bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3190: Genomic profiling of salivary gland tumors identifies novel and targetable alterations
Authors: Majewska Hanna , Müller Judith , Lakis Sotirios , Czapiewski Piotr , Gorczyński Adam , Iliszko Mariola , Skalova Alena , Dziadziuszko Rafal , Jassem Jacek , Biernat Wojciech , Menon Roopika , Heuckmann Johannes M. , Heukamp Lukas C. 
Published: July 2016

Abstract
Background
Salivary gland neoplasms represent a heterogeneous group of benign and malignant tumors that comprise 6% of all head and neck cancers. Due to their low incidence, these tumors are poorly understood and remain a diagnostic and therapeutic challenge.
Methods
Out of 182 analyzed salivary gland tumors with various histologies, eight were positive for ALK immunohistochemistry. The cut-off was 15% positive cells in either membranous, nuclear or cytoplasmic compartments. The ALK positive tumors were first subjected to FISH analysis. Subsequently, these tumors were analyzed using hybrid capture based next generation sequencing to confirm possible ALK gene fusions or copy number alterations, and to detect additional genomic alterations of clinical relevance.
Results
An in-depth genomic analysis of the samples resulted in the detection of inactivating mutations in BRAF (p.D594N) and TP53 (p.C238S), as well as amplifications of ERBB2 and ALK. Strikingly, a novel MYO18A (Exon1-40)-ALK (exon 20-29) gene fusion was detected in a patient with adenocarcinoma not otherwise specified. This tumor was FISH positive and 100% of cells showed strong membranous staining for ALK. MYO18A (Exon1-40)-ALK (exon 20-29) gene fusion resulted in the retention of the kinase domain of ALK and the coiled-coil domain of MYO18A. Similarly to other ALK fusions, we hypothesize that the coiled-coil domain of MYO18A mediates the dimerization and activation of MYO18A-ALK, thereby resulting in an overexpression of constantly activated ALK.
Conclusion
Using hybrid capture based next generation sequencing, we identified in salivary gland tumors numerous genomic alterations in therapeutically relevant genes and a novel gene fusion (MYO18A-ALK). Patients harboring this fusion may potentially benefit from treatment with ALK inhibitors.
Citation Format: Hanna Majewska, Judith Müller, Sotirios Lakis, Piotr Czapiewski, Adam Gorczyński, Mariola Iliszko, Alena Skalova, Rafal Dziadziuszko, Jacek Jassem, Wojciech Biernat, Roopika Menon, Johannes M. Heuckmann, Lukas C. Heukamp. Genomic profiling of salivary gland tumors identifies novel and targetable alterations. [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 3190.
Abstract 321: S49076, a novel kinase inhibitor of MET, AXL and FGFR, demonstrates marked in vitro and in vivo efficacy in hepatocellular carcinoma
Authors: Tijeras-Raballand Annemilai , Pasteur-Rousseau Adrien , Martinet Matthieu , Bonnin Philippe , Pocard Marc , Banquet Sébastien , Cattan Valérie , Raymond Eric , de Gramont Armand 
Published: July 2016

Abstract
Introduction: Hepatocellular carcinoma (HCC) is the second cause of cancer-related deaths worldwide. While sorafenib may improve overall survival in advanced HCC, new therapies are needed. Both preclinical and clinical data support a role of MET and AXL receptor tyrosine kinases in HCC progression. We thus evaluated S49076, a novel MET/AXL/FGFR inhibitor in HCC cell lines in vitro and in a transgenic mouse model of HCC.
Materials and Methods: MET and AXL expressions were assessed in a panel of HCC cell lines by western blot. Downstream signaling pathways were investigated in the presence of HGF, GAS6 and S49076. Cell invasion was evaluated on matrigel assay. Transgenic mice developing stage-defined HCC were treated with S49076 (50mg/kg). Tumor response was evaluated measuring liver volume by echo-doppler and the number of tumor nodules at intermediary (12weeks) and final sacrifice (16 weeks).
Results: Both MET and AXL are expressed in the majority of HCC lines screened. Notably, a high level of AXL was observed in the SK-HEP1 cells which were therefore selected for further investigation. MET and AXL pathways were strongly stimulated by their respective ligands, HGF and GAS6. Combination of HGF and GAS6 led to marked activation of ERK. S49076 inhibited MET and AXL pathway activation and HGF- and GAS6- induced invasion at nanomolar concentrations. In vivo anti-tumor efficacy of S49076 was demonstrated in a transgenic MET-expressing mouse model of HCC.
Conclusion: S49076 displayed strong MET and AXL pathway inhibition and anti-invasive properties in SK-HEP1 HCC cells. Moreover, S49076 demonstrated antitumor activity in a mouse model of HCC. Together, these results would support development of S49076 as an innovative treatment in HCC patients.
Citation Format: Annemilai Tijeras-Raballand, Adrien Pasteur-Rousseau, Matthieu Martinet, Philippe Bonnin, Marc Pocard, Sébastien Banquet, Valérie Cattan, Eric Raymond, Armand de Gramont. S49076, a novel kinase inhibitor of MET, AXL and FGFR, demonstrates marked in vitro and in vivo efficacy in hepatocellular 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 321.
Abstract 3215: GITRL-Fc can significantly reduce tumor growth by stimulating innate and adaptive immunity
Authors: Jie Hyun-Bae , Srivastava Minu K. , Mayes Erin , Yun Rui , Axelrod Fumiko , Monteon Jorge , Gurney Austin , Park. Angie In-Kyung 
Published: July 2016

