tbuckley/cabot-search huggingface dataset:
Abstract 4630: Development of selective and potent CDK8 inhibitors that increase NK cell activity, which translates in tumor surveillance
Authors: Marco H. Hofmann, Harald Engelhardt, Sebastian Carotta, Heribert Arnhof, Dirk Scharn, Marc Kerenyi, Moritz Mayer, Gerhard Gmaschitz, Georg Egger, Christian Engelhardt, Michael Sanderson, Maria A. Impagnatiello, Renate Schnitzer, Mark Pearson, Darryl McConnell, Norbert Kraut, Jürgen Moll
Journal: Cancer Research (2017)

Abstract Background: Cyclin-dependent kinase 8 (CDK8) is part of the mediator complex that can either positively or negatively influence transcription. CDK8 is known to phosphorylate signal transducer and activator of transcription 1 (STAT1) at the position Ser727. STAT1 activity is regulated by JAK-mediated phosphorylation of tyrosine701 which leads to dimerization, nuclear translocation and IFN-γ induced phosphorylation mediated by CDK8. Introduction of an alanine mutation at the phosphorylation site STAT1-S727 results in enhanced NK cell cytotoxicity accompanied by increased levels of perforin and granzyme B (Putz et al. 2013). Method: Here we present the discovery and development of potent and selective CDK8 inhibitors guided by crystallography. The inhibitory effect of optimized compounds BI 9811 and BI 1347 on STAT1 phosphorylation and perforin release was investigated in the human NK cell line NK-92MI. Direct effects on cancer cells were furthermore analyzed in a broad panel of cell lines. The compound BI 1347 was profiled in vivo in the orthotopic B16-F10 melanoma mouse model. Results: Highly potent and selective CDK8 inhibitors were identified with an IC50 of below 10 nM in a biochemical kinase assay, which translated in a potent down regulation of the STAT1- Ser727 signal and in increased perforin and granzyme B secretion. BI 9811 and BI 1347 were highly selective for CDK8, as tested in a broad kinase panel and showed no cytotoxic activity on NK cells and most cancer cell lines, which distinguishes this compound class from published CDK8 inhibitors. A representative molecule out of this compound class demonstrated in vivo biomarker modulation and survival increase in the murine B16-F10 melanoma mouse model. Conclusion: We developed potent CDK8 inhibitors that show activation of NK cells that translates into biomarker modulation (pSTAT1Ser727) and in vivo efficacy. Citation Format: Marco H. Hofmann, Harald Engelhardt, Sebastian Carotta, Heribert Arnhof, Dirk Scharn, Marc Kerenyi, Moritz Mayer, Gerhard Gmaschitz, Georg Egger, Christian Engelhardt, Michael Sanderson, Maria A. Impagnatiello, Renate Schnitzer, Mark Pearson, Darryl McConnell, Norbert Kraut, Jürgen Moll. Development of selective and potent CDK8 inhibitors that increase NK cell activity, which translates in tumor surveillance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4630. doi:10.1158/1538-7445.AM2017-4630
Abstract 1231: Restoration of tumor suppression <i>in vivo</i> by systemic delivery of PTEN mRNA nanoparticles
Authors: Yingjie Xu, Mohammad Ariful Islam, Harshal Zope, Morteza Mahmoudi, Robert S. Langer, Jinjun Shi, Bruce R. Zetter, Omid C. Farokhzad
Journal: Cancer Research (2017)

Abstract PTEN (phosphatase and tensin homolog on chromosome ten) is one of the most common lost or mutated tumor suppressor genes in human cancers, including ~50% of metastatic castration-resistant prostate cancer (mCRPC). By catalyzing PIP3 dephosphorylation, PTEN negatively regulates the PI3K-AKT-mTOR pathway, which is frequently altered in mCRPC. Reintroduction of functional PTEN for mCRPC treatment has proven difficult. By employing self-assembled lipid-polymer hybrid nanoparticle platforms, we successfully reintroduced PTEN mRNA to PTEN-null prostate cancer cells both in vitro and in vivo. These mRNA-loaded nanoparticles demonstrate high protein expression efficiency, low toxicity and good stability in serum and tumor accumulation. We confirmed that restoration of PTEN in PTEN-null prostate cancer cells inhibits the PI3k-AKT pathway, reduces cell viability and enhances apoptosis in vitro. Systemic delivery of PTEN mRNA-loaded nanoparticles in prostate xenograft tumors results in ~85% inhibition of tumor growth and leads to tumor cell death without toxic side effects in vivo. In summary, this work provides proof of concept of mRNA-based gene therapy for systemic restoration of functional PTEN for tumor suppression in vivo. It represents a novel approach to PI3K-AKT pathway inhibition, with the potential to specifically target cancers with loss of PTEN function. Citation Format: Yingjie Xu, Mohammad Ariful Islam, Harshal Zope, Morteza Mahmoudi, Robert S. Langer, Jinjun Shi, Bruce R. Zetter, Omid C. Farokhzad. Restoration of tumor suppression in vivo by systemic delivery of PTEN mRNA nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1231. doi:10.1158/1538-7445.AM2017-1231
Molecular analysis of thymic epithelial tumors (TETs): A report by The Cancer Genome Atlas (TCGA) research network.
Authors: Patrick J. Loehrer, Anne S. Tsao, Milan Radovich, Ina Felau
Journal: Journal of Clinical Oncology (2017)

