Types Of Human Cancer Research Articles

Abstract 506: TRIP13 is a promising therapeutic target for bladder cancer

Abstract Bladder cancer (BCa) is the second most common genitourinary cancer. High recurrence rate, progression to MIBC and poor prognosis in metastatic disease are major challenges for this disease management. Therapeutic options for advanced stage BCa are very limited, hence developing agents to treat this disease progression are highly needed. Thyroid receptor-interacting protein 13 (TRIP13), a member of the AAA-ATPase family, regulates various cellular processes such as DNA repair and spindle assembly. TCGA data analysis showed significant overexpression of TRIP13 that correlates with disease stage and mortality. Recent studies have shown that TRIP13 amplification occurs in several types of human cancers, including BCa, and it regulates cell proliferation, tumor growth, and drug resistance. However, the role of TRIP13 in BCa and its potential as a therapeutic target remain elusive. Therefore, in the present study we performed a preclinical investigation of the TRIP13 role in BCa progression, underlying molecular mechanisms, and develop promising therapeutics against BCa. Initially we profiled TRIP13 expression in 10 different bladder cancer cell lines from a panel of human and rodent origin and found elevated protein expression in multiple BCa cell lines. TRIP13 levels were also significantly elevated in the BBN induced rat- and SV40T driven mouse- bladder tumor tissues compared to normal bladder tissues. Pharmacological inhibition of TRIP13 with a potent drug DCZ0415 significantly suppressed cell proliferation (IC50 ~7μM) in J82, NBT-II and MB49 cell lines and induced cell death. DCZ0415 treatment led to cell cycle arrest at G1 phase (P<0.001) in BCa cells. In mechanistic investigations on its effect on cell cycle progression by DCZ0415 treatment decreased the expression of CDK4, CDK6, Cyclin D1, and PCNA protein expression. TRIP13 inhibition also suppressed the migration and invasion potential of BCa cells. Annexin V and γ-H2AX staining suggested that DCZ0415 induced apoptosis in BCa cells and increased DNA damage. These findings were also complemented by an increase in cleaved caspase-3 and PARP proteins. We also observed modulation of cGAS-STING signaling pathway in BCa cells with DCZ0415 treatment, indicating potential for its combination with cGAS-STING stimulators. Importantly, we found that TRIP13 inhibition with DCZ0415 significantly suppressed the growth of 3D BCa models as well BBN-induced rat BCa tumoroids and spheroids. Overall, these results suggest that TRIP13 could be a potential therapeutic target for prevention of bladder cancer and warrants further validation in in vivo models (Funding supported by P30CA225520 and ACS-IRG grant). Citation Format: Surya Pratap Singh, Krishnendu Goswami, Adam S. Asch, Chinthalapally V. Rao, Venkateshwar Madka. TRIP13 is a promising therapeutic target for bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 506.

Abstract 4506: Discovery of potent, highly selective and orally efficacious SMARCA2 degraders

Abstract In human non-small cell lung cancer, melanoma and other types of human cancers, the mammalian SWItch/Sucrose Non-Fermentable (SWI/SNF) helicase SMARCA4 is frequently mutated, which leads to inactivation of its functions. SMARCA2, a close homologous protein of SMARCA4, is an attractive synthetic lethality target for human cancers with SMARCA4 deficiency. Herein, we report the discovery and biological evaluation of potent, highly selective, orally efficacious SMARCA2 PROTAC degraders exemplified by UM-SMD-8801. UM-SMD-8801 has DC50 <10 nM and Dmax >90% against SMARCA2 and >1,000-fold degradation selectivity over SMARCA4. Consistently, UM-SMD-8801 potently inhibits cell growth in SMARCA4 mutated cancer cell lines with low nanomolar IC50 values and shows >100-fold weaker activity in SMARCA4 wild-type cancer cell lines. UM-SMD-8801 has a good overall pharmacokinetic profile and an excellent oral bioavailability in mice. Oral administration of UM-SMD-8801 is highly effective in reducing SMARCA2 protein by >90% in tumor tissues in mice, while having minimal effect on SMARCA4 protein. UM-SMD-8801 represents a very promising SMARCA2 degrader for extensive evaluation as a potential new therapy for the treatment of SMARCA4-deficient human cancers. Citation Format: Lingying Leng, Lin Yang, Wenbin Tu, Rohan Rej, Srinivasa Rao Allu, Liyue Huang, Wei Jiang, Yu Wang, Jeanne Stuckey, Farzad R Sarkari, Meilin Wang, Lu Wang, Bo Wen, Duxin Sun, Shaomeng Wang. Discovery of potent, highly selective and orally efficacious SMARCA2 degraders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4506.

