Castration-resistant prostate cancer (CRPC) is a frequently occurring disease with adverse clinical outcomes and limited therapeutic options. Here, we identify methionine adenosyltransferase 2a (MAT2A) as a critical driver of the androgen-indifferent state in ERG fusion-positive CRPC. MAT2A is upregulated in CRPC and cooperates with ERG in promoting cell plasticity, stemness and tumorigenesis. RNA, ATAC and ChIP-sequencing coupled with histone post-translational modification analysis by mass spectrometry show that MAT2A broadly impacts the transcriptional and epigenetic landscape. MAT2A enhances H3K4me2 at multiple genomic sites, promoting the expression of pro-tumorigenic non-canonical AR target genes. Genetic and pharmacological inhibition of MAT2A reverses the transcriptional and epigenetic remodeling in CRPC models and improves the response to AR and EZH2 inhibitors. These data reveal a role of MAT2A in epigenetic reprogramming and provide a proof of concept for testing MAT2A inhibitors in CRPC patients to improve clinical responses and prevent treatment resistance.

The pharmaceutical industry is a cornerstone in the global healthcare system, renowned for its pioneering discoveries and unwavering commitment to addressing complex health challenges. Over decades, it has proven its resilience in ensuring the availability of life-saving treatments. However, this stalwart industry is not without its challenges, from high costs and intricate regulations to the complexities of intellectual property protection, drug pricing, and the ever-looming spectre of emerging health threats, (as witnessed in recent pandemics). Amidst these diverse challenges, technological advancements in Artificial Intelligence (AI) emerge as a beacon of hope, positioned to transform the industry. This article explores the transformative role of AI within the pharmaceutical industry, unravelling its multifaceted impact across crucial domains. From revolutionizing drug discovery and development to optimizing clinical trials, enabling personalized medicine, enhancing manufacturing and quality control, ensuring pharmacovigilance, streamlining supply chain management, and even influencing drug marketing and sales, AI’s influence is pervasive. The integration of AIs into the pharmaceutical industry signifies a transformative moment in the course of healthcare evolution. In summary, as we navigate this era of unprecedented technological advancement, the pharmaceutical landscape is poised for a profound and drastic change, signalling a leap toward enhanced patient outcomes and a more resilient healthcare ecosystem. The integration of AI offers numerous benefits, including faster and more cost-effective drug discovery, enhanced precision in personalized medicine, improved clinical trials through better data analysis etc. However, AI also faces limitations such as the need for high-quality, unbiased datasets, regulatory and ethical concerns regarding transparency and data privacy, and the inherent complexity of biological systems that can sometimes outstrip AI’s current capabilities. In light of these opportunities and challenges, the future of AI in pharmaceuticals hinges on careful implementation, continuous innovation, ethical considerations and a collaborative approach to addresses these challenges.

AbstractBackgroundOncogenic transformation alters intracellular metabolism and contributes to the growth of malignant cells. Metabolomics, or the study of small molecules, can reveal insight about cancer progression that other biomarker studies cannot. Number of metabolites involved in this process have been in spotlight for cancer detection, monitoring, and therapy.Recent FindingsIn this review, the “Metabolomics” is defined in terms of current technology having both clinical and translational applications. Researchers have shown metabolomics can be used to discern metabolic indicators non‐invasively using different analytical methods like positron emission tomography, magnetic resonance spectroscopic imaging etc. Metabolomic profiling is a powerful and technically feasible way to track changes in tumor metabolism and gauge treatment response across time. Recent studies have shown metabolomics can also predict individual metabolic changes in response to cancer treatment, measure medication efficacy, and monitor drug resistance. Its significance in cancer development and treatment is summarized in this review.ConclusionAlthough in infancy, metabolomics can be used to identify treatment options and/or predict responsiveness to cancer treatments. Technical challenges like database management, cost and methodical knowhow still persist. Overcoming these challenges in near further can help in designing new treatment régimes with increased sensitivity and specificity.