8520 Background: Thymoma (T) and thymic carcinoma (TC) are the most common malignancies of the anterior mediastinum. Additionally, thymoma has an unique association with autoimmune disorders, notably myasthenia gravis (MG). Histologic classification of TETs has been largely based on the gross description of the epithelial cell appearance and the relative abundance of associated lymphocytes. A comprehensive molecular analysis of TETs has not heretofore been conducted. Methods: The TCGA Research Network conducted multi-platform analyses of 117 TETs (T = 105; TC = 10 and micronodular T = 2), which included whole-exome, transcriptome, methylome and targeted proteome analysis. Patient characteristics: median age = 60 years (range 17-84); M:F (%) = 52:48; Masaoka Stage (I-36, IIA-39, IIB-19; III-15; IVA-1; IVB-5); mg was present in 32 patients. No patient had prior therapy for metastatic disease, but 14 had prior chemotherapy and 39 had prior radiation therapy in adjuvant setting. WHO histologic classification (blinded review) revealed A = 10; A/B = 48, B1 = 12, B2 = 25, B3 = 10, micronodular T = 2 and TC = 10. Results: T has one of the lowest mutational loads of any tumor in the TCGA. A unique transcription factor, GTF2I, was the most commonly observed mutation in WHO Types A and A/B. All GTF2I mutations were exclusively at the amino acid 424 locus. This is the only tumor with this specific mutation within the entire TCGA database. HRAS, NRAS and TP53 mutations were less commonly noted among all TETs. Four distinct molecular-driven subtypes of TETs were identified that strongly correlated with the current WHO histologic classification. Increased aneuploidy and overexpression of muscle auto-antigens were associated with mg phenotype. Conclusions: Based on molecular analysis, four clusters were identified that correlated strongly with the current WHO Histologic Classification. Also identified was a unique mutation in GTF2I, which was associated with WHO Type A and A/B thymoma. This international effort represents the largest and most comprehensive molecular analysis of TETs conducted to date is expected to have important clinical and translational implications for this rare disease.
Abstract 2430: The expression of BCL6 and ZEB family transcription factors and their correlation in breast cancers
Authors: Min Zhao, Lin Ang, Li Zheng, Jin Wang, Jin Huang, Hongguang Hu, Qiang Zou
Journal: Cancer Research (2017)

