tbuckley/cabot-search huggingface dataset:
Abstract 3839: MLN8237 treatment in an orthoxenograft rodent model for malignant peripheral nerve sheath tumors
Authors: Oliver Mrowczynski
Journal: Cancer Research (2017)

Abstract Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that arise from peripheral nerves and often occur in the extremities. MPNSTs arise sporadically or in the neurofibromatosis type one (NF1). NF1 is an autosomal-dominant disorder characterized by neurofibromas, cutaneous hyperpigmentation, and intellectual deficits affecting 1 in 3000 births. The lifetime risk of a person with NF1 developing MPNSTs ranges between 8-13%. MPNSTs have increased expression of the oncogene Aurora kinase A. This leads to enhanced cell proliferation, making MPNSTs extremely aggressive, with high potential for metastasis, and devastating prognosis, with five year survival estimates ranging from a dismal 15-60%. MPNSTs are currently treated with surgical resection, sometimes requiring limb amputation, as well as chemoradiation, all of which demonstrate limited effectiveness, and highlight the necessity for novel therapies. To evaluate the effectiveness of new treatments, a translationally accurate, robust, and cost-effective model is crucial. A major goal of this study was to produce an orthotopic xenograft murine MPNST model for evaluation of novel therapies, which we created by intra-neural injection of luciferase transfected MPNST cells into the mice sciatic nerve. Our model circumvents drawbacks of previous in vivo models by producing a robust tumor in the physiologically relevant microenvironment of the nerve that allows for accurate tumor burden quantification through luciferin fluorescence. Another goal of this study was to demonstrate the effectiveness of MLN8237 for MPNST treatment. MLN8237 is an aurora kinase A inhibitor that we demonstrate to decrease MPNST burden and increase survival significantly. This study provides a robust and reproducible MPNST model, allowing for the advancement of MPNST therapy. This study also demonstrates the effectiveness of MLN8237 for MPNST treatment. Together, our data has major implications on the future of MPNST research by providing a robust murine model as well providing evidence that MLN8237 is an effective treatment for MPNSTs. Note: This abstract was not presented at the meeting. Citation Format: Oliver Mrowczynski. MLN8237 treatment in an orthoxenograft rodent model for malignant peripheral nerve sheath tumors [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 3839. doi:10.1158/1538-7445.AM2017-3839
Abstract 64: Meditope SnAP-body technology facilitates enhanced internalization andin vivoefficacy of antibody therapeutics
Authors: Karin Forster, Elisabeth Gardiner, Stephanie Hsieh
Journal: Cancer Research (2017)

Abstract Meditope Biosciences has developed a way to use SnAP technology to promote internalization of antibody receptor complexes through a novel construct called a SnAP-body. Meditope’s SnAP platform functionalizes monoclonal antibodies to bind to specific meditope peptides; this property can be used to directly facilitate receptor crosslinking when meditope-enabled antibodies are bound to cell surface receptors. SnAP-bodies are self-crosslinking meditope-enabled antibodies which permit a meditope peptide to specifically interact with a meditope-enabled antibody at the cell surface upon antigen engagement. Antigen-antibody complex formation through the specific contact of the SnAP-bodies and their cognate epitopes on the target antigen can increase clustering or co-localization of a cell surface antigen on a cell, which can promote enhanced internalization of the SnAP-body. The increased internalization can be used to clear or reduce the concentration of a cell surface antigen from the surface of a target cell or tumor. Enhancing internalization can increase the efficacy of antibody-based therapeutics, and in the case of antibody-drug conjugates, which require receptor internalization to deliver cytotoxic payloads, can reduce the amount of drug necessary to achieve a therapeutic effect. In vitro studies of SnAP-body binding to cell surface antigens demonstrate accelerated internalization of the antibody. In vivo, this translates into enhanced efficacy. The ability to see equivalent efficacy in the absence of toxin suggests a unique role for SnAP-body constructs in cancer therapeutics, especially in cases where lack of efficacy for a specific target is correlated with poor receptor internalization. Citation Format: Karin Forster, Elisabeth Gardiner, Stephanie Hsieh. Meditope SnAP-body technology facilitates enhanced internalization and in vivo efficacy of antibody therapeutics [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 64. doi:10.1158/1538-7445.AM2017-64
Abstract 1980: Fusion of cancer and stromal cells imaged by color -coded imaging of metasasis
Authors: Miki Nakamura, Atsushi Suetsugu, Kousuke Hasegawa, Takuro Matsumoto, Hitomi Aoki, Takahiro Kunisada, Masahito Shimizu, Shigetoyo Saji, Hisataka Moriwaki, Robert M. Hoffman
Journal: Cancer Research (2017)