Abstract 4338: A pan-cancer single-cell analysis of intratumoral copy number diversity and evolution

Abstract Aneuploidy is a hallmark of human cancers and studies have shown that cancer patients harbor many differences in their copy number aberrations (CNAs) reflecting interpatient heterogeneity (IPH). While IPH has been studied extensively, the intratumoral heterogeneity (ITH) of CNAs within a tumor remains understudied. Here, we conducted a pan-cancer analysis of 94 human tumor samples at single cell genomic resolution, representing seven major cancer types: bladder, breast, colon, glioblastoma, kidney, lung, and ovary. In total, 62,646 aneuploid cells were analyzed by single cell copy number profiling and bulk exome sequencing was performed. In most cancer types, increased subclonal diversity was associated with higher CNA burden, whole genome doubling (WGD) events, and TP53 mutations. In all tumors, our data show that cancer cells share a clonal set of truncal CNAs or mutations, suggesting these tumors evolved from a single ancestral cell. In 18/94 cases we identified subclonal WGD events, which resulted in a higher number of copy number losses after tetraploidization. Macro-spatial sampling showed that increased clonal diversity also correlated with increased spatial geographical diversity. We found that many cancers evolved CNAs in short punctuated bursts of evolution, and that this was not restricted to a specific cancer type. Collectively, these data show that copy number ITH is universally associated with molecular features across these human cancer types. Citation Format: Hanghui Ye, Thomas McDonald, Emi Sei, Darlan Conterno Minussi, Min Hu, Chenling Tang, Junke Wang, Kaile Wang, Anna Casasent, Hui Chen, Franziska Michor, Nicholas Navin. A pan-cancer single-cell analysis of intratumoral copy number diversity and evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4338.

Abstract 7115: Mutational signatures in PDXs for improved understanding of drug response and companion biomarkers identification

Abstract Genomic DNA editing is a continuous process that occurs during the entire cell life span. The type and frequency of these modifications can be related to the physiological or pathological activity of intrinsic mechanisms such as DNA surveillance and repair or to extrinsic events that may induce an alteration of DNA sequence by exposure to agents that directly or indirectly induce accumulations of DNA alterations. In the past few years, large-scale analyses have revealed mutational signatures across human cancer types. These signatures can be used as markers of defective internal processes, such as DNA repair deficiency, or external exposures, such as carcinogens, like tobacco, or genotoxic therapies such as radiation and chemotherapy. Our TumorGraft platform, a collection of 1500 patient-derived xenograft generated from more than 50 different types of cancer, is one of the most comprehensive preclinical oncology platforms worldwide, and aims to recapitulate the variety of the patient population and tumor biology complexity. This platform is currently used to evaluate the efficacy of new drugs, and all our models are very well characterized at the molecular level, including whole transcriptome, proteomics and phospho-proteomics, quantification, and genomic variation calls. This allows accurate selection of models with the molecular characteristics of the target patient population, as well as to identify biomarkers predictive of treatment efficacy. This could eventually lead to the development of companion biomarkers in the clinical setting to improve the identification of patients that will benefit from the treatment and those that should be spared. To maximize the chances of identifying relevant molecular traits associated with tumor response, we have been utilizing the Pharmaco-Pheno-Multiomic (PPMO) integration workflow, a machine learning approach which combines phenotypic and therapeutic response profiles with multiple omics datatypes to generate complex biomarker profiles. To provide additional insights on the molecular characteristics of our tumors, we decided to perform the mutational signatures profiling of our models by using whole exome sequencing data. The results obtained were crossed with patient’s clinical history and showed good correlation between the mutational signatures identified and the treatments received by the patient, in particular for exposure to platinum salts. The addition of PDXs mutational signatures strongly improves our knowledge on these models and confers an important parameter for model selection. Moreover, the integration of mutational signature profiles in the PPMO workflow would make a significant contribution for companion biomarkers identification. Citation Format: Haia Khoury, Stefano Cairo, Mara Gilardi, Michael Ritchie, Gilad Silberberg. Mutational signatures in PDXs for improved understanding of drug response and companion biomarkers identification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7115.