Abstract The proto-oncogene B-cell lymphoma 6 (BCL6) is an evolutionarily conserved zinc finger protein and a potent transcriptional repressor. It is also the master regulator of B-lymphocyte development. Emerging evidence indicates that BCL6 may play an important role in breast cancer progression. In this study, we investigated the expression of BCL6 and tis correlation with the expression of epithelial-mesenchymal transition (EMT)-associated transcription factors zinc finger E-box-binding homeobox 1 (ZEB1) and ZEB2 in invasive breast cancers. The mRNA and protein expression of BCL6, ZEB1 and ZEB2 were examined using in situ hybridization and immunohistochemistry, respectively, in 228 breast cancer patients and 80 patients with breast benign diseases. The association of BCL6, ZEB1 and ZEB2 expression with clinicopathological parameters and patient survival were analyzed. We found that the expression of BCL6, ZEB1 and ZEB2 protein and mRNA were significantly higher in breast cancer tissues than in breast benign disease tissues (P&amp;lt;0.05). The expression levels of BCL6, ZEB1 and ZEB2 were all positively correlated with the tumor size, lymph node metastasis and higher tumor stages (P&amp;lt;0.05). Furthermore, patients with BCL6, ZEB1 and ZEB2 protein-positive primary tumors were associated with a significant lower overall survival (OS) rate (P=0.001, 0.002 and 0.001, respectively) and post-operative relapse-free survival (RFS) rate (P=0.002, 0.001 and 0.003 for the expression of BCL6, ZEB1 and ZEB2, respectively). The mRNA expression of ZEB1 and ZEB2 were positively correlated with BCL6 mRNA expression (rs=0.326, P&amp;lt;0.001; and rs=0.382, P&amp;lt;0.001, respectively); the protein expression of ZEB1 and ZEB2 were also positively correlated with BCL6 protein expression (rs=0.449, P&amp;lt;0.001; and rs=0.669, P&amp;lt;0.001, respectively). These results indicate that BCL6, ZEB1 and ZEB2 may be as potential biomarkers for predicting invasion, metastasis and prognosis of breast cancer and that BCL6 may be a regulator of ZEB family transcription factors (ZEB1 and ZEB2). Note: This abstract was not presented at the meeting. Citation Format: Min Zhao, Lin Ang, Li Zheng, Jin Wang, Jin Huang, Hongguang Hu, Qiang Zou. The expression of BCL6 and ZEB family transcription factors and their correlation in breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2430. doi:10.1158/1538-7445.AM2017-2430
Abstract 843: CLDN1 mediates tumor invasion in HNSCC by regulation of EMT through AMPK-TGF-β signalling
Authors: Jae Won Chang, Seung-Nam Jung, Lihua Liua, Jin Man Kim, Myung Jin Ban, Yeon Soo Kim, Bok-Soon Lee, Yang Eun Kim, Ho Ryun Won, Chul-Ho Kim, Bon Seok Koo
Journal: Cancer Research (2017)

Abstract Background: Claudin-1 (CLDN1), a major component of tight junction complexes in epithelium, maintains cellular polarity and plays critical roles in cell-to-cell communication and epithelial cell homeostasis. Although, the role of CLDN1 in cancer has been generally studied in cancers, the exact regulatory mechanisms and downstream pathways in cancer have been controversial and are not completely understood. Materials and Methods: After, analysed mutational profiling of tumor/non-tumor paired tissue in the patients with head and neck squamous cell carcinoma (HNSCC) by next-generation sequencing (NGS), CLDN1 expression levels were measured in human HNSCC cell lines and tissues from HNSCC patients using next-generation sequencing. For functional in vitro analysis, cell proliferation testing using a WST-1 assay, an invasion assay, and Western blotting was performed after CLDN1 expression regulation. In vivo validations were performed using nude mouse and patient-derived tumor xenograft (PDTX) model. Results: Mutational profiling of tumor/non-tumor paired HNSCC tissue by NGS revealed that HNSCC tumor tissues and cell lines had relatively high levels of CLDN1 expression. Although, CLDN1 regulation did not affect proliferation of HNSCC cell lines, knock down of CLDN1 inhibited invasive characteristics (migration/invasion) with down-regulation of EMT associated proteins (vimentin and slug). We also found that CLDN1 negatively correlated with AMPK phosphorylation and AMPK activator (AICAR) showed the same effect with CLDN1 suppression on HNSCC cells without change in CLDN1 expression which lead to inhibition of TGF-β-induced Smad phosphorylation and their transcriptional activity, suggesting that CLDN1/AMPK/TGF-β cascade. Then, we confirmed antitumorigenic effects of suppression of CLDN1 in HNSCC in a nude mouse and PDTX model. Conclusions: Our findings suggest that CLDN1 acts as oncogenic driver in HNSCC via regulating EMT through AMPK/TGF-β signalling and if validated in further studies, a CLDN1-targeting agent partnered with an existing anti-TGF-β modality could be a novel tactic to overcome HNSCC. Citation Format: Jae Won Chang, Seung-Nam Jung, Lihua Liua, Jin Man Kim, Myung Jin Ban, Yeon Soo Kim, Bok-Soon Lee, Yang Eun Kim, Ho Ryun Won, Chul-Ho Kim, Bon Seok Koo. CLDN1 mediates tumor invasion in HNSCC by regulation of EMT through AMPK-TGF-β signalling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 843. doi:10.1158/1538-7445.AM2017-843
Abstract 2102: ONC201 targets AR and AR-V7 signaling pathways, reduces PSA and synergizes with everolimus in castration resistant prostate cancer
Authors: Avital Lev, Amriti R. Lulla, David T. Dicker, Wafik S. El-Deiry
Journal: Cancer Research (2017)

