tbuckley/cabot-search huggingface dataset:
Abstract 4715: Combination of Tacedinaline and EHMT2 inhibition increases breast cancer cell death involving BIRC5 repression and GADD45A induction
Authors: Pei-Yi Chu, Ji-Ching Lai, Ming-Feng Hou, Chang-Shen Lin
Journal: Cancer Research (2019)

Abstract The genomes of cancer cells are different from those of normal cells. These differences include genetic and epigenetic alterations, such as variations of DNA methylation and histone modifications, which cause differential gene expression, increased cell growth/migration capacity, and may induce resistance to anticancer therapy. Thus, epigenetic modulation may have a chance to correct abovementioned cancer cell’s aberrations in gene expression and cell behaviors, resulting in eradication of primary and/or suppression of refractory cancers. Tacedinaline (CI-994) and UNC0638 are specific inhibitors of class I histone deacetylase (HDAC) and histone methyltransferase EHMT2 (G9a), which cause an increase of histone acetylation and a decrease of histone H3 dimethylation at lysine 9, respectively. Here we examined the therapeutic effect of CI-994 and UNC0638 combination on the triple-negative (MDA-MB-231) and estrogen receptor-positive (MCF-7) breast cancer cell lines. The results showed that the combination of CI-994 and UNC0638 was able to induce more severe cell death than either agent alone. Although the sub-G1 fraction and Annexin V-positive cells were increased, CI-994 and UNC0638 did not significantly induce the activities of caspases 3, 8 and 9, suggesting the involvement of non-canonical and caspase-independent cell death mechanism. Instead, CI-994 suppressed the expression of BIRC5 (Survivin, a member of the inhibitor of apoptosis protein) and, in combination with UNC0638, induced the expression of GADD45A (involved in stress-induced apoptosis). Mechanistically, combination of CI-994 and UNC0638 resulted in the changes of epigenetic marks, such as acetylation and methylation of histone H3, at the loci of BIRC5 and GADD45A, which were correlated with their altered gene expressions. Genetic knockdown of BIRC5 expression in MCF-7 decreased cell viability, supporting the pro-survival role of BIRC5 in breast cancer cells. Importantly, the targets of CI-994 (HDAC1, HDAC2) and UNC0638 (EHMT2), as well as BIRC5 were overexpressed in breast cancer specimens, especially those of triple-negative breast cancer (TNBC), based on the analyses of The Cancer Genome Atlas dataset. Meanwhile, the expression of GADD45A was downregulated. BIRC5 upregulation and GADD45A downregulation in breast cancer were associated with patient’s overall survival. These results suggest that Tacedinaline and UNC0638, or targeting the class I HDAC and EHMT2, may be a potential strategy to treat breast cancer including TNBC. Citation Format: Pei-Yi Chu, Ji-Ching Lai, Ming-Feng Hou, Chang-Shen Lin. Combination of Tacedinaline and EHMT2 inhibition increases breast cancer cell death involving BIRC5 repression and GADD45A induction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4715.
Abstract 19851: Phenotyping or Genotyping to capture Clopidogrel Active Metabolite Generation.
Authors: Heleen Bouman, Jochem W van Werkum, Ankie M Harmsze, Nicoline J Breet, Hugo ten Cate, Christian M Hackeng, Vera H Deneer, Jurriën M ten Berg
Journal: Circulation (2010)

Introduction: To assure an efficient and safe clopidogrel therapy in the individual patient, two different strategies have been proposed to optimize the response to clopidogrel. However, whether (1...
Linear and Arborizing Atrophic Plaque in an Elderly Man
Authors: Viseslav Tonkovic-Capin, Rick S. Bains
Journal: JAMA Dermatology (2019)

A man in his 80s presented with an 18-month history of an irregularly linear, rusty-brown, atrophic, streaklike plaque extending from the tip of his right shoulder to the right biceps, where it ended in arborizing purple plaque. What is your diagnosis?
Abstract 3378: Systematic pharmacogenomic analysis of large patient derived xenografts data
Authors: Arvind Singh Mer, Wail Ba-alawi, Petr Smirnov, Yi Xiao Wang, Ben Brew, Ming-Sound Tsao, David Cescon, Anna Goldenberg, Benjamin Haibe-Kains
Journal: Cancer Research (2019)

