tbuckley/cabot-search huggingface dataset:
Abstract 535: Deregulated Myc is an immunosuppressive switch
Authors: Roderik M. Kortlever, Nicole M. Sodir, Catherine H. Wilson, Deborah L. Burkhart, Lamorna Swigart, Trevor D. Littlewood, Gerard I. Evan
Journal: Cancer Research (2016)

Abstract Early tumor evolution through sustained oncogene activity selectively bypasses the engagement of cell-intrinsic tumor-suppressor signaling and cell-extrinsic microenvironmental restrictions. How the immune system may be involved is virtually unknown. We describe here the contributions of a conditional and reversible low-level expression of Myc in a mouse model of KrasG12D-driven non-small cell lung cancer. Deregulated Myc activity results in highly expansive tumors that appear embedded in inflamed regions and leads to a rapid reduction of mouse survival. Myc activation imposes an immediate switch to an immunosuppressive and pro-angiogenic microenvironment, facilitated through IL23- and CCL9-associated recruitment of PD-L1 loaded macrophages and local exclusion of T-lymphocytes. Reversibly, blocking the activity of Myc-driven IL23 and CCL9 expression or withdrawal of deregulated Myc activity in tumors established by oncogene cooperation results in tumor cell death and regression, associated with a collapse of the established microenvironmental changes and re-engagement of cytotoxic T-cells. During oncogene cooperation with Ras, deregulated Myc directs a sufficient and necessary switch to a microenvironment that shields tumor growth and expansion from immune suppression. Citation Format: Roderik M. Kortlever, Nicole M. Sodir, Catherine H. Wilson, Deborah L. Burkhart, Lamorna Swigart, Trevor D. Littlewood, Gerard I. Evan. Deregulated Myc is an immunosuppressive switch. [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 535.
Interlobar collateral ventilation in severe emphysema
Authors: Samih Khauli, Servet Bolukbas, Robert M Reed, Michael Eberlein
Journal: Thorax (2016)

A 72-year-old female with extensive smoking history and severe emphysema presented with weight loss and failure to thrive. A large right hilar mass was found on a CT of the chest, figure 1A. Despite complete obstruction of the bronchus intermedius, there was full inflation of the right lung, figure 1B, C.



Figure 1 
CT of the chest. (A) Coronal cut in mediastinal windows showing a large right hilar mass. The mass measured 4.1×4.5 cm and involved the right hilum and subcarinal mediastinum. There was complete encasement and endobronchial obstruction of the bronchus intermedius. (B) Airway segmentation using VIDA|vision software demonstrating the complete endobronchial obstruction of the bronchus intermedius. (C) Three-dimensional segmented airway overlaid on a coronal cut CT of the chest in lung windows. This image demonstrates that, despite the complete obstruction of the bronchus intermedius, there was full inflation of …
Abstract 1987: Recurrent chromosomal translocations mediate reprogramming of Myb dependent regulatory networks in adenoid cystic carcinoma
Authors: Kathryn Brayer, Scott A. Ness
Journal: Cancer Research (2016)

Abstract Adenoid Cystic Carcinoma (ACC), the second most common malignancy of salivary glands, is a rare tumor with bleak prognosis for which therapeutic targets are unavailable. Recently, we used RNA-sequencing (RNA-Seq) to analyze low-quality RNA from archival, formaldehyde-fixed, paraffin-embedded samples (1). In addition to detecting the most common ACC translocation, t(6;9) fusing the MYB proto-oncogene to NFIB, we also detected previously unknown t(8;9) and t(8;14) translocations fusing the MYBL1 gene to the NFIB and RAD51B genes, respectively. Mutated versions of c-Myb are potent oncoproteins, and Myb proteins are over- or highly-expressed in a wide variety of human tumors. Interestingly, ACC tumors with MYB and MYBL1 translocations displayed similar gene expression profiles, and the combined MYB and MYBL1 expression correlated with outcome, suggesting that the related Myb proteins are interchangeable oncogenic drivers in ACC. While RNA-Seq provides information about gene fusions, alternative RNA splicing and gene expression signatures, this type of data does not address how translocations alter transcription factor function. Previous studies in our lab, and others, have demonstrated that Myb proteins contain C-terminal regulatory domains and are known to interact with several proteins via C-terminal motifs (2). These regulatory and interaction sites are lost upon chromosomal translocation in ACC; however, the downstream affect of this loss is not understood. Do the translocations merely relieve Myb transcription factors of repressive regulatory signals, thereby globally increasing Myb-dependent gene expression or, does the altered protein allow novel protein-protein interactions which re-target Myb transcription factors? Furthermore, the most frequent translocations involve the relocation of a large enhancer regions. What role does the recruitment of novel enhancer regions play in up-regulating Myb protein expression? Using a combination of ChIP-Seq and digital genomic footprinting, we are attempting to understand the mechanism of regulatory rewiring observed in ACC tumors. References 1. Brayer et al. Recurrent Fusions in MYB and MYBL1 Define a Common, Transcription Factor-Driven Oncogenic Pathway in Salivary Gland Adenoid Cystic Carcinoma. Cancer Discovery. In press. 2. George and Ness (2014) Situational Awareness: Regulation of the Myb Transcription Factor in Differentiation, the Cell Cycle and Oncogenesis. Cancers: 6, 2049-2071. Citation Format: Kathryn Brayer, Scott A. Ness. Recurrent chromosomal translocations mediate reprogramming of Myb dependent regulatory networks in adenoid cystic carcinoma. [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 1987.
Specific Blood Pressure Targets for Patients With Diabetic Nephropathy?
Authors: Guido Grassi, Giuseppe Mancia, Peter M. Nilsson
Journal: Diabetes Care (2016)