Abstract We report here imaging of stroma during the metastatic process. RFP-EL4 lymphoma cells were injected subcutaneously in C57/BL6 GFP transgenic mice. Subcutaneous tumors were resected and immediately transplanted to the abdominal cavity of BALB/c nude mice. Metastases to the liver, perigastric lymph node, ascites, bone marrow and as well as the primary tumor were imaged. Metastases expressed GFP at low magnification. At higher magnification, yellow-remaining cancer cells resulting from fusion of GFP stromal cells and RFP cancer cells were observed. Metastasis contained fusion of caner and stromal cells which may be a feature of metastasis. Citation Format: Miki Nakamura, Atsushi Suetsugu, Kousuke Hasegawa, Takuro Matsumoto, Hitomi Aoki, Takahiro Kunisada, Masahito Shimizu, Shigetoyo Saji, Hisataka Moriwaki, Robert M. Hoffman. Fusion of cancer and stromal cells imaged by color -coded imaging of metasasis [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 1980. doi:10.1158/1538-7445.AM2017-1980
The periodontal war: microbes and immunity
Authors: Jeffrey L. Ebersole, Dolph Dawson, Pinar Emecen‐Huja, Radhakrishnan Nagarajan, Katherine Howard, Martha E. Grady, Katherine Thompson, Rebecca Peyyala, Ahmad Al‐Attar, Kathryn Lethbridge, Sreenatha Kirakodu, Octavio A. Gonzalez
Journal: Periodontology 2000 (2017)

Maintenance of periodontal health or transition to a periodontal lesion reflects the continuous and ongoing battle between the vast microbial ecology in the oral cavity and the array of resident and emigrating inflammatory/immune cells in the periodontium. This war clearly signifies many 'battlefronts' representing the interface of the mucosal-surface cells with the dynamic biofilms composed of commensal and potential pathogenic species, as well as more recent knowledge demonstrating active invasion of cells and tissues of the periodontium leading to skirmishes in connective tissue, the locality of bone and even in the local vasculature. Research in the discipline has uncovered a concerted effort of the microbiome, using an array of survival strategies, to interact with other bacteria and host cells. These strategies aid in colonization by 'ambushing, infiltrating and outflanking' host cells and molecules, responding to local environmental changes (including booby traps for host biomolecules), communicating within and between genera and species that provide MASINT (Measurement and Signature Intelligence) to enhance sustained survival, sabotage the host inflammatory and immune responses and by potentially adopting a 'Fabian strategy' with a war of attrition and resulting disease manifestations. Additionally, much has been learned regarding the ever-increasing complexity of the host-response armamentarium at both cellular and molecular levels that is addressed in this review. Knowledge regarding how these systems fully interact requires both new laboratory and clinical tools, as well as sophisticated modeling of the networks that help maintain homeostasis and are dysregulated in disease. Finally, the triggers resulting in a 'coup de main' by the microbiome (exacerbation of disease) and the characteristics of susceptible hosts that can result in 'pyrrhic victories' with collateral damage to host tissues, the hallmark of periodontitis, remains unclear. While much has been learned, substantial gaps in our understanding of the 'parameters of this war' remain elusive toward fulfilling the Sun Tzu adage: 'If you know the enemy and know yourself, you need not fear the result of a hundred battles.'
Abstract 2618: Agonist antibodies targeting OX40 and GITR enhance the activity of the IDO1-selective inhibitor epacadostat in preclinical models
Authors: Holly K. Koblish, Brendan Horton, Michael Hansbury, Sybil O'Connor, Kerri Lasky, Christina Stevens, Thomas Condamine, Leslie Hall, Liang-Chuan Wang, Yue Zhang, Horacio Nastri, Gregory Hollis, Reid Huber, Thomas Gajewski, Peggy Scherle
Journal: Cancer Research (2017)