BackgroundCancer poses a significant global challenge, and with the projected rise in cancer incidence, there is an urgent need to discover new targets and treatments to improve patient outcomes. Recent advancements in genomics technologies have enhanced our understanding of cancer's complexities and led to the emergence of pan‐cancer analysis as a valuable approach for identifying tumor targets. Torsin‐1A‐interacting protein 1 (TOR1AIP1) is a membrane protein involved in various cellular processes. Emerging evidence suggests its potential involvement in cancer.MethodsIn this study, we conducted a comprehensive analysis of multiple databases to explore TOR1AIP1 expression across different cancer types and stages. We also investigated its correlation with clinical outcomes, such as survival rates and drug sensitivity.ResultsThe results of our analysis showed significant deregulation of TOR1AIP1 expression in multiple cancer types and its association with clinical outcomes, with a particular emphasis on kidney renal clear cell carcinoma. The results of our study highlight the potential predictive value of TOR1AIP1 in cancer prognosis and therapy.ConclusionsThis study establishes a solid foundation and rationale for future experimental investigations, which will contribute to a deeper understanding of the significance of TOR1AIP1 in different cancer types, specifically in kidney renal clear cell carcinoma.

The multi-kinase inhibitor sorafenib is a primary treatment modality for advanced-stage hepatocellular carcinoma (HCC). However, the therapeutic benefits are short-lived due to innate and acquired resistance. Here, we examined how HCC cells respond to sorafenib and adapt to continuous and prolonged exposure to the drug. Sorafenib-adapted HCC cells show a profound reprogramming of mitochondria function and marked activation of genes required for mitochondrial protein translation and biogenesis. Mitochondrial ribosomal proteins and components of translation and import machinery are increased in sorafenib-resistant cells and sorafenib-refractory HCC patients show similar alterations. Sorafenib-adapted cells also exhibited increased serine 727 phosphorylated (pSer727) STAT3, the prevalent form in mitochondria, suggesting that STAT3 might be an actionable target to counteract resistance. Consistently, a small-molecule STAT3 inhibitor reduces pSer727, reverts mitochondrial alterations, and enhances the response to sorafenib in resistant cells. These results sustain the importance of mitochondria plasticity in response to sorafenib and identify a clinically actionable strategy for improving the treatment efficacy in HCC patients.

Extracellular vesicles (EVs) are relevant means for transferring signals across cells and facilitate propagation of oncogenic stimuli promoting disease evolution and metastatic spread in cancer patients. Here, we investigated the release of miR-424 in circulating small EVs or exosomes from prostate cancer patients and assessed the functional implications in multiple experimental models. We found higher frequency of circulating miR-424 positive EVs in patients with metastatic prostate cancer compared to patients with primary tumors and BPH. Release of miR-424 in small EVs was enhanced in cell lines (LNCaPabl), transgenic mice (Pb-Cre4;Ptenflox/flox;Rosa26ERG/ERG) and patient-derived xenograft (PDX) models of aggressive disease. EVs containing miR-424 promoted stem-like traits and tumor-initiating properties in normal prostate epithelial cells while enhanced tumorigenesis in transformed prostate epithelial cells. Intravenous administration of miR-424 positive EVs to mice, mimicking blood circulation, promoted miR-424 transfer and tumor growth in xenograft models. Circulating miR-424 positive EVs from patients with aggressive primary and metastatic tumors induced stem-like features when supplemented to prostate epithelial cells. This study establishes that EVs-mediated transfer of miR-424 across heterogeneous cell populations is an important mechanism of tumor self-sustenance, disease recurrence and progression. These findings might indicate novel approaches for the management and therapy of prostate cancer.

The TMPRSS2-ERG gene fusion is the most frequent alteration observed in human prostate cancer. However, its role in disease progression is still unclear. In this study, we uncover an important mechanism promoting ERG oncogenic activity. We show that ERG is methylated by Enhancer of zest homolog 2 (EZH2) at a specific lysine residue (K362) located within the internal auto-inhibitory domain. Mechanistically, K362 methylation modifies intra-domain interactions, favors DNA binding and enhances ERG transcriptional activity. In a genetically engineered mouse model of ERG fusion-positive prostate cancer ( Pb-Cre4 Pten flox/flox Rosa26-ERG, ERG/PTEN ), ERG K362 methylation is associated with PTEN loss and progression to invasive adenocarcinomas. In both ERG positive VCaP cells and ERG/PTEN mice, PTEN loss results in AKT activation and EZH2 phosphorylation at serine 21 that favors ERG methylation. We find that ERG and EZH2 interact and co-occupy several sites in the genome forming trans-activating complexes. Consistently, ERG/EZH2 co-regulated target genes are deregulated preferentially in tumors with concomitant ERG gain and PTEN loss and in castration-resistant prostate cancers. Collectively, these findings identify ERG methylation as a post-translational modification sustaining disease progression in ERG-positive prostate cancers.