Abstract One of the key challenges in cancer precision medicine is finding robust biomarkers of drug response. Patient-derived tumor xenografts (PDXs) have emerged as reliable preclinical models since they better recapitulate tumor response to chemo- and targeted therapies. However, the lack of standard tools poses a challenge in the analysis of PDXs with molecular and pharmacological profiles. Efficient storage, access and analysis is key to the realization of the full potential of PDX pharmacogenomic data. To address this, we have developed Xeva (XEnograft Visualization &amp; Analysis), an open-source software package for processing, visualization and integrative analysis of a compendium of in vivo pharmacogenomic datasets. The Xeva package follows the PDX minimum information (PDX-MI) standards and can handle both replicate-based and 1x1x1 experimental designs. We used Xeva to characterize the variability of gene expression and pathway activity across passages. We found that only a few genes and pathways have passage specific alterations (median intraclass correlation of 0.53 for genes and positive enrichment score for 92.5% pathways). For example, activity of the mRNA 3'-end processing and elongation arrest and recovery pathways were strongly affected by model passaging (gene set enrichment analysis false discovery rate [FDR] &amp;lt;5%). We then leveraged our platform to link the drug response and the pathways whose activity is consistent across passages by mining the Novartis PDX Encyclopedia (PDXE) data containing 1,075 PDXs spanning 5 tissue types and 62 anticancer drugs. We identified 87 pathways significantly associated with response to 51 drugs (FDR &amp;lt; 5%), including associations such as erlotinib response and signaling by EGFR in cancer pathways and MAP kinase activation in TLR cascade and binimetinib response. Among the significant pathway-drug associations, we found novel biomarkers based on gene expressions, Copy Number Aberrations (CNAs) and mutations predictive of drug response (concordance index &amp;gt; 0.60; FDR &amp;lt; 0.05). Xeva provides a flexible platform for integrative analysis of preclinical in vivo pharmacogenomics data to identify biomarkers predictive of drug response, a major step toward precision oncology. Citation Format: Arvind Singh Mer, Wail Ba-alawi, Petr Smirnov, Yi Xiao Wang, Ben Brew, Ming-Sound Tsao, David Cescon, Anna Goldenberg, Benjamin Haibe-Kains. Systematic pharmacogenomic analysis of large patient derived xenografts data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3378.
Abstract 4443: Targeting E3 ligase PJA1 via TGF-β pathway in hepatocellular carcinoma
Authors: Kazufumi Ohshiro, Jian Chen, Wilma Jogunoori, Chu-Xia Deng, Bibhuti Mishra, Shulin Li, Lopa Mishra
Journal: Cancer Research (2019)