Abstract
Although the interaction between GITR (Glucocorticoid-Induced Tumor Necrosis Factor Receptor) and GITRL (its ligand) is important for the development of immune responses, the cellular mechanisms underlying anti-tumor immunity including both innate and adaptive immunity is not fully understood. We generated a novel single-gene linkerless GITRL trimer fused to an immunoglobulin Fc domain (GITRL-Fc), and investigated its effect on controlling tumor growth and immune responses in preclinical tumor models. Treatment with GITRL-Fc significantly reduced tumor growth in several preclinical tumor models by inducing Th1 biased anti-tumor immunity and reducing Treg-mediated immune suppression. Immune cell depletion studies showed that anti-tumor immunity induced by GITRL-Fc depended on CD8+ T cells as well as NK cells. Furthermore, the combination of GITRL-Fc with PD-1 blockade significantly reduced the tumor growth in the Renca murine kidney adenocarcinoma tumor model. Taken together, these results suggest that GITRL-Fc can improve cancer treatment as a single agent or in combination therapy by enhancing innate and adaptive cellular immunity.
Citation Format: Hyun-Bae Jie, Minu K. Srivastava, Erin Mayes, Rui Yun, Fumiko Axelrod, Jorge Monteon, Austin Gurney, Angie In-Kyung Park. GITRL-Fc can significantly reduce tumor growth by stimulating innate and adaptive immunity. [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 3215.
Abstract 3240: Prostate cancer exosomes and their effects on macrophage engulfment and polarization
Authors: Weagel Evita G. , Meng Wei , Robison Richard A. , O’Neill. Kim L. 
Published: July 2016

Abstract
The purpose of this study is to explore the effects of prostate cancer-derived exosomes on macrophage engulfment and polarization. Exosomes are small vesicles secreted by virtually all cells, which contain nucleic acids, lipids, proteins, and carbohydrates. Exosomes can be abundantly found in cancer patient secretions (serum, urine, etc.) and contain a high amount of RNA molecules, some of them being miRNA, and parts of the DNA of the cell of origin. One of the functions of exosomes is to mediate cellular communication. This occurs as they are secreted from one cell and then distribute their contents into other cells. Some exosomes specifically target immune cells. The miRNA the exosomes carry can silence genes involved in the activation of these immune cells, leading to immune suppression and tumor growth. Macrophages are often found surrounding the tumor microenvironment, as they are recruited by tumor signals to promote angiogenesis and metastasis. These macrophages, which are often called tumor associated macrophages (TAMs), are exposed to various signals derived from the tumor microenvironment, including exosomes. Previous data generated in our lab suggests that the co-culture of macrophages with PC3 and DU145 cell lines results in a decrease in macrophage phagocytosis and an M2-like polarization state. For this study, we exposed U937 cells to phorbol 12-myristate 13-acetate (PMA) for 24 hours to allow for differentiation. Then, we co-cultured these macrophages with isolated exosomes from spent media from both PC3 and DU145 cell lines at 1, 2, 3, 4, 5, 6, 12, and 24 hours. We then allowed the macrophages to phagocytose fluorescent microbeads for 1 hour. Flow cytometry analysis of these macrophages revealed that the total bead phagocytosis starts decreasing at 3 hours of exosome co-culture compared to control. Interestingly, total bead phagocytosis resumes to normal at 12 and 24 hours of exosome co-culture. Gene expression analysis of these macrophages suggests an M2 phenotype from hours 2-24. These results suggest that prostate cancer-derived exosomes can target macrophages and affect their phagocytosis. Further research is required to elucidate the specific genes these exosomes target.
Citation Format: Evita G. Weagel, Wei Meng, Richard A. Robison, Kim L. O’Neill. Prostate cancer exosomes and their effects on macrophage engulfment and polarization. [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 3240.
Abstract 3246: Phytotherapy boosts innate immunity to maximize cancer survival
Authors: Lau Benjamin H. 
Published: July 2016