Since growing tumors stimulate angiogenesis, via vascular endothelial growth factor (VEGF), angiogenesis inhibitors (AIs, blockers of the VEGF signaling pathway) have been introduced to cancer therapy. However, AIs often yielded only modest and short-lived gains in cancer patients and more invasive tumor phenotypes in animal models. Combining anti-VEGF strategies with lactate uptake blockers may boost both efficacy and safety of AIs. We assessed this hypothesis by using the ex ovo chorioallantoic membrane (CAM) assay. We show that AI-based monotherapy (Avastin®, AVA) increases tumor hypoxia in human CAM cancer cell xenografts and cell spread in human as well as canine CAM cancer cell xenografts. In contrast, combining AVA treatment with lactate importer MCT1 inhibitors (α-cyano-4-hydroxycinnamic acid (CHC) or AZD3965 (AZD)) reduced both tumor growth and cell dissemination of human and canine explants. Moreover, combining AVA+AZD diminished blood perfusion and tumor hypoxia in human explants. Thus, the ex ovo CAM assay as an easy, fast and cheap experimental setup is useful for pre-clinical cancer research. Moreover, as an animal-free experimental setup the CAM assay can reduce the high number of laboratory animals used in pre-clinical cancer research.

In this study, we extracted prostate cell-specific gene sets (metagenes) to define the epithelial differentiation status of prostate cancers and, using a deconvolution-based strategy, interrogated thousands of primary and metastatic tumors in public gene profiling datasets. We identified a subgroup of primary prostate tumors with low luminal epithelial enrichment (LumE(low)). LumE(low) tumors were associated with higher Gleason score and mutational burden, reduced relapse-free and overall survival, and were more likely to progress to castration-resistant prostate cancer (CRPC). Using discriminant function analysis, we generate a predictive 10-gene classifier for clinical implementation. This mini-classifier predicted with high accuracy the luminal status in both primary tumors and CRPCs. Immunohistochemistry for COL4A1, a low-luminal marker, sustained the association of attenuated luminal phenotype with metastatic disease. We found also an association of LumE score with tumor phenotype in genetically engineered mouse models (GEMMs) of prostate cancer. Notably, the metagene approach led to the discovery of drugs that could revert the low luminal status in prostate cell lines and mouse models. This study describes a novel tool to dissect the intrinsic heterogeneity of prostate tumors and provide predictive information on clinical outcome and treatment response in experimental and clinical samples.

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Prostate cancer is the most common malignancy in men and the second cause of cancer-related deaths in western countries. Despite the progress in the treatment of localized prostate cancer, there is still lack of effective therapies for the advanced forms of the disease. Most patients with advanced prostate cancer become resistant to androgen deprivation therapy (ADT), which remains the main therapeutic option in this setting, and progress to lethal metastatic castration-resistant prostate cancer (mCRPC). Current therapies for prostate cancer preferentially target proliferating, partially differentiated, and AR-dependent cancer cells that constitute the bulk of the tumor mass. However, the subpopulation of tumor-initiating or tumor-propagating stem-like cancer cells is virtually resistant to the standard treatments causing tumor relapse at the primary or metastatic sites. Understanding the pathways controlling the establishment, expansion and maintenance of the cancer stem cell (CSC) subpopulation is an important step toward the development of more effective treatment for prostate cancer, which might enable ablation or exhaustion of CSCs and prevent treatment resistance and disease recurrence. In this review, we focus on the impact of transcriptional regulators on phenotypic reprogramming of prostate CSCs and provide examples supporting the possibility of inhibiting maintenance and expansion of the CSC pool in human prostate cancer along with the currently available methodological approaches. Transcription factors are key elements for instructing specific transcriptional programs and inducing CSC-associated phenotypic changes implicated in disease progression and treatment resistance. Recent studies have shown that interfering with these processes causes exhaustion of CSCs with loss of self-renewal and tumorigenic capability in prostate cancer models. Targeting key transcriptional regulators in prostate CSCs is a valid therapeutic strategy waiting to be tested in clinical trials.