Abstract 4590: Antitumor effects of histone deacetylase inhibitors on breast cancer cell viability and mammosphere formation

Abstract Histone deacetylases (HDACs) are overexpressed in various types of primary human cancer and have become attractive targets for cancer therapy. This study aimed to evaluate the cytotoxic properties of three HDAC inhibitors (suberoylanilide hydroxamic acid (SAHA, or Vorinostat), Valproic Acid (VPA) and CAY10603) and compare them to Paclitaxel (PTX), a chemotherapy agent used to treat Triple Negative Breast Cancers (TNBCs). In the present study, drug response in the MDA-MB-231, MDA-MB-468, and MCF-10A cell lines was evaluated by cell viability assays. Apoptosis and cell cycle distribution were analyzed by flow cytometry. Mammospheres generated from MDA-MB-231 and MDA-MB-468 breast cancer cells were also subjected to drug treatment; their response was assessed under both normoxic and hypoxic conditions. We found that SAHA and CAY10603 inhibited breast cancer cell viability without significantly affecting MCF-10A cells. SAHA, CAY10603, and VPA all arrested a significant percentage of MDA-MB-231 cells at G2/M phase after 24h compared to controls. TNBC cells experienced an increase in both early and late apoptosis following treatment with the most effective concentrations of SAHA, CAY10603, and VPA (1.8µM, 2µM, and 0.4mM, respectively). SAHA proved to be the most effective drug for induction of apoptosis compared to the control, followed by CAY10603 (8.26% and 6%, 3.67%). In both TNBCs and mammospheres under hypoxic conditions, SAHA and CAY10603 down regulated HIF-1α expression significantly, but PTX did not. In contrast, VPA and PTX down regulated CTNNB1 gene expression. This study indicates that epi-drugs exert an anti-tumor effect on TNBCs, suggesting a potential role for HDAC inhibitors as novel therapeutics for breast cancer patients. Citation Format: Golnaz Asaadi Tehrani, Becca Kubick, Meenal Datta. Antitumor effects of histone deacetylase inhibitors on breast cancer cell viability and mammosphere formation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4590.

Abstract 6611: Unbiased functional genetic screens reveal essential RNA modifications in human cancer and drug resistance

Abstract RNA modification pathways are mis-regulated in multiple types of human cancer. To comprehensively identify cancer-relevant RNA modifications and their regulators, we screened all 150 annotated human RNA modifying proteins across 18 different normal and cancer cell lines using a CRISPR-based genetic knockout system. Fifty RNA modifying proteins were essential for survival of at least one cell type. A third of these essential genes were amplified in 38 different human primary cancer types and potentially drive cancer growth. Unexpectedly, the number of essential genes per cell line varied considerably, and this variation was not due to tissue of origin. Instead, we found that cancer cell-specific mitochondrial metabolic plasticity was responsible for the unique requirement of certain RNA modifications. For example, leukemia cells with high intrinsic drug tolerance required mitochondrial flexibility to survive treatment with the anti-leukemic drugs cytarabine and venetoclax. Synthetic lethality screens revealed that drug-resistance is abolished by deleting the mitochondrial methyltransferase TRMT5, which is responsible for the formation of N1-methylguanosine (m1G) in the tRNA anticodon loop. In summary, our study identifies cancer-relevant RNA modifying enzymes, and reveals a novel promising drug target for therapy-resistant acute myeloid leukemia. Citation Format: Cornelius Pauli, Michael Kienhöfer, Carsten Müller-Tidow, Michaela Frye. Unbiased functional genetic screens reveal essential RNA modifications in human cancer and drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6611.

Abstract 4660: Characterization of a nicotinamide-based kinase inhibitor HSN748 for inhibition of RET-driven tumors