Abstract The majority of immunotherapeutic agents developed thus far either attempt to stimulate a more productive anti-tumor immune response or to inhibit key proteins in the immunosuppressive tumor milieu. PD-1/PD-L1 axis blockade, CTLA-4 blockade and IDO1 inhibition are examples of the latter approach and have been utilized to reverse the suppressive tumor microenvironment, resulting in clinical benefit for cancer patients. Recent clinical and preclinical data have also demonstrated that combining these approaches results in enhanced therapeutic benefit. Notably, the IDO1-selective inhibitor epacadostat has been shown to increase the efficacy of two checkpoint inhibitors, the anti-CTLA-4 antibody ipilimumab and the anti-PD-1 antibody pembrolizumab, in patients with melanoma. Because both checkpoint receptors and IDO1 serve as negative regulators of the immune response, we also explored the ability of IDO1 inhibition to combine with agents that directly activate T cells through costimulatory receptors of the tumor necrosis factor receptor (TNFR) superfamily. Rodent active surrogate agonist antibodies to 4-1BB, OX40 and GITR were tested with epacadostat in multiple preclinical models. In the B16-SIY melanoma model that does not express IDO1 in tumor cells, both epacadostat and anti-OX40 had little effect, but the combination resulted in enhanced efficacy. This was associated with increased infiltrates of CD8+ T cells and decreased numbers of FoxP3+ TILs. Increased numbers of SIY-reactive T cells were found in both the tumor and the TDLN post-therapy. In contrast, epacadostat did not provide any enhancement to the activity seen with 4-1BB. Clear combinatorial effects were seen with anti-GITR and epacadostat in the more inflamed, IDO1-expressing PAN02 pancreatic cancer model. These data suggest that IDO1 inhibition can be effective in combination with agents that agonize T cell costimulatory receptors as well as with agents that block coinhibitory receptors. Citation Format: Holly K. Koblish, Brendan Horton, Michael Hansbury, Sybil O'Connor, Kerri Lasky, Christina Stevens, Thomas Condamine, Leslie Hall, Liang-Chuan Wang, Yue Zhang, Horacio Nastri, Gregory Hollis, Reid Huber, Thomas Gajewski, Peggy Scherle. Agonist antibodies targeting OX40 and GITR enhance the activity of the IDO1-selective inhibitor epacadostat in preclinical models [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 2618. doi:10.1158/1538-7445.AM2017-2618
Abstract 5847: SIRT1 protects against radiation-induced lung injury via de-acetylating the Ku70 and P65
Authors: Jianxin Xue, Lin Zhou, Feifei Na, Lei Deng, Jie Lan, Bo Lu, Adam Dicker, You Lu
Journal: Cancer Research (2017)