Background: Chemotherapy is the treatment of choice for metastatic castration-resistant prostate cancer (mCRPC) nonresponsive to androgen receptor-targeted therapies. Nevertheless, the impact of chemotherapy on patient survival is limited and clinical outcome remain dismal. Bromodomain and extraterminal inhibitors (BETis) are attractive therapeutic agents and currently in clinical trials to be tested for their efficacy in prostate cancer patients. Objective: In this study, we evaluated the activity of two clinical stage BETis, INCB054329 and INCB057643, alone and in combination with chemotherapeutics used for the treatment of mCRPC. Design, setting, and participants: Drug activity was evaluated in vitro by MTT, clonogenic, prostato-sphere, and flow cytometry assays. The activity in vivo was evaluated in mice bearing prostate tumor (22Rv1) xenografts. Outcome measurements and statistical analysis: Cell growth data were analyzed to determine the maximum effect and the concentration that reduces by 50%. For concomitant treatments, the combination index was determined according to the Chou-Talalay method. For in vivo activity, changes in tumor size (T/C-i%), weight (T/C-d%), doubling time, and mouse body weight were monitored. Statistical significance was determined by oneway analysis of variance followed by a Student-Newman-Keuls or Turkey a posteriori test. Results and limitations: INCB054329 and INCB057643 had significant activity as single agents in human prostate cancer cell lines and 22Rv1 tumor xenografts. Combined treatment with INCB057643 and any of docetaxel, olaparib, or carboplatin was synergistic/additive in vitro. Notably, INCB057643, given with a low-intensity dosing schedule, greatly enhanced the anti-tumor activity of docetaxel, carboplatin, and olaparib in 22Rv1 tumor xenografts. Conclusions: Collectively, these results provide the first evidence of the therapeutic benefit obtainable by combining BETis with non-androgen receptor-targeted therapies for the treatment of mCRPC. Patient summary: Chemotherapy has limited efficacy in patients with metastatic castration-resistant prostate cancer. This study provides evidence of enhanced efficacy of clinically used chemotherapeutics when given in combination with the bromodomain and extraterminal inhibitor INCB057643, expanding the horizon of the current options for the treatment of prostate cancer. (C) 2019 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology.

Abstract The TMPRSS2-ERG gene fusion occurs frequently in prostate cancers and leads to over-expression of the ETS transcription factor ERG. We have recently described a novel mechanism cooperating with ERG fusion and enhancing ERG oncogenic activity. We found that the protein methyltransferase Enhancer of zest homolog 2 (EZH2) interacts with ERG and catalyzes methylation of a specific lysine residue in the ERG DNA binding domain. Lysine methylation of ERG alters intra-domain dynamics leading to increased chromatin binding and transcriptional activity. These events result in the formation of ERG/EZH2 co-activator complexes on selected gene promoters and enhancers and in broad transcriptional reprogramming in prostate epithelial cells. In this study we examined whether ERG methylation and ERG/EZH2 crosstalk were associated with ERG-driven tumor progression in genetically engineered mouse models represented by mice with prostate-specific expression of ERG (Pb-Cre4; Rosa26ERG/ERG) and mice with combined prostate-specific expression of ERG and deletion of PTEN (Pb-Cre4; Ptenflox/flox; Rosa26ERG/ERG). Only the combined ERG/PTEN mice exhibit progressive disease and develop invasive adenocarcinomas, whereas ERG mice fail to do so. We detected ERG methylation exclusively in ERG/PTEN mice. Enhanced methylation was linked to increased expression and AKT-induced phosphorylation of EZH2 at Serine 21 (pS21). Consistently, we observed higher promoter occupancy by ERG/EZH2 complexes and increased expression of selected ERG/EZH2 co-regulated genes in ERG/PTEN mice. Thus, enhanced ERG methylation and EZH2 activation occur in mice with combined ERG gain and PTEN loss and are concomitant with the emergence of an invasive phenotype. Systemic treatment with pharmacological inhibitors of EZH2, such as GSK343 blocked ERG methylation and expression of ERG/EZH2 co-regulated genes in ERG/PTEN mice. Moreover, GSK343 significantly reduced prostate volume, Ki67 immuno-staining and areas of invasive adenocarcinomas compared to control mice. Relevantly, we found preferential upregulation of ERG/EZH2 co-regulated genes in human prostate cancers exhibiting combined ERG over-expression and PTEN loss. These data establish the association of ERG methylation with enhanced ERG oncogenic activity and provide mechanistic insights into the synergy between ERG gain and PTEN loss in human tumors. Furthermore, these results establish the efficacy of EZH2 inhibitors in antagonizing ERG oncogenic activity in the ERG/PTEN model providing a strong rationale for developing new therapeutic strategies for the management of ERG fusion positive prostate cancers. Citation Format: Marita Zoma, Dheeraj Shinde, Domenico Albino, Simone Mosole, Jacopo Sgrignani, Andrea Cavalli, Carlo V. Catapano, Giuseppina M. Carbone. ERG lysine methylation promotes prostate cancer progression in ERG transgenic mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-201.