Diabetic nephropathy represents a condition frequently detected in current clinical practice characterized by a very high cardiovascular risk profile. Blood pressure reduction via antihypertension drug treatment represents a therapeutic approach capable of exerting favorable effects on renal and cardiovascular outcomes. The purpose of this article is to review the current literature and results of key clinical trials pertaining to blood pressure goals of antihypertension treatment in these patients. The pros and cons of a less or a more intensive blood pressure goal in diabetic nephropathy will be discussed, with particular emphasis on the cardiovascular and renal effects of each therapeutic strategy.
Abstract 4952: Co-expression of pAKT and MYC is associated with aggressive disease in human prostate cancer
Authors: Nelma Pértega-Gomes, Svitlana Tyekucheva, Kathryn Penney, Giorgia Zadra, Lorelei A. Mucci, Massimo Loda
Journal: Cancer Research (2016)

Abstract Introduction: AKT and MYC are amongst the most prevalent oncogenes in prostate cancer (PCa). MYC cooperates with activated AKT in pre-clinical, genetically engineered in vivo models accelerating disease progression and increasing resistance to therapy. However, the clinical relevance of phosphoAKT/MYC co-expression in human prostate tumors remains unknown. Experimental Procedures: A prospective cohort (Physicians’ Health Study and Health Professionals Follow-up Study) of 578 men with PCa with a mean 13-year follow up was used. Protein expression of MYC and phosphoAKT (Serine 473) was characterized by immunohistochemistry on tissue microarrays. pAKT and MYC expression was analyzed using the Cri Vectra/InForm multispectral analysis platform. The InForm software package was trained to segment PCa regions only (i.e., no stromal regions were included in the analysis). We used quantile normalization to adjust for the potential batch effects of protein expression staining across each of the tissue microarrays using the limma package R. The continuous score for pAKT and MYC were divided into quartiles and assigned a value of 1, 2, 3 or 4 for low (1), moderate (2 or 3) and high staining (4). Spearman correlations between pAKT, MYC and the clinico-pathological data were calculated. Results: High pAKT and High MYC were co-expressed in 10% of patients. (Quartile 4). Also 10% were negative or weakly positive for both pAKT and MYC (Quartile 1). Only 3% of the High pAKT patients had weak or no expression of MYC and 4% of High_MYC patients had Low pAKT expression. The majority of patients were distributed in the Quartiles 2 and 3 (73%). Importantly, only High pAKT and High pMYC co-expressors were associated with tumor stage (pT3 or pT4) (p = 0.03), high Gleason Score (p = 0.021) and presence of metastatic disease (p = 0.011). GEP analysis showed that the same patients exhibited up-regulation of genes involved in cell invasion/migration capacity and stromal remodeling. Conclusions: Co-expression of AKT and MYC is associated poor clinical outcome in PCa patients. Gene expression profiling suggest that concomitant activation of AKT and MYC results in the activation of pathways associated with an invasive phenotype. Citation Format: Nelma Pértega-Gomes, Svitlana Tyekucheva, Kathryn Penney, Giorgia Zadra, Lorelei A. Mucci, Massimo Loda. Co-expression of pAKT and MYC is associated with aggressive disease in human prostate cancer. [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 4952.
Abstract 4726: Inhibitors of histone deacetylase 1 reverse the immune evasion phenotype to enhance T-cell-mediated lysis of prostate and breast carcinoma cells
Authors: Sofia R. Gameiro, Anthony S. Malamas, Massimo Fantini, Kwong Y. Tsang, Soldano Ferrone, James W. Hodge
Journal: Cancer Research (2016)