Abstract Androgen receptor (AR) signaling plays a key role in prostate cancer progression; thus Androgen Deprivation Therapy (ADT) is a mainstay therapy for patients with advanced prostate cancer. However, in most cases the tumor becomes androgen-independent and resistant to ADT with patients ultimately progressing to metastatic castration resistant prostate cancer (mCRPC). Constitutively activated AR splice variants (AR-Vs) have emerged as major mediators of resistance to AR-targeted therapy and progression of mCRPC, representing an important therapeutic target for mCRPC. Out of at least 15 AR-Vs described thus far, AR-V7 is the most abundant in prostate cancer and its expression correlates with ADT resistance. ONC201 is the founding member of the imipridone class of small molecules that induces apoptosis in a variety of tumor types tested. It is currently in Phase I/II clinical trials for advanced solid tumors and hematological malignancies, including mCRPC with encouraging activity observed in patients in early clinical testing (Stein et al., ASCO, 2016). We demonstrate here that ONC201 treatment induces apoptosis in both castration-resistant and –sensitive human prostate cancer cell lines. Furthermore, an in-vitro synergistic effect is observed with ONC201 and FDA approved drugs for prostate cancer such as enzalutamide, docetaxel and everolimus. Mechanistically, we found that ONC201 inhibits both AR and AR-V7 signaling pathways. Analysis of AR+ cell lines stimulated with DHT showed a significant decrease in both RNA and protein levels of AR, AR-V7, PSA and other AR-target genes following ONC201 treatment. Ongoing experiments are aimed at better understanding the molecular and cellular mechanisms that enable ONC201 to inhibit the AR signaling pathway. In-vivo studies with AR-negative hormone refractory prostate cancer xenografts demonstrate single agent ONC201 anti-tumor efficacy. Ongoing studies are further evaluating the in-vivo efficacy of ONC201 as a single agent or in combination with enzalutamide and everolimus using mouse models of both castration-resistant and -sensitive prostate cancer. These preclinical results indicate that ONC201 is well suited to address mCRPC, including tumors that harbor AR-V7, as a single agent that may be combined synergistically with enzalutamide or everolimus . With these observations we envision further development a combination of ONC201 plus everolimus in CRPC with or without enzalutamide resistance. Citation Format: Avital Lev, Amriti R. Lulla, David T. Dicker, Wafik S. El-Deiry. ONC201 targets AR and AR-V7 signaling pathways, reduces PSA and synergizes with everolimus in castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2102. doi:10.1158/1538-7445.AM2017-2102
Abstract 5627: Uncovering novel signaling pathways that mediate tumor cell killing by T effector cells
Authors: Thomas Kuilman, David Vredevoogd, Daniel S. Peeper
Journal: Cancer Research (2017)

Abstract Recent advances in the understanding of tumor immunology have led to the development of various immunotherapeutic strategies, some of which show unprecedented clinical efficacies. Two of the most effective treatments, ipilimumab and pembrolizumab / nivolumab target the immune checkpoints factors CTLA-4 and PD-1, respectively. While not all patients respond to immunotherapy, those that do frequently show long-lasting clinical responses. These accomplishments have led to a surge in research focusing on the question how the immune system can be stimulated for more common durable therapy responses. A current focus of tumor immunological research is the identification of mechanisms allowing cancer cells to evade recognition and/or killing by the immune system while facing immunotherapy. For example, abrogation of interferon-γ signaling pathway has been shown to result in escape of immune surveillance after pembrolizumab treatment. However, it is likely that other tumor cell-intrinsic mechanisms play a role, too. To uncover novel pathways that are involved in resistance to immune checkpoint inhibitors, we aim to identify transcriptional changes in tumor cells that result from effector T-cell exposure. To this end, we established a co-culture platform of a panel of Mart1-expressing melanoma cell lines with primary CD8+ T cells expressing a matching TCR. The cell lines display varying degrees of sensitivity to T cells, allowing us to bioinformatically uncover differential expression depending on this range of sensitivities. Rather than concentrating on single genes, we have focused on pathways, gene sets and ontologies. These analyses have been integrated with various publically available transcriptomic data sets to identify a set of mechanisms that may contribute to T-cell mediated killing. We will systematically abrogate key factors using CRISPR technology in our co-culture platform and assess whether this affects T-cell mediated killing. Our ultimate goal is to test whether these factors, or their signaling pathways, are involved in resistance to immunotherapy in patients, and to develop new strategies to prevent immunotherapy resistance. Note: This abstract was not presented at the meeting. Citation Format: Thomas Kuilman, David Vredevoogd, Daniel S. Peeper. Uncovering novel signaling pathways that mediate tumor cell killing by T effector cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5627. doi:10.1158/1538-7445.AM2017-5627
Abstract 5677: Performance of a robust and sensitive liquid biopsy workflow for mutation detection in plasma
Authors: Jonathan Choi, Cindy Choi, Jorge Dinis, Jingchuan Li, Sean Chien, Bosun Min, Abraham Munoz, Janet Jin, Amrita Pati, Liang Feng, Johnny Wu, Ashla Singh, Fergal Casey
Journal: Cancer Research (2017)