Abstract
We studied surgery, radiation, and chemotherapy in animals and found all these modalities suppressed cancer growth but they also impaired the immune functions of the animal host. We also studied phytotherapy (use of plant chemicals) and found it to have no side effects and with more lasting benefits. Using in vitro cell culture system with both malignant and non-malignant cells, and immune cells (macrophages and natural killer cells), we compared crude extract of Pacific yew and the chemotherapeutic drug Paclitaxel derived from Pacific yew. The crude extract or the drug was incubated separately with: human malignant ovarian cells, nonmalignant ovarian cells, macrophages, and natural killer cells. Cell viability was determined by MTT (methylthiazol tetrazolium) assay. Results show the drug damaged all these four types of cells while the crude plant extract only damaged the cancer cells showing its selective toxicity for cancer cells. Study with other phytochemicals also shows selective toxicity for cancer cells while enhancing the activities of immune cells. Phytotherapy is thus a non-toxic chemotherapy and immunotherapy. In our clinical observation, 160 men and women diagnosed with five types of cancer (72 with breast cancer, 28 with prostate cancer, 18 with colon cancer, 14 with lung cancer, 28 with ovarian cancer) chose to use phytotherapy (a plant-based diet) plus lifestyle modification. The five year survival of these patients were 90%, 89%, 83%, 86%, and 82%, respectively. Compared with five year survival data from National Cancer Institute (www.seer.cancer.gov) for these five types of cancer: 82%, 50%, 62%, 15%, and 45%, respectively, the phytotherapy group exhibits greater cancer survival. Since numerous studies have now revealed that cancer is attributable to our lifestyle habits – the way we eat, and the way we live, our data suggest that regardless of treatment choices, a change in diet and lifestyle is likely to improve cancer survival.
Citation Format: Benjamin H. Lau. Phytotherapy boosts innate immunity to maximize cancer survival. [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 3246.
Abstract 3255: Inhibition of intracrine VEGF signaling prevents colorectal cancer cell migration and invasion
Authors: Bhattacharya Rajat , Xia Ling , Fan Fan , Wang Rui , Boulbes Delphine , Ye Xiang-Cang , Ellis Lee 
Published: July 2016

Abstract
Introduction: Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis and vascular function. The mechanisms of VEGF signaling in angiogenesis have been extensively studied. However, its effects on tumor cell function remain to be elucidated. Our studies on depletion of VEGF by somatic knockout of the VEGF gene or by siRNA in human colorectal cancer (CRC) cell lines have demonstrated that loss of VEGF expression led to significantly decreased cell growth, increased apoptosis, and enhanced chemo-sensitivity of CRC cells through an intracrine signaling mechanism. These intracrine effects were mediated through VEGF by regulation of the activity of multiple receptor tyrosine kinases (e.g. EGFR, cMET) and downstream AKT signaling. Similar effects were observed by depletion of VEGF receptor 1 (VEGFR1), supporting the role of a novel intracellular VEGF-VEGFR1 complex in CRC cell survival. Since VEGF signaling has been shown to effect endothelial and tumor cell migration, we attempted to determine if inhibition of intracrine VEGF signaling affected CRC cell motility.
Methods: Migration and invasion of CRC cells, with and without VEGF depletion, were assayed using Boyden chambers and a serum gradient. Changes in cell morphology and epithelial to mesenchymal transition (EMT) markers and markers of cell motility were assessed by microscopy, immunostaining, and western blot analyses.
Results: Depletion of VEGF by siRNAs in multiple CRC cell lines led to a very strong inhibition of migration and invasion of CRC cells. Such inhibition was not observed when CRC cells were treated with bevacizumab to inhibit paracrine or autocrine signaling. Further examination revealed no significant changes in cell morphology. Other than Twist, there were no significant differences between specific markers of EMT indicating that differences in migration and invasion were not due to classic alterations in EMT. However, significant changes in activation of mediators of cell motility were observed. VEGF depleted CRC cells demonstrated significantly lower levels of phosphorylated focal adhesion kinase (p-FAK) compared to cells with normal VEGF expression. Analyses of upstream regulators indicated strong reduction in either p-cMET or p-SRC depending on cell type.
Conclusions: Inhibition of intracrine VEGF signaling strongly inhibits CRC cell migration and invasion by regulating proteins involved in cell motility.
Citation Format: Rajat Bhattacharya, Ling Xia, Fan Fan, Rui Wang, Delphine Boulbes, Xiang-Cang Ye, Lee Ellis. Inhibition of intracrine VEGF signaling prevents colorectal cancer cell migration and invasion. [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 3255.
Abstract 3276: The tissue and cellular destination of therapeutic IgGs in glioblastoma
Authors: Muller-Greven Gaelle , Carlin Cathleen , Toms Steven , Ahluwalia Manmeet , Bredel Markus , Lathia Justin , Rich Jeremy , Hamerlik Petra , Gladson Candece L. 
Published: July 2016