Abstract Rearranged during transfection (RET) is a protein tyrosine kinase that is aberrantly activated by gene fusions or mutations in many types of human cancer including thyroid cancer and non-small cell lung cancer (NSCLC). Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are FDA approved RET-selective tyrosine kinase inhibitors (TKIs) being used to treat RET-altered cancer. However, these tumors develop selpercatinib/pralsetinib-resistance via acquisition of RET(G810C/R/S) mutations located at the solvent front of the ATP binding pocket. The overall goal of our research is to discover next-generation of RET kinase inhibitors to inhibit selpercatinib/pralsetinib-resistant RET solvent-front mutants. In this study, we characterized one of the nicotinamide-based RET kinase inhibitor, HSN748, in vitro and in vivo. HSN748 was able to inhibit selpercatinib/pralsetinib-resistant RET(G810C/R) solvent-front mutations. In BaF3/KIF5B-RET(G810C) tumor xenograft experiment, HSN748 treatment resulted in tumor regression. In immune competent transgenic mice, KIF5B-RET-induced lung tumors regressed after HSN748 treatment by oral gavage for one month (10-15 mg/kg, QD) without affecting body weight. These results identify HSN748 as an orally available RET inhibitor capable of inhibiting KIF5B-RET and its solvent-front mutant-driven tumors. Citation Format: Ujjwol Khatri, Neetu Dayal, Tao Shen, Xueqing Hu, Herman Sintim, Jie Wu. Characterization of a nicotinamide-based kinase inhibitor HSN748 for inhibition of RET-driven tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4660.

Abstract 4183: Utility of the highly immunodeficient SRG rat for combined drug efficacy, pharmacokinetics, and toxicology studies in tumor-bearing animals

Abstract Immunodeficient rodents are vital pre-clinical disease models. Historically, immunodeficient mice have been standard for hosting human cell and tissue xenografts, enabling cancer drug efficacy and tolerability testing. However, an immunodeficient rat that supports a variety of human cancer types provides a larger model for easier surgical manipulation and serial blood and tumor tissue sampling, allowing for efficacy, pharmacokinetics, and toxicology testing in the same animal. We created a Sprague Dawley Rag2 -/-, Il2rg -/- rat (SRG Rat®; SRG) that is highly supportive of human cell and tissue engraftment. The SRG rat lacks B, T, and NK cells and is more immunodeficient than the Nude rat. Here we show comparative pathology between the SRG rat and its parental strain, the CRL Sprague Dawley (CD). We also present data from an efficacy study in tumor bearing SRG rats, demonstrating that serial blood draws and tumor biopsies can be performed in tumor bearing animals to assess drug pharmacokinetics and pharmacodynamics within a single study. First, we assessed 10 SRG (5/sex) and 10 CD (5/sex) at 8-10 weeks of age. Body weight, hematology, and clinical chemistry parameters were measured. Microscopic examinations were performed on routine H&E slide preparations. Male and female SRG displayed lower mean body weight when compared to sex- and age-matched CD. Compared to CD, SRG had reduced lymphoid tissue and circulating monocytes, and highly reduced circulating lymphocytes, neutrophils, eosinophils, and basophils; expected phenotypes for this severely immunodeficient rat. Thymus was not present in SRG rats, spleens were grossly smaller, and bone marrow cellularity was decreased compared to CD. Microscopically, mandibular lymph nodes and lymphoid tissue in spleen, lung, and intestine were not observed in SRG rats, consistent with the 92% decrease in circulating lymphocytes. To demonstrate the utility of the SRG for tumor inhibition, pharmacokinetics, and pharmacodynamics, we inoculated rats with human VCaP prostate cancer cell-derived tumors, then treated these animals and collected serial blood samples and tumor biopsies to assess tumor biomarkers. Treatment led to decreased PSA and AR, two key proteins expressed in prostate cancer, correlating to decreased tumor growth. These data demonstrate that the SRG rat is suitable for toxicology studies and has comparable pathology to the CD rat, except for reduced lymphoid tissue and WBCs, which are expected phenotypes. In addition, the SRG rat supports the growth of human cancer tissue for treatment studies. The large size of the SRG rat and comparative pathology to the CD rat support its value as an immunodeficient model for assessing toxicity during efficacy testing for de-risking safety concerns in the presence of the human target tissue. Citation Format: Diane Begemann, Cynthia Dunn, Darrell Robertson, Lauren Keach, Emily Baldwin, R. Grace Walton, Alex Van Engelenburg, Jessica Durrant, Laura Healy, Koh Meng Aw Yong, Michael J. Schlosser, Fallon K. Noto. Utility of the highly immunodeficient SRG rat for combined drug efficacy, pharmacokinetics, and toxicology studies in tumor-bearing animals [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4183.