Abstract Radiation-induced lung injury (RILI) is a common and serious complication in the radiation therapy of thoracic cancer, which significantly restricts the radiation doses of tumor. The prevention and treatment of RILI have long been clinical challenges. SIRT1 is an NAD+ dependent protein deacetylase and the exact role of SIRT1 in RILI remains unclear. The aim of this study is to investigate the prevention and repairing efficacy of RILI by adenovirus-mediated SIRT1 gene overexpression in a mice model. Our studies confirmed that the protein expression and activity of SIRT1 in lung tissues were decreased in RILI mice models in a time-dependent manner, but the mRNA expression level was not obviously changed. The activity of SIRT1 was elevated by orally given resveratrol, an agonist of SIRT1. The extent of RILI could be evidently alleviated by orally given resveratrol, as assayed by histopathology, malondialdehyde (MDA) and plasma cytokines (IL-1β, TNF-α and active TGF-β1). Overexpressing SIRT1 could obviously mitigate the extent of RILI (H&amp;E staining and CT scan), the concentration of MDA and ROS in lung, IL-1β and active TGF-β1 in plasma; as well as improve the mice survival. Moreover, SIRT1 could inhibit the radiation-induced DNA damage in vivo and in vitro, and decreased the expression of acetylated- Ku70 in the lung. In vitro Co-IP experiment showed that the expression of SIRT1 in irradiated cells was reduced and the acetylated- Ku70 was increased; over-expressing SIRT1 promoted the de-acetylation of Ku70; interference of Ku70 could reverse the effect of SIRT1 in DNA repair. Furthermore, overexpressing SIRT1 could inhibit the acetylation level of NF-κB subunit RELA (P65) in the lung; in vitro report gene experiment showed that SIRT1 suppressed the NF-κB transcriptional activity. In conclusion, our results suggest that SIRT1 could evidently mitigate the RILI, repair the irradiation-induced DNA damage and inflammation via de-acetylating the Ku70 and P65. Our study may provide new avenue for the prevention and treatment of RILI in clinic. Note: This abstract was not presented at the meeting. Citation Format: Jianxin Xue, Lin Zhou, Feifei Na, Lei Deng, Jie Lan, Bo Lu, Adam Dicker, You Lu. SIRT1 protects against radiation-induced lung injury via de-acetylating the Ku70 and P65 [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 5847. doi:10.1158/1538-7445.AM2017-5847
Abstract 3209: Polo-like kinase 1 as a new molecular target for small cell lung carcinoma
Authors: Noro Rintaro, Masahiro Seike, Fenfei Zou, Akihiko Miyanaga, Kaoru Kubota, Akihiko Gemma
Journal: Cancer Research (2017)

No target therapies are presently available in the treatment of small-cell lung cancer of Lung (SCLC). Therefore there is a need to develop new therapeutic agents. The protein kinases are a family of genes that play critical roles in various signaling pathways. Some cancer cells show addiction to constitutive activation of certain signaling pathways for proliferation and survival. To identify new drug targets for SCLC, we screened a panel of small interfering RNAs (siRNAs) that target 720 genes encoding human protein kinases and related proteins using SBC5 SCLC cell (SN38 (irinotecan hydrochloride) resistant cell). PLK1 inhibition suppressed cell proliferation strongest among 20 significant promising total genes using different 5 SCLC cells as a varidation study). PLK1 mRNA expression was significantly higher than other pathological phenotypes among 20 celllines and the 200 clinical samples consist of three independent cohorts. The patients with high PLK1 expresssion was significantly associated with poor prognosis in SCLC patients. Furthermore we investigated the change of SN 38 sensitivity and preventing from SN38 resistance after knockdown PLK1.  Our results indicated that PLK1 inhibitor as BI 2536 and Volasertib, was a promising molecular target therapy for pharmacologic intervention in SCLC in both monotherapy and the combination therapy with SN38.  Note: This abstract was not presented at the meeting.  Citation Format: Noro Rintaro, Masahiro Seike, Fenfei Zou, Akihiko Miyanaga, Kaoru Kubota, Akihiko Gemma. Polo-like kinase 1 as a new molecular target for small cell lung carcinoma [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 3209. doi:10.1158/1538-7445.AM2017-3209
Abstract 487: A comprehensive target enrichment panel for fusion detection
Authors: Ashesh Saraiya, Brandon Young, Tobias Meißner, Brian L. Jones, Stephanie C. Huelga, Doug A. Amorese
Journal: Cancer Research (2017)