Background: The TMPRSS2-ERG gene fusion is the most frequent genetic rearrangement in prostate cancers and results in broad transcriptional reprogramming and major phenotypic changes. Interaction and cooperation of ERG and SP1 may be instrumental in sustaining the tumorigenic and metastatic phenotype and could represent a potential vulnerability in ERG fusion-positive tumors. Objective: To test the activity of EC-8042, a compound able to block SP1, in cellular and mouse models of ERG-positive prostate cancer. Design, setting, and participants: We evaluated the activity of EC-8042 in cell cultures and ERG/PTEN transgenic/knockout mice that provide reliable models for testing novel therapeutics in this specific disease context. Using a new protocol to generate tumor spheroids from ERG/PTEN mice, we also examined the effects of EC-8042 on tumor-propagating stem-like cancer cells with high self-renewal and tumorigenic capabilities. Outcome measurements and statistical measurements: The efficacy of EC-8042 was determined by measuring the proliferative capacity and target gene expression in cell cultures, invasive and metastatic capabilities in chick chorioallantoic membrane assays, and tumor development in mice. Significance was determined using statistical test. Results and limitations: EC-8042 blocked transcription of ERG-regulated genes and reverted the invasive and metastatic phenotype of VCaP cells. EC-8042 blocked the expansion of stem-like tumor cells in tumor spheroids from VCaP cells and mouse-derived tumors. In ERG/PTEN mice, systemic treatment with EC-8042 inhibited ERG-regulated gene transcription, tumor progression, and tumor-propagating stem-like tumor cells. Conclusions: Our data support clinical testing of EC-8042 for the treatment of ERG-positive prostate cancer in precision medicine approaches. Patient summary: In this study, EC-8042, a novel compound with a favorable pharmacological and toxicological profile, exhibited relevant activity in cell cultures and in vivo in a genetically engineered mouse model that closely recapitulates the features of clinically aggressive ERG-positive prostate cancer. Our data indicate that further evaluation of EC-8042 in clinical trials is warranted. (C) 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Castration-resistant prostate cancer (CRPC) is an advanced stage of the disease for which there are limited treatment options. Multiple genetic and epigenetic events contribute to the emergence of CRPC. Bromodomain and extra-terminal (BET) proteins are attracting considerable attention as targets for prostate cancer therapy due to their regulatory role and impact on multiple genes involved in tumor progression and treatment resistance. Several BET bromodomain inhibitors are currently in clinical trials for cancer treatment. In this study, we evaluated the efficacy of the BET inhibitor INCB057643, which is currently in phase 2 clinical trials, as single agent and in combination with enzalutamide or docetaxel in prostate cancer models. The anti-proliferative activity and the effects of INCB057643 on colony and tumor-sphere forming capacity were evaluated in vitro in androgen-dependent (LNCaP and VCaP) and androgen-independent (DU145, PC3, 22Rv1) cells. The effect of the combination of INCB057643 with enzalutamide or docetaxel on cell growth was evaluated with MTT or SRB methods. The in vivo efficacy of INCB057643 as single agent and in combination was assessed in 22Rv1 mouse xenografts. INCB057643 showed significant anti-proliferative activity in all the prostate cancer cell lines. Interestingly, INCB057643 exhibited substantially higher activity in colony and tumor-sphere forming assays in all cell lines. This was particularly evident in 22Rv1 cells, suggesting a strong impact on tumorigenic stem-like cell subpopulation in this CRPC cell model. The combination of INCB057643 with docexatel was additive or synergistic in DU145, 22Rv1 and LNCaP cells (CI of 0.46, 1.04 and 0.66, respectively). Also, concomitant and sequential treatment with INCB057643 and enzalutamide resulted in potentiation of the antiproliferative effect in 22Rv1 and LNCaP cells. These results were mirrored in 22Rv1 tumor xenografts, where the INCB057643/docetaxel and INCB057643/enzalutamide combinations resulted in potentiation and significant reduction of tumor growth compared to control and/or single agent-treated mice. In summary, INCB057643 has significant activity both in vitro and in vivo and enhances the antitumor effect of both docetaxel and enzalutamide in 22Rv1 cells, a model of CRPC. These results point to INCB057643 as promising agent for treatment of CRPC and development of novel drug combination strategies. Citation Format: Ramiro Vazquez, Gianluca Civenni, Giada Zoppi, Dheeraj Shinde, Aleksandra Kokanovic, Phillip Liu, Bruce Ruggeri, Giuseppina M. Carbone, Carlo V. Catapano. Anti-tumor efficacy of INCB057643, a novel BET bromodomain inhibitor, in castration-resistant prostate cancer as single agent and in combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5793.