Abstract Background: RING-finger E3 ligases are instrumental in the regulation of inflammatory cascades, apoptosis, and cancer. However, their roles are relatively unknown for specific pathways such as TGF-β/Smad signaling that when disrupted, drive hepatocellular carcinoma (HCC). We, therefore, analyzed the TCGA database for the TGF-β pathway associated 22 E3 ligases, and identified mRNA alterations in 55% of tumors, most prominently for UCHL5 (16.4%), PJA (12.7%), WWP2 (11.8%), SKP2 (9.1%), SMURF1 and SMURF2 (8.2 and 9.1%, respectively), ITCH (6.4%) and KEAP1 (6.4%). We previously uncovered increased PJA1 expression with loss of TGF-β substrates Smad3 and β2SP in TGF-β deficient mice (β2SP+/-/Smad3+/- mice), which spontaneously develop characteristics of a human stem cell syndrome, and HCC by 12-15 months. Here, we report PJA1 oncogenic function in HCC progression. HCC. Methods &amp; Results: (1) Analyses of primary HCC datasets (91 cases) reveal increased PJA1 correlates with decreased levels of TGF-β/Smad3 and their regulated genes including Smad8 and TGFBR3. (2) To better understand the implications of PJA1-mediated deregulation of Smad3-promoted transcription in HCC, we compared transcriptomes of HepG2 cells silenced by PJA1 shRNA or treated with TGF-β: 1,584 genes including c-FOS were co-up-regulated and 1,279 genes including TERT were co-down-regulated. PJA1 expression in HCC was negatively associated with c-FOS and SERPINE1 expression. (3) PJA1 interacts with the Smad3 MH2 and Linker domains and multiple domains of β2SP to promote ubiquitin-mediated phosphor-Smad3 degradation in a TGF-β dependent manner, resulting in decreased TGF-β target gene activity. (4) We found that PJA1 expression in HCC is negatively associated with c-FOS and SERPINE1 expression. (5) Overexpression of a RING-domain-deleted PJA1 mutant reduced the proliferation rate in HCC cells and PJA1 knockdown significantly decreased anchorage-independent growth and tumorigenicity of HCC cells. (6) Our results also demonstrate that PJA1 promotes liver cancer stem cell formation in Smad3+/- mice. Conclusions: This study demonstrates that loss of expression of β2SP and Smad3 through PJA1 could play an important role in HCC progression and that PJA1 is a potential novel therapeutic target for this lethal disease. Citation Format: Kazufumi Ohshiro, Jian Chen, Wilma Jogunoori, Chu-Xia Deng, Bibhuti Mishra, Shulin Li, Lopa Mishra. Targeting E3 ligase PJA1 via TGF-β pathway in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4443.
Phase 2 study results of murlentamab, a monoclonal antibody targeting the Anti-Mullerian-Hormone-Receptor II (AMHRII), acting through Tumor-Associated Macrophage engagement in advanced/metastatic colorectal cancers
Authors: E. Van Cutsem, B. Melichar, M. Van den Eynde, J. Prausova, K. Geboes, J. Dekervel, D. Vitaskova, A. De Cuyper, Z. Linke, N. Van Acker, F. Frenois, G. Noel, J. Prost, J. Barret, B. Jean, I. Tabah-Fisch
Journal: Annals of Oncology (2019)
Abstract 1391: Development of <i>in vitro</i> multiplex colorectal cancer associated mutation detection assay powered with xenonucleic acid
Authors: Michael Y. Sha, Anna J. Lee, Michael J. Powell, Aiguo Zhang
Journal: Cancer Research (2019)

Abstract Precise detection of cancer associated mutations have many advantages including diagnosis and monitoring of the disease and monitoring development of drug resistance. However, unlike germline mutations, somatic mutations in cancer are found at a much lower frequency. For this reason it remains a challenge especially when trying to detect mutations from limited amount of patient tissue biopsy or liquid samples. Currently, detection and genotyping of these mutations is heavily dependent on deep NGS methods. These procedures, however, are costly and time consuming. Here, we developed an alternative high-throughput method that combines DiaCarta’s proprietary xenonucleic acid (XNA) technology that allows target enrichment, and Luminex MAGPIX platform technology that enables simultaneous detection of up to 50 mutation targets. Briefly, multiplex PCR amplification of cancer associated genes is conducted in the presence of XNA. In this reaction, XNA specifically suppresses the wild-type DNA from being amplified and thus, only generates amplicons from the genes that carry mutations. The amplicons are then hybridized in a single tube that contains a set of magnetic beads. Each bead is uniquely color-coded for identification, and each corresponds to a single mutation of interest. The beads are analyzed on Luminex platform for genotyping of the mutations. Using this method, we compared conditions with or without XNA for target amplification. Our preliminary data show that when we tested the cancer oncogene KRAS exon 2 mutation variations, we find that 100% correct allele call was made with XNA for all 7 reference mutations genes. However, in conditions without XNA, the PCR product was composed of mostly wild-type sequences, and thus, only two correct allele calls (28.6%) were made. Consequently we have showed a clear advantage of XNA technology for efficient mutant target enrichment, followed by Luminex MAGPIX platform technology for simultaneous detection of multiple genetic targets. Multiplex capacity of both PCR and Luminex MAGPIX platform allows a significant reduction in the total amount of patient samples needed for precise mutation detection from each assay, especially for the mutations with low allelic frequency. Further development on this assay will provide a more reliable, sensitive and quick method for simultaneously detecting mutations associated with cancer in a single reaction. Citation Format: Michael Y. Sha, Anna J. Lee, Michael J. Powell, Aiguo Zhang. Development of in vitro multiplex colorectal cancer associated mutation detection assay powered with xenonucleic acid [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1391.
Quality of life and preoperative chemotherapy in gastric cancer in Chile: results from the observational study of perioperative chemotherapy in gastric cancer (PRECISO)
Authors: P. Betancour, B. Mueller, J. Sola, J. Arancibia, R. Ascui, I. Araya, M. Cerda, J. Miranda, E. Strube
Journal: Annals of Oncology (2019)
Abstract 2331: Intratumor adoptive transfer of IL-12 mRNA transiently engineered anti-tumor CD8+ T cells
Authors: Inaki Etxeberria, Elixabet Bolaños, Alvaro Teijeira, Arantza Azpilicueta, Jose Ignacio Quetglas, Alfonso Rodriguez Sanchez-Paulete, Itziar Otano, Uxua Mancheño, Sandra Hervas-Stubbs, Susana Inoges, Saray Garasa, Maite Alvarez, Pedro Berraondo, Ignacio Melero
Journal: Cancer Research (2019)