Abstract The clinical promise of cancer immunotherapy relies on the premise that the immune system can effectively recognize and eliminate tumor cells identified as non-self. However, tumors can evade host immune surveillance through multiple mechanisms, including epigenetic silencing of genes involved in antigen processing and immune recognition. Hence, there is an unmet clinical need to develop effective therapeutic strategies that can restore tumor immune recognition and thus promote long-lasting tumor control when combined with immunotherapy, such as immune checkpoint blockade and therapeutic cancer vaccines. Although epigenetic therapies have shown limited clinical benefit for patients harboring solid tumors, recent clinical reports suggest a strong potential for clinical synergy when combined with immunotherapy. We sought to examine the potential of clinically relevant exposure of prostate and breast human carcinoma cells to histone deacetylase (HDAC) inhibitors to reverse tumor immune escape to T-cell mediated lysis. Here we demonstrate that prostate and breast carcinoma cells are more sensitive to T-cell mediated lysis in vitro after clinically relevant exposure to epigenetic therapy with either the pan-HDAC inhibitor vorinostat or the class I HDAC inhibitor entinostat. This pattern of immunogenic modulation was observed against a broad range of tumor-associated antigens, such as CEA, MUC-1, PSA, and brachyury, and associated with augmented expression of multiple proteins involved in antigen processing and tumor immune recognition. Genetic and pharmacological inhibition studies identified HDAC1 as a key determinant in the reversal of carcinoma immune escape. Further, our findings suggest that the observed reversal of tumor immune evasion is driven by a response to cellular stress through activation of the unfolded protein response. This offers the rationale for combining HDAC inhibitors with immunotherapy, including therapeutic cancer vaccines. Citation Format: Sofia R. Gameiro, Anthony S. Malamas, Massimo Fantini, Kwong Y. Tsang, Soldano Ferrone, James W. Hodge. Inhibitors of histone deacetylase 1 reverse the immune evasion phenotype to enhance T-cell-mediated lysis of prostate and breast carcinoma cells. [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 4726.
Abstract 699: Inhibition of cathepsin L1 by U87 KIF9 suppression in glioblastoma multiforme: a potential therapeutic target
Authors: Maria M. Rubinstein, Jeffrey Segall
Journal: Cancer Research (2016)

Abstract Glioblastoma multiforme is a fatal primary brain cancer. It has remained one of the most difficult cancers to treat because of glioblastomas’ aggressive and local invasive nature. Glioblastoma tumors have many myeloid cells, especially microglia. Increased levels of microglia result in increased glioblastoma invasion and are associated with worse clinical outcomes. Glioblastomas’ infiltrative mechanisms are mostly unknown which hinder the efficacy of current treatments. Therefore, further investigations on the mechanisms responsible for local invasion are potential targets for therapeutic interventions. Recently, there has been interest in evaluating the role of kinesin family members (KIFs) and cathepsins (CTS) as possible targets for therapeutic interventions. KIFs play an essential role in both physiological axonal transport processes and in processes of cell division. Previous studies have investigated the inhibition of KIF11 as a possible therapeutic target in glioblastoma. Preliminary studies in our group have found that the inhibition of KIF9 reduces microglia-stimulated glioma invasion. CTS, which are proteases that function in many pathways and increase neoplastic progression, are other possible therapeutic targets. Specifically in glioblastoma, inhibition of cathepsin L1 (CTSL1) (i) promotes tumor cell death, (ii) decreases apoptosis threshold and (iii) sensitizes glioblastoma cells to radiation. Our study investigated the role of KIF9 suppression in secretion and production of CTSL1. In order to investigate this relationship, U87 cells were incubated with and without the presence of microglia. Non-targeting and stable KIF9 knockdown cells were incubated with and without the presence of microglia. CTSL1 concentration levels were measured by enzyme immunoassay (ELISA). We investigated CTSL1 concentrations in the cell lysates as well as the cell supernatants. Our results demonstrated an overall decrease in production and secretion of CTSL1 in KIF9 knockdown cells as compared to non-targeting shRNA cells. The effect of KIF9 knockdown was evident in the presence and absence of microglia. Although the exact mechanism needs to be further clarified, inhibition of CTSL1 by KIF9 suppression could be a possible potential target for therapeutic intervention. Citation Format: Maria M. Rubinstein, Jeffrey Segall. Inhibition of cathepsin L1 by U87 KIF9 suppression in glioblastoma multiforme: a potential therapeutic target. [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 699.
Abstract 159: Analysis of resistance to the combination of a PI3K- and Parp-inhibitor using a genomic sequencing approach
Authors: Sheida Nabavi, Ashish Juvekar, Nicholas Wang, Lewis C. Cantley, Gerburg M. Wulf
Journal: Cancer Research (2016)

