide association study showed possible side effects of ZG16B, PEX14 and NAPG as drug targets. 10 plasma proteins (RBP7, TPST1, NFASC, LAYN, HDGF, SERPIMA5, DLL4, EFNA3, LIMA1, and CCL27) could be modulated by lifestyle-related factors.ConclusionThis study explores the genetic associations between plasma proteins and PCa, provides evidence that plasma proteins serve as potential drug targets and enhances the understanding of the molecular etiology, prevention and treatment of PCa.

Identifying new biomarkers and potential therapeutic targets for breast cancer through the integration of human plasma proteomics: a Mendelian randomization study and colocalization analysis.

The proteome is a crucial reservoir of targets for cancer treatment. While some targeted therapies have been developed, there are still significant challenges in early diagnosis and treatment, highlighting the need to identify new biomarkers and therapeutic targets for breast cancer. Therefore, we conducted a comprehensive proteome-wide Mendelian randomization (MR) study to identify novel biomarkers and potential therapeutic targets for breast cancer. Protein quantitative trait locus (pQTL) data were extracted from two published plasma proteome-wide association studies. Genetic variants associated with breast cancer were obtained from the Breast Cancer Association Consortium, which included 133,384 cases and 113,789 controls, and the Finnish cohort study, comprising 18,786 cases and 182,927 controls. We employed summary-based MR and colocalization methods to identify potential drug targets for breast cancer, which were subsequently validated using a two-sample MR approach. Finally, a protein-protein interaction (PPI) network was constructed to detect interactions between the identified proteins and existing cancer drug targets. Gene-predicted levels of ten proteins were associated with breast cancer risk. Decreased levels of CASP8, DDX58, CPNE1, ULK3, PARK7, and BTN2A1, as well as increased levels of TNFRSF9, TNXB, DNPH1, and TLR1, were linked to an elevated risk of breast cancer. Among these, CASP8 and DDX58 were supported by tier-one evidence, while CPNE1, ULK3, PARK7, and TNFRSF9 received tier-two evidence support. The remaining proteins, TNXB, BTN2A1, DNPH1, and TLR1, were supported by tier-three evidence. CASP8, DDX58, CPNE1, ULK3, PARK7, and TNFRSF9 have already been identified as targets in drug development and potential therapeutic targets for breast cancer treatment. Additionally, ULK3 showed promise as a prognostic biomarker for breast cancer. The present study identified several novel potential drug targets and biomarkers for breast cancer, providing new insights into its diagnosis and treatment. The integration of PPI and druggability evaluations enhances the prioritization of these therapeutic targets, paving the way for future drug development efforts.

The up-regulation of SYNCRIP promotes the proliferation and tumorigenesis via DNMT3A/p16 in colorectal cancer

Heterogeneous nuclear ribonucleoproteins (hnRNPs), a group of proteins that control gene expression, have been implicated in many post-transcriptional processes. SYNCRIP (also known as hnRNP Q), a subtype of hnRNPs, has been reported to be involved in mRNA splicing and translation. In addition, the deregulation of SYNCRIP was found in colorectal cancer (CRC). However, the role of SYNCRIP in regulating CRC growth remains largely unknown. Here, we found that SYNCRIP was highly expressed in colorectal cancer by analyzing TCGA and GEPIA database. Furthermore, we confirmed the expression of SYNCRIP expression in CRC tumor and CRC cell lines. Functionally, SYNCRIP depletion using shRNA in CRC cell lines (SW480 and HCT 116) resulted in increased caspase3/7 activity and decreased cell proliferation, as well as migration. Meanwhile, overexpression of SYNCRIP showed opposite results. Mechanistically, SYNCRIP regulated the expression of DNA methyltransferases (DNMT) 3A, but not DNMT1 or DNMT3B, which affected the expression of tumor suppressor, p16. More importantly, our in vivo experiments showed that SYNCRIP depletion significantly inhibited colorectal tumor growth. Taken all together, our results suggest SYNCRIP as a potent therapeutic target in colorectal cancer.

Helicobacter pylori induces GBA1 demethylation to inhibit ferroptosis in gastric cancer.

This research investigates potential therapeutic targets for gastric cancer, focusing on ferroptosis-related genes. Gastric cancer is known for its lower survival rates, necessitating new treatment strategies. This study employed Mendelian randomization to identify ferroptosis-related genes and methylation sites in gastric cancer, examining correlations between Helicobacter pylori infection, GBA1 gene expression, and promoter methylation with single-cell datasets and the TCGA-STAD database. We used Helicobacter pylori-infected gastric cancer cell models and used next-generation sequencing to monitor methylation changes pre- and post-infection. GBA1 expression levels were assessed via qRT-PCR and Western blot both before and after infection. The effect of Helicobacter pylori on GC cell proliferation was analyzed using CCK-8 and EdU assays after knocking down the GBA1 gene. The association between Helicobacter pylori infection and ferroptosis, including its reversibility after GBA1 knockdown, was evaluated using FerrOrange, GSH, MDA, and C11-BODIPY assays. Mass spectrometry measured the impact of Helicobacter pylori and GBA1 knockdown on lipid metabolism. An in vivo subcutaneous tumor-bearing model was also established to confirm these findings. Mendelian randomization analysis revealed that high GBA1 expression and reduced methylation levels of its promoter are risk factors for gastric cancer. Single-cell sequencing and TCGA-STAD datasets indicated a positive correlation between Helicobacter pylori infection and GBA1 expression, with a concurrent negative correlation between GBA1 promoter methylation and GBA1 expression. In gastric cancer cell lines, Helicobacter pylori infection was observed to enhance GBA1 expression and decrease methylation levels at its promoter. Additionally, Helicobacter pylori promoted GC cell proliferation, an effect mitigated by knocking down GBA1. Infection also reduced lipid peroxidation, increased glutathione levels, and impeded ferroptosis in GC cells; however, these effects were reversed following GBA1 knockdown. Changes in sphingolipid metabolism induced by I were detected in GC cell lines. In vivo experiments using a subcutaneous tumor-bearing model demonstrated that Helicobacter pylori infection fosters tumorigenesis in GC cells. Our study demonstrates that Helicobacter pylori infection triggers demethylation and upregulation of GBA1, subsequently inhibiting ferroptosis in gastric cancer cells. These findings suggest that targeting the GBA1 pathway may offer a novel therapeutic approach for managing gastric cancer.