Abstract
Most patients with recurrent glioblastoma (GBM) are treated with bevacizumab, a humanized monoclonal antibody (mAb) that binds VEGF-A and inhibits its binding to VEGFR. Approximately 30% of GBM patients are non-responsive to bevacizumab and the underlying mechanism for the lack of response is not known. It has been assumed that bevacizumab solely targets circulating VEGF-A in blood. We hypothesized that bevacizumab and human IgGs in general gain access to the perivascular niche that contains cancer stem cells (CSCs) in GBM. We found that bevacizumab gains access to the perivascular tumor area through leaky blood vessels and was internalized by tumor cells in an orthotopic xenograft mouse model of GBM. In vitro, CSCs (CD133+) from GBM rapidly internalized either bevacizumab or human IgG into membrane protrusions that contained actin and internalization was significantly inhibited by a macropinocytosis inhibitor (EIPA), suggesting CSCs internalize bevacizumab or human IgG via macropinocytosis. Furthermore, bevacizumab or human IgG was largely detected in the Rab4+ “fast” recycling compartment at 5 min, and both were largely detected in the LAMP1+ compartment (late endosome/lysosome) at 3 hr in the CSCs. CSCs (CD133+) from GBM do not express the neonatal Fc receptor, the canonical pathway for recycling of IgG. Administration of bevacizumab to an orthotopic xenograft mouse model of established GBM showed that bevacizumab was partially co-localized with Rab4+ or with LAMP1+ in perivascular tumor cells, consistent with our in vitro findings. Taken together, our data show that in GBM, humanized IgG, including bevacizumab, gains access to the perivascular tumor space and is then macropinocytosed by CSCs and trafficked to a recycling compartment or to the late endosome/lysosome. These data suggest that alterations in endocytosis or recycling in the CSCs could impact the fate of therapeutic IgGs like bevacizumab and ultimately influence a patients’ response to GBM therapy.
Citation Format: Gaelle Muller-Greven, Cathleen Carlin, Steven Toms, Manmeet Ahluwalia, Markus Bredel, Justin Lathia, Jeremy Rich, Petra Hamerlik, Candece L. Gladson. The tissue and cellular destination of therapeutic IgGs in glioblastoma. [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 3276.
Abstract 3283: APRIL/BCMA activation promotes human multiple myeloma progression and further induces immunosuppressive bone marrow microenvironment
Authors: Tai Yu-Tzu , Acharya Chirag , An Gang , Moschetta Michele , Zhong Mike Y. , Feng Xiaoyan , Cea Michele , Cagnetta Antonia , Wen Kenneth , van Eenennaam Hans , van Elsas Andrea , Munshi Nikhil , Anderson Kenneth 
Published: July 2016