Abstract The objective of this study is to investigate the genomic and transcriptonal changes that are associated with resistance to treatment with the combination of a PI3K-inhibitor (NVP-BKM120) and a PARP-inhibitor (Olaparib). Previous studies have shown that the combination of a PI3K-inhibitor and a PARP-inhibitor synergistically reduced the growth of BRCA-related xenograft tumors derived from patients with TNBC. However, in clinical practice, primary and secondary resistance to this combination is observed. We hypothesize that acquired resistance is the result of a genomic evolution resulting from the selection pressure exerted by the drug treatment. We used a genetically engineered mouse model, K14-Cre BRCA1f/fp53f/f, where primary tumors had been propagated in Cre-negative littermates and treated to point of resistance with NVP-BKM120 or NVP-BKM120 plus Olaparib. For each of the three tumors, we analyzed exome sequencing and RNA-seq using Illumina technology at the stage of sensitivity (C), resistance to PI3K-inhibition (B) and resistance to the combination (BO); i.e. for each individual tumor a parental clone and its drug-resistant subclones, obtained in vivo, were analyzed. We used the Mutect software tool to call somatic mutations, VarScan2 to call somatic copy number variations, Cuffdiff for differential expression analysis, and TophatFusion. Data were integrated to identify genes for functional analyses using MetaCore and MSigDB software tools. We found that tumors resistant to the combination drug treatment in general had fewer gross genomic alterations (CNVs) than parental tumors, indicative of evolution of a less variable subclone. However, these tumors also displayed a higher number of non-synonymous mutations than their parental clone. Pathway analysis showed that somatically mutated genes in PI3K-inhibitor resistant tumors were highly enriched for antigen processing and presentation, while those of tumors resistant to the combination treatment were enriched for histone modification pathways. Notably, the tumors resistant to PI3K-inhibitor alone were enriched for Insulin-processing pathways. Genomic losses in PI3K-inhibitor treated tumors enriched for the estrogen receptor pathway (ESR) in breast cancer and DNA damage pathways. In conclusion, our experimental design of analyzing isogenic tumors resistant to PI3K- or combined PI3K- and Parp-inhibitors enabled us to identify genomic alterations and pathways that explain the evolution to drug resistance. Citation Format: Sheida Nabavi, Ashish Juvekar, Nicholas Wang, Lewis C. Cantley, Gerburg M. Wulf. Analysis of resistance to the combination of a PI3K- and Parp-inhibitor using a genomic sequencing approach. [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 159.
Abstract 4844: Thymoquinone induces apoptosis through inhibition of JAK2/STAT3 signaling via production of ROS in human renal cancer Caki cells
Authors: In Gyeong Chae, Kyung-Soo Chun
Journal: Cancer Research (2016)