Abstract Growing interest in cancer classification and progression has accelerated the rate of novel gene fusions discovery with increasing recognition of their roles as biomarkers. RNA-Seq is an attractive method for expressed fusion discovery and detection because of its ability to provide unbiased fusion sequencing information. The ability to detect low expressing fusion transcripts, however, require high sequencing depth and represents a significant financial barrier and identification of clinically relevant fusion sequences from a large data set can be a bioinformatics challenge. To address these challenges we have tested the Ovation® Fusion Panel Target Enrichment System V2, a targeted RNA sequencing method using the Single Primer Enrichment Technology (SPET), with a number of control and clinical samples. Initial studies were performed using a comprehensive target enrichment panel targeting 502 genes with three samples from Horizon DX containing known fusions. Target enriched libraries were constructed with 10 ng and 100 ng inputs and the data was analyzed using the NuFuseD pipeline (available as a point and click BaseSpace application or downloadable linux package) which has been optimized for fusion analysis from this data. Expected fusions were identified at both input levels, even when down sampled to 500K reads, with fewer fusion calls compared to other publically available fusion detection software (Chimerascan and SOAPFuse), suggesting a lower false positive rate. NuFuseD fusion calls are provided with a P-value to help prioritize the identified fusions for subsequent validation. Additionally, NuFuseD detected novel fusions in the control samples demonstrating the advantage of a comprehensive panel compared to more restricted panels. We further validated the target panel using control RNA (UHR and Human Brain) and fresh or FFPE cell lines (NCI-H2228, HCC1937) to further demonstrate our ability to identify known fusions. Finally, the system was evaluated at an external site using patient FFPE samples. These samples (N=8) were from a set of breast, liver and ovarian cancers, containing a unique fusion in 4 of the samples based on DNA based sequencing. Only 1 of the 4 expected fusions were identified using whole transcriptome data (100 million reads) while 3 of the 4 fusions were detected with this assay (10 million reads) demonstrating its ability to generate targeted RNA sequencing libraries with increased sensitivity of gene fusion detection and reduced sequencing costs compared to standard RNA-Seq methods. Citation Format: Ashesh Saraiya, Brandon Young, Tobias Meißner, Brian L. Jones, Stephanie C. Huelga, Doug A. Amorese. A comprehensive target enrichment panel for fusion detection [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 487. doi:10.1158/1538-7445.AM2017-487
Abstract 3167: MIF-induced stat3 activation promotes resistance to MEK blockade in KRAS mutant colorectal cancer cells
Authors: Seul-Ki Cheon, Hwang-Phill Kim, Ye-Lim Park, Si Hyun Lee, Jun-Kyu Kang, Yoojoo Lim, Sang-Hyun Song, Sae-Won Han, Tae-You Kim
Journal: Cancer Research (2017)

Abstract Although MEK blockade has been highlighted as a promising anti-tumor drug, it has poor clinical efficacy in KRAS mutant colorectal cancer. Several feedback systems have been described in which inhibition of one intracellular pathway leads to activation of a parallel signaling pathway, thereby decreasing the effectiveness of single-MEK targeted therapies. In this study, we describe a feedback mechanism in which MEK inhibition leads to activation of macrophage migration inhibitory factor (MIF)-induced stat3 signaling pathway in KRAS mutant colorectal cancer (CRC) cells. We found that KRAS mutant CRC cells with refametinib, MEK inhibitor, induced MIF secretion and resulted in activation of Stat3. MIF knockdown by siRNA partially restored sensitivity to refametinib in KRAS mutant cells. In addition, combination with refametinib and 4IPP, a MIF inhibitor, effectively reduced the activity of stat3 and MAPK, more than single agent treatment. As a result, combined therapy was found to exhibit a synergistic growth inhibitory effect against refametinib-resistant cells by downregulating MIF expression. These results reveal that MIF-induced stat3 activation evoked an intrinsic resistance to refametinib. Our results provide the basis for a rational combination strategy against KRAS mutant colorectal cancers, predicated on the understanding of cross-talk between the MEK and MIF pathways. Citation Format: Seul-Ki Cheon, Hwang-Phill Kim, Ye-Lim Park, Si Hyun Lee, Jun-Kyu Kang, Yoojoo Lim, Sang-Hyun Song, Sae-Won Han, Tae-You Kim. MIF-induced stat3 activation promotes resistance to MEK blockade in KRAS mutant colorectal cancer 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 3167. doi:10.1158/1538-7445.AM2017-3167