Abstract Adoptive T-cell therapy with TILs, CAR-T cells, and TCR-engineered T-cells is achieving remarkable clinical efficacy. Retroviral gene transfer of IL-12 into the T cell cultures markedly enhances efficacy but has shown unacceptable severe side effects in the clinic. To ensure transient gene transfer, tumor specific CD8 T cells were engineered by electroporation of mRNA encoding single chain IL-12 into OT1 and Pmel-1 TCR transgenic lymphocytes. Engineered T cells were injected intratumorally and achieved complete rejections not only of the injected lesion but also of distant concomitant tumors. Efficacy was further enhanced if a small dose of agonist anti-CD137 mAb was co-injected or if CD137-ligand mRNA was co-electroporated. Importantly, intratumor T-cell administration was more efficacious that the intravenous or subcutaneous routes. Therapeutic effects were dependent on IFNγ, cDC1 dendritic cells and endogenous T cells. Interestingly, treatment induced epitope spreading of the immune response to antigens not recognized by the adoptively transferred lymphocytes. Efficacy was also achieved when mouse TILs cultures were used and human TIL cultures can also be transiently IL-12 mRNA engineered. Intratumor release, transient IL-12 mRNA-engineering and repeated administration jointly constitute a safe, feasible and powerful cancer immunotherapy strategy. Note: This abstract was not presented at the meeting. Citation Format: Inaki Etxeberria, Elixabet Bolaños, Alvaro Teijeira, Arantza Azpilicueta, Jose Ignacio Quetglas, Alfonso Rodriguez Sanchez-Paulete, Itziar Otano, Uxua Mancheño, Sandra Hervas-Stubbs, Susana Inoges, Saray Garasa, Maite Alvarez, Pedro Berraondo, Ignacio Melero. Intratumor adoptive transfer of IL-12 mRNA transiently engineered anti-tumor CD8+ T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2331.
Abstract 649: Alpha -Santalol, a component of sandalwood oil inhibits migration of breast cancer cells by targeting beta-catenin pathway
Authors: Ajay Bommareddy, Kacey Knapp, Abigail Nemeth, Chandradhar Dwivedi
Journal: Cancer Research (2019)

Abstract Alpha-santalol, a terpenoid found in sandalwood oil has been shown to inhibit breast cancer cell growth in vitro by inducing apoptosis but the mechanisms underlying the growth inhibitory effects of alpha-santalol are not fully understood. In this study, we demonstrate that alpha-santalol treatment targets Wnt/beta-catenin pathway to inhibit migration of cultured breast cancer cells. Exposure of MDA-MB 231 and MCF-7 cells to alpha-santalol resulted in a significant reduction in their migratory potential and wound healing ability. In addition alpha-santalol affected the localization of beta-catenin from cytosol to nucleus in MDA-MB 231 cells. In conclusion, the present study indicates that alpha-santalol inhibited migration of breast cancer cells may be mediated in part by targeting Wnt//β-catenin pathway, and that beta-catenin represents an important target of alpha-santalol’s response for future pre-clinical studies. Citation Format: Ajay Bommareddy, Kacey Knapp, Abigail Nemeth, Chandradhar Dwivedi. Alpha -Santalol, a component of sandalwood oil inhibits migration of breast cancer cells by targeting beta-catenin pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 649.
Abstract LB-052: Detection of rare, deleterious clonal mutations during unrelated allogeneic hematopoietic stem cell transplants using an error correction pipeline for NGS
Authors: Wing Hing Wong, Andrew Young, Todd Druley
Journal: Cancer Research (2019)