Abstract Thymoquinone (TQ), a compound isolated from black seed oil (nigella sativa), has been reported to possess anti-inflammatory and anticancer activities. However, the molecular mechanisms underlying the anticancer effects of TQ in renal cell carcinoma (RCC) remain poorly understood. This study revealed that treatment with TQ significantly reduced the cell viability and induced apoptosis in Caki cells as evidenced by the induction of p53 and Bax, release of cytochrome c, cleavage of caspase-9, and -3 and PARP and the inhibition of Bcl-2 and Bcl-xl expression. TQ inhibited the constitutive phosphorylation of signal transducer and activator of transcription-3 (STAT3) in Caki cells by blocking the phosphorylation of upstream Janus-activated kinase-2 (JAK2) kinases. Moreover, TQ attenuated the expression of STAT3 target gene products, such as survivin, cyclin D1, and D2. Since ROS is a universal entity mediating apoptosis, we examined whether TQ induced apoptosis via ROS formation. Treatment with TQ generated ROS in these renal cancer cells. Pretreatment of cells with ROS scavenger N-acetyl cysteine (NAC) abrogated the inhibitory effect of TQ on the JAK2/STAT3 signaling and rescued cells from TQ-induced apoptosis by blocking the induction of p53, and the cleavage of caspase-3, -9 and PARP in Caki cells. In conclusion, TQ induced apoptosis in Caki cells via generation of ROS, induction of p53, activation of caspases and inhibition of STAT3 signaling pathway. Citation Format: In Gyeong Chae, Kyung-Soo Chun. Thymoquinone induces apoptosis through inhibition of JAK2/STAT3 signaling via production of ROS in human renal cancer Caki cells. [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 4844.
Secondary Central Nervous System (CNS) Involvement in Patients Diagnosed with Diffuse Large B-Cell Lymphoma (DLBCL) during the First Line R-CHOP Treatment and after the End of Treatment
Authors: Joanna Romejko-Jarosinska, Michal Osowiecki, Beata Ostrowska, Martyna Kotarska, Katarzyna Domanska-Czyz, Marcin Szymanski, Lukasz Targonski, Anna Borawska, Agnieszka Druzd-Sitek, Ewa Paszkiewicz-Kozik, Lidia Poplawska, Grzegorz Rymkiewicz, Jan Walewski
Journal: Blood (2015)
Abstract 4824: Synergistic interaction of PIM kinase inhibitor, JP_11646, and cytotoxic or targeted therapies in acute leukemia models
Authors: Krista Pundt, Camern Baldino, Justin Caserta, Alex Adjei, Kelvin Lee, Xu Zhu, Alissa Verone-Boyle, Frank Engler, Laura Pitzonka, Gerald Fetterly
Journal: Cancer Research (2016)

Abstract Standard therapy for acute myeloid leukemia (AML) results in significant mortality and morbidity with an overall cure rate of only 25%. Implementation of novel therapeutic options is needed in order to significantly improve patient survival and outcome. PIM serine/threonine kinases are overexpressed in hematological malignancies and regulate cell cycle, survival and drug resistance pathways—thus providing viable therapeutic targets. We hypothesized that targeted or cytotoxic therapy will enhance anti-tumor activity in combination with JP-11646, a novel PIM2 inhibitor, in preclinical AML models. Preclinical data has shown JP-11646 exerted potent inhibition of AML cells in vitro and in vivo in subcutaneous AML xenograft models. An in vitro MTT assay was used to determine the overall anti-proliferative effects of single and combination therapies with respect to the downstream effects of PIM kinase and mechanism of action of JP-11646 in leukemia. First, the single agent efficacy in human AML (HEL, and MV(4;11)) cell lines were examined after 72 hours of exposure to JP-11646, rapamycin, daunorubicin and cytarabine. Overall potency, IC50, (0.17 μM (0.15-0.19), 0.003 μM (0.002-0.004), 0.067 μM(0.065-0.0699) and 0.31 μM (0.294-0.345), respectively) and maximal inhibition, Imax, of the various therapies was determined. Potential synergistic effects were first tested by treating AML cell lines with JP-11646 and daunorubicin, cytarabine, or rapamycin (an inhibitor of a pathway that regulates downstream molecules of the PIM kinase pathway). To quantify the synergy or interaction of JP-11646 in combination, a simple inhibitory non-competitive interaction model with an interaction parameter (Ø) as well as a three dimensional interaction surface was employed (Ø&amp;lt;1 synergism, Ø&amp;gt;1 antagonism). The intensity of the interaction (Ø) of JP-11646 with rapamycin (0.819 (0.395-0.543)), daunorubicin (0.469 (0.665-0.975)) or cytarabine (0.173 (0.118-0.229)) demonstrated synergistic effects across all combinations. Here, we demonstrate that novel drug targets and drugs for AML treatment alone, and in combination with pre-existing therapies, may lead to improved strategies for AML treatment and these findings support future development of JP-11646 in novel combinatorial regimens for AML therapy. Citation Format: Krista Pundt, Camern Baldino, Justin Caserta, Alex Adjei, Kelvin Lee, Xu Zhu, Alissa Verone-Boyle, Frank Engler, Laura Pitzonka, Gerald Fetterly. Synergistic interaction of PIM kinase inhibitor, JP_11646, and cytotoxic or targeted therapies in acute leukemia models. [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 4824.