Abstract 2764: Ubiquitin-specific peptidase 22 controls integrin-dependent cancer cell stemness & metastasis

Abstract Integrins play critical roles in connecting the extracellular matrix and actin skeleton for cell adhesion, migration, signal transduction, and gene transcription. While the upregulation of integrins is thought to promote cancer stemness and metastasis, the mechanisms underlying their upregulation in cancer stem cells (CSCs) remain poorly understood. Herein, we show that the death from cancer signature gene, USP22, is essential in maintaining breast cancer cell stemness by promoting the transcription of a group of integrin family members, in particular, integrin β1 (ITGB1). Both genetic and pharmacological inhibition of USP22 largely impaired breast cancer stem cell self-renewal and prevented their metastasis. Reconstitution of Integrin β1 partially rescued USP22-null breast cancer stemness and their metastasis. At the molecular level, USP22 functions as a bona fide deubiquitinase to protect the proteasomal degradation of the forkhead box M1 (FoxM1), a transcription factor for tumoral ITGB1 gene transcription. Importantly, unbiased analysis of the TCGA database revealed a strong positive correlation between USP22 and ITGB1 in more than 90% of human cancer types, implying that USP22 functions as a key factor in maintaining stemness across a broad spectrum of human cancer types possibly through regulating ITGB1. To support this notion, immunohistochemistry staining detected a positive correlation among USP22, FoxM1 and integrin β1 in human breast cancers. Collectively, our study identifies the USP22-FoxM1-integrin β1 signaling axis as critical for cancer stemness and offers a potential target for antitumor therapy. Citation Format: Qiong Gao, Kun Liu, Yuzhi Jia, Juncheng Wei, Shuvam Mohan Chaudhuri, Shengnan Wang, Amy Tang, Nikita Lavanya Mani, Radhika Iyer, Yang Cheng, Beixue Gao, Weiyuan Lu, Zhaolin Sun, Huiping Liu, Deyu Fang. Ubiquitin-specific peptidase 22 controls integrin-dependent cancer cell stemness & metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2764.

Discovery of CBPD-268 as an Exceptionally Potent and Orally Efficacious CBP/p300 PROTAC Degrader Capable of Achieving Tumor Regression.

CBP/p300 proteins are key epigenetic regulators and promising targets for the treatment of castration-resistant prostate cancer and other types of human cancers. Herein, we report the discovery and characterization of CBPD-268 as an exceptionally potent, effective, and orally efficacious PROTAC degrader of CBP/p300 proteins. CBPD-268 induces CBP/p300 degradation in three androgen receptor-positive prostate cancer cell lines, with DC50 ≤ 0.03 nM and Dmax > 95%, leading to potent cell growth inhibition. It has an excellent oral bioavailability in mice and rats. Oral administration of CBPD-268 at 0.3-3 mg/kg resulted in profound and persistent CBP/p300 depletion in tumor tissues and achieved strong antitumor activity in the VCaP and 22Rv1 xenograft tumor models in mice, including tumor regression in the VCaP tumor model. CBPD-268 was well tolerated in mice and rats and displayed a therapeutic index of >10. Taking these results together, CBPD-268 is a highly promising CBP/p300 degrader as a potential new cancer therapy.

Remarkable response to capmatinib in a patient with intrahepatic cholangiocarcinoma harboring TFG-MET fusion.

Dysregulation of mesenchymal-epithelial transition factor (MET) gene due to amplification, mutation, and fusion has been reported in various types of human cancers. Recently, the efficacy of small-molecule tyrosine kinase inhibitors (TKIs) targeting MET has been demonstrated in a wide range of MET-dysregulated tumors. The majority of biliary tract cancers including intrahepatic cholangiocarcinoma (iCCA) are diagnosed at an advanced stage, and the utility of conventional chemotherapy is limited. Here, we present a case of metastatic iCCA harboring TFG-MET gene fusion, which demonstrated a remarkable response to treatment with capmatinib, a selective MET inhibitor. The patient was a 46-year-old man diagnosed with iCCA with hepatic, intraabdominal lymph nodes, and peritoneal metastases. Comprehensive genomic profiling (CGP) revealed TFG-MET gene fusion in his tumor. After becoming refractory to standard chemotherapy, he received capmatinib, which resulted in a marked shrinkage of the liver masses and lymph node metastases, as well as a drastic decrease in serum CA19-9 level. Our case reinforces the importance of CGP in exploring targeted therapy and supports the potential role of capmatinib in the treatment of tumors harboring MET fusions.