Abstract The TMPRSS2-ERG gene fusion is found in about half of prostate tumors and represents one of the most frequent genetic rearrangements in human cancers. The gene fusion provides a mechanism for androgen-stimulated ERG over-expression and broad transcriptional reprogramming in prostate cancer. However, the biological impact of aberrant ERG expression on tumor initiation and progression is still unclear. ERG apparently requires additional co-factors to fully exert its oncogenic effects but the molecular details of these interactions are not defined yet. Understanding these mechanisms could have a huge impact on the clinical management of this disease. Enhancer of zest homolog 2 (EZH2), the catalytic subunit of the Polycomb repressive complex 2 (PRC2) catalyzing histone H3 lysine 27 tri-methylation, is over-expressed in many human cancers and is associated with prostate cancer progression. In primary and metastatic prostate tumors ERG and EZH2 are frequently and concomitantly up-regulated. In this study we tested the hypothesis that EZH2 could act as a co-factor of ERG enhancing its transcriptional and oncogenic activity and identified a novel mechanism driving ERG activation and prostate cancer progression. We found that EZH2 physically interacts with ERG in ERG fusion positive cell lines and human tumors. Moreover, ERG/EZH2 co-occupied multiple genomic sites forming co-activator/co-repressor complexes and enabling massive transcriptional reprogramming. Expression of ERG/EZH2 co-occupied genes reflected the level of ERG activation, was preferentially deregulated in ERG-positive tumors and predicted clinical outcome. Furthermore, EZH2 catalyzed the methylation of ERG at a highly conserved lysine (K362) residue, which resulted in increased chromatin binding and transcriptional activity of ERG. PTEN deficiency and AKT activation promoted ERG methylation and ERG/EZH2 genomic co-occupancy along with a more aggressive and metastatic phenotype in ERG fusion positive cancer cells. Thus, this study identifies the ERG/EZH2 interaction and EZH2-induced ERG methylation as important elements promoting prostate tumorigenesis and at the center of cross-talks between the ERG gene fusion and PTEN deficiency in prostate cancer. Notably, these events were blocked effectively by pharmacological inhibitors of EZH2 providing the rationale for novel context-dependent therapeutic strategies in ERG positive prostate cancer. Citation Format: Giuseppina M. R. Carbone, Laura Curti, Marita Zoma, Abhishek Mitra, Dheeraj Shinde, Domenico Albino, Simona Rossi, Gianluca Civenni, George N. Thalmann, Giovanna Chiorino, Carlo Catapano. EZH2-induced lysine methylation and ERG-EZH2 genomic co-occupancy set the basis for extensive transcriptome reprogramming and prostate cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-152.

BACKGROUND:The prognosis of patients with Ewing sarcoma (ES) has improved over the course of the last decades. However, those patients suffering from metastatic and recurrent ES still have only poor chances of survival and require new therapeutic approaches. Interleukin-6 (IL6) is a pleiotropic cytokine expressed by immune cells and a great variety of cancer cells. It induces inflammatory responses, enhances proliferation and inhibits apoptosis in cancer cells, thereby promoting chemoresistance.METHODS:We investigated expression of IL6, its receptors and the IL6 signal transduction pathway in ES tumor samples and cell lines applying reverse transcriptase PCR, immunoblot and immunohistochemistry. The impact of IL6 on cell viability and apoptosis in ES cell lines was analyzed by MTT and propidium iodide staining, migration assessed by chorioallantoic membrane (CAM) assay.RESULTS:Immunohistochemistry proved IL6 expression in the stroma of ES tumor samples. IL6 receptor subunits IL6R and IL6ST were expressed on the surface of ES cells. Treatment of ES cells with rhIL6 resulted in phosphorylation of STAT3. rhIL6 protected ES cells from serum starvation-induced apoptosis and promoted migration. IL6 blood serum levels were elevated in a subgroup of ES patients with poor prognosis.CONCLUSIONS:These data suggest that IL6 contributes to ES tumor progression by increasing resistance to apoptosis in conditions of cellular stress, such as serum starvation, and by promotion of metastasis.