Abstract
Elevated B cell maturation antigen (BCMA) and its ligand a proliferation-inducing ligand (APRIL) may directly advance human multiple myeloma (MM) malignancy in vivo. Here, we first show that BCMA downregulation potently diminishes viability and colony formation of MM cells while BCMA overexpression augments MM cell growth and survival via induction of AKT, MAPK, and NFκB signaling cascades and molecules essential for proliferation and anti-apoptosis. Importantly, BCMA itself forces accelerated tumor growth of xenografted MM cells harboring p53 mutation in mice. BCMA-overexpressing tumors exhibit significantly enhanced CD31/microvessel density and VEGF than paired control tumors. Concurrently, these tumors express increased factors crucial for osteoclast activation, adhesion, and angiogenesis/metastasis, as well as immune inhibition including PD-L1, TGFβ and IL-10 which further triggers 38 IL-10 signaling molecules. In parallel, these identified target genes are induced by paracrine APRIL binding to BCMA in MM cells and they are potently blocked by an antagonistic anti-APRIL monoclonal antibody hAPRIL01A (01A). 01A is cytotoxic against MM cells protected by abnormal bone marrow (BM) myeloid cells, i.e., osteoclasts, macrophages, and plasmacytoid dendritic cells. It further decreases APRIL-induced adhesion and migration of MM cells via blockade of canonical and non-canonical NFκB pathways. It prevents in vivo MM cell growth within implanted human bone chips in SCID mice. 01A-inhibited MM cell viability induced by osteoclasts is further enhanced by lenalidomide and bortezomib. Taken together, these results further characterize new molecular mechanisms of APRIL/BCMA-induced in vivo MM progression and immunosuppressive BM microenvironment, strongly supporting targeting this prominent pathway in MM.
Citation Format: Yu-Tzu Tai, Chirag Acharya, Gang An, Michele Moschetta, Mike Y. Zhong, Xiaoyan Feng, Michele Cea, Antonia Cagnetta, Kenneth Wen, Hans van Eenennaam, Andrea van Elsas, Nikhil Munshi, Kenneth Anderson. APRIL/BCMA activation promotes human multiple myeloma progression and further induces immunosuppressive bone marrow microenvironment. [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 3283.
Abstract 3285: HTLV-1 viral oncogene Hbz induces leukemia with osteolytic bone involvement in mice
Authors: Esser Alison , Rauch Dan , Xiang Jingyu , Harding John , Kohart Nicole , Green Patrick , Niewiesk Stefan , Rosol Thomas , Ratner Lee , Weilbaecher Katherine 
Published: July 2016

Abstract
Adult T-cell leukemia/lymphoma (ATL) develops in a subset of patients infected with the HTLV-1 virus. Most ATL patients become refractory to chemotherapy and have a median survival time of 6 months. Although uncommon in hematologic malignancies, 80% of ATL patients develop osteolytic lesions and hypercalcemia of malignancy. Bone resident and metastatic tumors release paracrine factors that modulate the bone microenvironment to facilitate disease progression and decrease survival. HTLV-1 encodes 2 viral oncogenes, Tax and Hbz. Tax is critical to ATL development and regulates tumor growth and proliferation in part through trans-activation of NFκB and CREB. We have previously shown Tax expression driven by the Granzymbe B promoter is sufficient for the development of leukemia/lymphoma with osteolytic lesions and hypercalcemia. We and others have shown that Tax alters the expression of paracrine factors that modulate the bone microenvironment through effects on bone forming osteoblasts (OB) and bone resorping osteoclasts (OC). Tax is expressed in early lymphocyte transformation with low expression in advanced ATL. HBZ is expressed early in lymphocyte transformation and throughout ATL progression. We hypothesize that in ATL cells, HTLV-1 viral oncogenes Tax and Hbz cooperate to modulate bone metabolism in a paracrine manner to enhance ATL tumor growth and progression. Mice with Granzyme B driven Hbz expression (T and NK cells) develop leukemia/lymphoproliferative disease in lymph nodes correlating with increased spleen weight. We found that lymphoproliferative disease is also present in the bone marrow. Hbz mice have decreased trabecular bone at 18 months by microCT and radiographic analysis. These data suggest Hbz can alter bone metabolism. Future studies will define the effects of Hbz on bone formation, OB and OC specific effects and tumor progression. Understanding HTLV-1 oncogene modulation of the bone microenvironment will uncover critical pathways in tumor/bone cross talk enabling the development of novel targeted therapies for ATL patients.
Citation Format: Alison Esser, Dan Rauch, Jingyu Xiang, John Harding, Nicole Kohart, Patrick Green, Stefan Niewiesk, Thomas Rosol, Lee Ratner, Katherine Weilbaecher. HTLV-1 viral oncogene Hbz induces leukemia with osteolytic bone involvement in mice. [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 3285.