Identification of gene variation feature for targeted therapy of non-small cell lung cancer through combined method of DNA and RNA sequencing

Next generation sequencing (NGS) is typically used to reveal tumor gene variation feature for targeted therapy of various types of human cancers, including non-small cell lung cancer (NSCLC). Here, we report the role and potential applicable value of combining DNA and RNA sequencing in gene variation detection in NSCLC. 386 NSCLC patients with stage II-IV were enrolled and detected using NGS sequencing of DNA and RNA panels that covered all well-documented target driver genes from the Chinese Society of Clinical Oncology (CSCO). The rate of epidermal growth factor receptor (EGFR) single nucleotide variation (SNV)/indel, mesenchymal-epithelial transition factor (MET) copy number variation (CNV) and anaplastic lymphoma kinase (ALK) fusion were 52.1%, 4.1% and 6.0% in the NSCLC cohort. The landscapes of SNV/indel, CNV and gene fusion in the cohort were depicted as well. Meanwhile, we assessed detection efficacy of DNA and RNA sequencing in gene fusion. Detected number and types of gene fusion using the RNA sequencing were better than those using the DNA sequencing. Gene fusion with intergenic region was only detected by DNA sequencing and MET exon 14 skipping (METΔex14) was more easily identified by RNA sequencing. Finally, we investigated clinical correlations of SNV/indel/CNV/fusion with clinicopathologic features in the NSCLC cohort. Taken together, RNA sequencing significantly complements deficiency of DNA sequencing for gene fusion, which cooperatively presents comprehensive and reliable gene variation features and facilitate the identification of potential drug targets for NSCLC patients.

CUL4A Ubiquitin Ligase Is an Independent Predictor of Overall Survival in Pancreatic Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with dismal prognosis. Genomic instability due to defects in cell-cycle regulation/mitosis or deficient DNA-damage repair is a major driver of PDAC progression with clinical relevance. Deregulation of licensing of DNA replication leads to DNA damage and genomic instability, predisposing cells to malignant transformation. While overexpression of DNA replication-licensing factors has been reported in several human cancer types, their role in PDAC remains largely unknown. We aimed here to examine the expression and prognostic significance of the DNA replication-licensing factors chromatin licensing and DNA replication factor 1 (CDT1), cell-division cycle 6 (CDC6), minichromosome maintenance complex component 7 (MCM7) and also of the ubiquitin ligase regulator of CDT1, cullin 4A (CUL4A), in PDAC. Expression levels of CUL4, CDT1, CDC6 and MCM7 were evaluated by immunohistochemistry in 76 formalin-fixed paraffin-embedded specimens of PDAC patients in relation to DNA-damage response marker H2AX, clinicopathological parameters and survival. We also conducted bioinformatics analysis of data from online available databases to corroborate our findings. CUL4A and DNA replication-licensing factors were overexpressed in patients with PDAC and expression of CDT1 positively correlated with H2AX. Expression of CUL4A and CDT1 positively correlated with lymph node metastasis. Importantly, elevated CUL4A expression was associated with reduced overall survival and was an independent indicator of poor prognosis on multivariate analysis. Our findings implicate CUL4A, CDT1, CDC6 and MCM7 in PDAC progression and identify CUL4A as an independent prognostic factor for this disease.

A comprehensive evaluation of the therapeutic potential of silibinin: a ray of hope in cancer treatment.

Natural compounds hold promise in the search for cancer therapies due to their unique chemical structures and combinations that may effectively combat cancer while minimizing toxicity and side effects compared to conventional treatments. Silibinin, a natural lignan, has been found to possess strong anti-cancer activity against several types of human cancers based on emerging research. This study aims to provide an overview of the therapeutic potential of silibinin in the treatment and prevention of cancers. A comprehensive search was conducted using various internet databases such as PubMed, Google Scholar, and ScienceDirect to identify relevant research papers. Silibinin has been shown to exhibit anticancer activity against several types of cancers, including liver, lungs, breast, prostate, colorectal, skin, and bladder cancers. Its multifaceted mechanisms of action contribute to its therapeutic effects. Silibinin exerts antioxidant, anti-inflammatory, anti-proliferative, pro-apoptotic, anti-metastatic, and anti-angiogenic activities, making it a promising candidate for cancer therapy. One of the key mechanisms underlying the anticancer effects of silibinin is its ability to modulate multiple signaling pathways involved in cancer development and progression. It can inhibit the activation of various oncogenic pathways, including PI3K/Akt, NF-κB, Wnt/β-catenin, and MAPK pathways, thereby suppressing cancer cell proliferation, inducing cell cycle arrest, and promoting apoptosis. Silibinin possesses great potential as an effective treatment agent for cancer. The multifaceted mechanisms of action, favorable safety profile, and potential synergistic effects of silibinin with conventional therapies make it an attractive candidate for further investigation and development as a cancer treatment. However, more extensive clinical studies are necessary to fully establish the efficacy, optimal dosage, and long-term effects of silibinin in cancer treatment.