Abstract The discovery of circulating tumor DNA (ctDNA) and the development of highly sensitive technologies have made the utility of liquid biopsies in clinical practice more feasible. Potential applications for liquid biopsies include early cancer detection, tumor genotyping in the absence of tissue biopsies, disease monitoring, and identification of drug resistance markers. However, there is a multitude of technical challenges to accurately detect ctDNA with high sensitivity and reproducibility. Various methods have been established by research centers and companies, each with its advantages and limitations. We have developed a sensitive NGS-based liquid biopsy assay, called the AVENIO ctDNA Analysis Kits (research use only), which includes three panels targeting biomarkers for solid tumors. The AVENIO ctDNA Analysis Kits include cfDNA extraction from up to 5ml plasma input, optimized reagents and workflow for NGS library preparation and target enrichment. It is accompanied with an intuitive software and data analysis package to easily obtain results. The assay sensitively detects 4 cancer relevant mutation classes - single nucleotide variations (SNVs), insertions/deletions, copy number variations and structural rearrangements. We conducted a study with 200+ samples of plasma-derived cfDNA, cell line blends containing relevant cancer mutations, and clinical samples, with which we demonstrate the analytical sensitivity of the three distinct AVENIO gene panels (covering 17, 77 and 197 genes). We demonstrate &amp;gt;95% sensitivity for SNVs at 0.5% mutant allele frequency; &amp;gt;95% sensitivity for 1% indels; &amp;gt;95% sensitivity for 1% structural variants. We also demonstrate assay robustness through multiple replicates, day-to-day, and operator-to-operator reproducibility. In conclusion, the AVENIO ctDNA Analysis Kits for solid tumors encompasses a comprehensive assay and analysis workflow aimed to provide researchers with robust, reliable, highly sensitive and ease to use liquid biopsy assays to conduct the necessary studies to demonstrate the utility of circulating biomarkers in routine clinical testing. Citation Format: Jonathan Choi, Cindy Choi, Jorge Dinis, Jingchuan Li, Sean Chien, Bosun Min, Abraham Munoz, Janet Jin, Amrita Pati, Liang Feng, Johnny Wu, Ashla Singh, Fergal Casey. Performance of a robust and sensitive liquid biopsy workflow for mutation detection in plasma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5677. doi:10.1158/1538-7445.AM2017-5677
Abstract 1493: LonP1 is required for tumor maintenance and growth
Authors: Benjamin S. Amidon, Dongyun Wu, John Bradley, Jingya Ma, Christopher Tsu, Elizabeth Carideo-Cunniff, Vihren Kolev, James Garnsey, Pooja Shah, Erik Koenig, Hua Liao, Courtney Cullis
Journal: Cancer Research (2017)

Abstract Proper mitochondrial function is critical for energy production and the cycling of metabolites required for tumor establishment and growth. LonP1 is an ATP-dependent serine protease that is critical for maintaining mitochondrial protein homeostasis by degrading misfolded and damaged proteins in the mitochondrial matrix. Knockdown of LonP1 has been shown to reduce tumorogenesis and is consistent with the model that requires properly functioning mitochondria for tumor establishment. It is unclear what the role of LonP1 is in tumor maintenance and growth from an established tumor, therefore the LonP1 gene was mutated and complemented by a doxycycline-inducible copy of LonP1. These complementation clones have the ability to establish tumors in vivo in the presence of doxycycline, however upon doxycycline withdrawal the tumors regress and show evidence of apoptosis. These xenograft lines permit unique insight into not only potential LonP1 substrates but also the direct and indirect effects from loss of mitochondrial matrix protein homeostasis. Comparison and contrast of these complemented cell lines in vitro and in vivo by expression and proteomic analysis will be discussed. Citation Format: Benjamin S. Amidon, Dongyun Wu, John Bradley, Jingya Ma, Christopher Tsu, Elizabeth Carideo-Cunniff, Vihren Kolev, James Garnsey, Pooja Shah, Erik Koenig, Hua Liao, Courtney Cullis. LonP1 is required for tumor maintenance and growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1493. doi:10.1158/1538-7445.AM2017-1493