Abstract While next-generation sequencing (NGS) has transformed our ability to characterize the genome, it is limited in detection of rare mutations due to a high error rate of ~0.5-2.0%. We have developed an error correction pipeline and previously demonstrated that our process is capable of detecting variants as rare as 1:10,000 or 0.0001 VAF. Using our error correction pipeline, we have recently identified leukemia-related hematopoietic clones in a cohort of young healthy bone marrow donors (median age 26). In the context of allogeneic hematopoietic stem cell transplantation (HSCT), we sought to determine whether these detected leukemia-related clones of donor origin selectively engraft and correlate with transplant-related morbidities in recipients post-HSCT. Genomic profiles of pre-transplant donor samples were compared to the genomic profiles of corresponding recipient samples post-HSCT. Results show that two-thirds of the healthy donor samples harbor deleterious hematopoietic clones and that these specific clones are significantly more likely to engraft compared to benign clones. We also found that 75% of recipients who had at least one persistently engrafted, deleterious mutation developed chronic GvHD versus 50% of those without persistently engrafted clones with deleterious mutations. In comparing the results from our error correction pipeline and conventional short tandem repeat (STR) testing for donor-patient chimerism, we showed that our method provides a highly sensitive approach to both screening for donors without deleterious clones and monitoring residual disease in recipients following hematopoietic stem cell transplants (HSCT). Furthermore, the clinical implications of these results warrant a large-scale study using our error correction pipeline to detect rare variants in HSCT. Citation Format: Wing Hing Wong, Andrew Young, Todd Druley. Detection of rare, deleterious clonal mutations during unrelated allogeneic hematopoietic stem cell transplants using an error correction pipeline for NGS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-052.
Abstract 2175: Synthetic antigen receptor mesenchymal stem cells (SAR-MSCs) targeting perlecan for drug delivery to ovarian cancer
Authors: Susheel Kumar Nethi, Dristhi Sehgal, Shen Cheng, Jayanth Panyam, Swayam Prabha
Journal: Cancer Research (2019)

Abstract Mesenchymal stem cells (MSCs) can be engineered with polymeric nanoparticles for tumor-targeted delivery of small molecule drugs. Such nano-engineered MSCs have demonstrated exciting anticancer activity in multiple ovarian cancer models. Despite significantly improved delivery of chemotherapeutics to tumor tissues, non-specific accumulation of MSCs in clearance organs remains a concern. Paralleling the concept of CAR-T cells, we advance here a strategy for synthetic modification of MSCs with antibodies targeting specific antigens overexpressed on cancer cells. Our approach consists of stably incorporating recombinant protein G (PG) on the surface of MSCs, followed by binding of a full-length IgG to the PG handle. Because protein G binds to the Fc region of IgG, antigen-binding affinity of the antibody is conserved. We have previously shown the overexpression of perlecan (HSPG2) on ovarian cancer cells and its correlation to poor patient survival. In the current study, we investigated the incorporation of anti-perlecan antibody on the surface of nano-engineered MSCs. The anti-perlecan IgG antibody was first derivatized with palmitic acid (PA), which was then used to insert PG on MSCs cell membrane. We characterized the PAPG derivative by LC/Q-TOF/MS. Flow cytometry and confocal microscopy were used to confirm the incorporation of fluorescently labeled PAPG handle on MSC surface. Similarly, the binding of fluorescently labeled anti-perlecan IgG to PAPG-functionalized MSCs was confirmed by flow cytometry. We are currently investigating the anticancer efficacy of paclitaxel-loaded, anti-perlecan SAR-MSCs using in vitro and mouse models of ovarian cancer. Citation Format: Susheel Kumar Nethi, Dristhi Sehgal, Shen Cheng, Jayanth Panyam, Swayam Prabha. Synthetic antigen receptor mesenchymal stem cells (SAR-MSCs) targeting perlecan for drug delivery to ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2175.