Knockdown of Antisense Noncoding Mitochondrial RNA Reduces Tumorigenicity of Patient-Derived Clear Cell Renal Carcinoma Cells in an Orthotopic Xenograft Mouse Model.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent form of renal cancer and its treatment is hindered by a resistance to targeted therapies, immunotherapies and combinations of both. We have reported that the knockdown of the antisense noncoding mitochondrial RNAs (ASncmtRNAs) with chemically modified antisense oligonucleotides induces proliferative arrest and apoptotic death in tumor cells from many human and mouse cancer types. These studies have been mostly performed in vitro and in vivo on commercially available cancer cell lines and have shown that in mouse models tumor growth is stunted by the treatment. The present work was performed on cells derived from primary and metastatic ccRCC tumors. We established primary cultures from primary and metastatic ccRCC tumors, which were subjected to knockdown of ASncmtRNAs in vitro and in vivo in an orthotopic xenograft model in NOD/SCID mice. We found that these primary ccRCC cells are affected in the same way as tumor cell lines and in the orthotopic model tumor growth was significantly reduced by the treatment. This study on patient-derived ccRCC tumor cells represents a model closer to actual patient ccRCC tumors and shows that knockdown of ASncmtRNAs poses a potential treatment option for these patients.

P90RSK pathway inhibition synergizes with cisplatin in TMEM16A overexpressing head and neck cancer

Head and neck squamous cell carcinoma (HNSCC) constitutes one of the most common types of human cancers and often metastasizes to lymph nodes. Platinum-based chemotherapeutic drugs are commonly used for treatment of a wide range of cancers, including HNSCC. Its mode of action relies on its ability to impede DNA repair mechanisms, inducing apoptosis in cancer cells. However, due to acquired resistance and toxic side-effects, researchers have been focusing on developing novel combinational therapeutic strategies to overcome cisplatin resistance. In the current study, we identified p90RSK, an ERK1/2 downstream target, as a key mediator and a targetable signaling node against cisplatin resistance. Our results strongly support the role of p90RSK in cisplatin resistance and identify the combination of p90RSK inhibitor, BI-D1870, with cisplatin as a novel therapeutic strategy to overcome cisplatin resistance. In addition, we have identified TMEM16A expression as a potential upstream regulator of p90RSK through the ERK pathway and a biomarker of response to p90RSK targeted therapy in the context of cisplatin resistance.

Guanylate binding protein 4 shapes an inflamed tumor microenvironment and identifies immuno-hot tumors

PurposeGuanylate binding protein 4 (GBP4) is induced by interferons and various cytokines and has been recognized as functionally relevant in numerous types of human cancers. While the role of GBP4 in cancer has been preliminarily summarized, its correlation with antitumor immunity remains unclear and requires further research.MethodsFirst, a comprehensive pan-cancer analysis was conducted, focusing on GBP4’s expression patterns and immunological functions. Subsequently, we explored the correlations between GBP4 and immunological features within the tumor microenvironment (TME) in non-small cell lung cancer (NSCLC) patients. Additionally, we examined the relationships between GBP4 and emerging immunobiomarkers, such as N6-methyladenosine (m6A) genes. Moreover, we assessed the utility of GBP4 in predicting the clinical characteristics and treatment responses of patients with NSCLC.ResultsPan-cancer analysis revealed that GBP4 plays a positive role in most cancer types via the majority of immunomodulators. Furthermore, GBP4 demonstrated positive associations with immunomodulatory factors, tumor-infiltrating immune cells (TIICs) and inhibitory immune checkpoints. Remarkably, the expression of GBP4 was found to be a predictor of significantly enhanced responsiveness to anti-EGFR therapy and immunotherapy.ConclusionsGBP4 expression profiles offer a promising avenue for identifying highly immunogenic tumors across a wide spectrum of cancers. GBP4 holds potential as a robust pan-cancer biomarker for assessing the immunological characteristics of tumors, with particular relevance to its ability to predict therapeutic responses, notably in the context of anti-EGFR therapy and immunotherapy.

MiRNome targeting NF-κB signaling orchestrates macrophage-triggered cancer metastasis and recurrence

Whether and how tumor intrinsic signature determines macrophage-elicited metastasis remain elusive. Here, we show, in detailed studies of data regarding 7,477 patients of 20 types of human cancers, that only 13.8%± 2.6%/27.9%± 3.03% of patients with high macrophage infiltration index exhibit early recurrence/vascular invasion. In parallel, although macrophages enhance the motility of various hepatoma cells, their enhancement intensity is significantly heterogeneous. We identify that the expression of malignant Dicer, a ribonuclease that cleaves miRNA precursors into mature miRNAs, determines macrophage-elicited metastasis. Mechanistically, the downregulation of Dicer in cancer cells leads to defects in miRNome targeting NF-κB signaling, which in turn enhances the ability of cancer cells to respond to macrophage-related inflammatory signals and ultimately promotes metastasis. Importantly, transporting miR-26b-5p, the most potential miRNA targeting NF-κB signaling in hepatocellular carcinoma, can effectively reverse macrophage-elicited metastasis of hepatoma invivo. Our results provide insights into the crosstalk between Dicer-elicited miRNome and cancer immune microenvironments and suggest that strategies to remodel malignant cell miRNome may overcome pro-tumorigenic activities of inflammatory cells.

Zinc Finger and BTB Domain-Containing 20: A Newly Emerging Player in Pathogenesis and Development of Human Cancers.

Zinc finger and BTB domain-containing 20 (ZBTB20), which was initially identified in human dendritic cells, belongs to a family of transcription factors (TFs) with an N-terminal BTB domain and one or more C-terminal DNA-binding zinc finger domains. Under physiological conditions, ZBTB20 acts as a transcriptional repressor in cellular development and differentiation, metabolism, and innate immunity. Interestingly, multiple lines of evidence from mice and human systems have revealed the importance of ZBTB20 in the pathogenesis and development of cancers. ZBTB20 is not only a hotspot of genetic variation or fusion in many types of human cancers, but also a key TF or intermediator involving in the dysregulation of cancer cells. Given the diverse functions of ZBTB20 in both health and disease, we herein summarize the structure and physiological roles of ZBTB20, with an emphasis on the latest findings on tumorigenesis and cancer progression.

Establishing a carcinoembryonic antigen-associated competitive endogenous RNA network and forecasting an important regulatory axis in colon adenocarcinoma patients.

Colorectal cancer is one of the top five malignant tumors in the world in terms of morbidity and mortality. Numerous long non-coding RNAs (lncRNAs) are specifically expressed in tumours and can affect various types of human cancer by participating in competitive endogenous RNA (ceRNA) regulatory networks. However, the specific mechanisms and complex networks of ceRNA regulatory patterns in colon adenocarcinoma (COAD) remain unclear. Using The Cancer Genome Atlas (TCGA) database, we identified the differentially expressed lncRNA, microRNA (miRNA), and messenger RNA (mRNA) between colon cancer and normal tissues, as well as between groups with high and low CEACAM5 expression. Then, we constructed CEACAM5-related ceRNA networks, established the key lncRNA-miRNA-mRNA regulatory axis, and explored the biological mechanisms of this axis and its clinical significance in colon cancer from multiomic aspects. We constructed a ceRNA network of 18 lncRNAs, 177 miRNAs, and 25 mRNAs associated with CEACAM5 and finally established the key LCMT1-AS2/miR-454-3p/ribosomal protein S6 kinase A5 (RPS6KA5) axis associated with overall survival. Subsequent investigations have indicated that this regulatory axis could potentially participate in the progression of COAD and exert influence on the therapeutic outcomes of chemotherapy and immunotherapy. It may be involved in the PI3K-Akt signaling pathway and may modify the tumor immune microenvironment and influence the course of COAD. Additionally, it may be related to ferroptosis, N6-methyladenosine (m6A) methylation, and tumor stemness and interfere with the sensitivity of tumor cells to 5-fluorouracil and immunotherapy. The LCMT1-AS2/RPS6KA5 axis may be instrumental in tumor progression, potentially acting as a prognostic biomarker and therapeutic target.