bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 117: Genetic landscapes of relapsed and refractory diffuse large B cell lymphomas
Authors: Johnson Nathalie , Assouline Sarit , Alcaide Miguel , Mohajeri Arezoo , Greenwood Celia , Riazalhosseini Yasser , Mann Koren , Morin Ryan 
Published: July 2016

Abstract
Purpose: Relapsed or refractory diffuse large B cell lymphoma (rrDLBCL) is fatal in 90% of patients and yet little is known about its biology.
Experimental Design: Using exome sequencing, we characterized the mutation profiles of 38 rrDLBCL biopsies obtained at the time of progression after immunochemotherapy. To identify genes that may be associated with relapse, we compared the mutation frequency in samples obtained at relapse to an unrelated cohort of 138 diagnostic DLBCLs and separately amplified specific mutations in their matched diagnostic samples to identify clonal expansions.
Results: Based on the a higher frequency at relapse and evidence for clonal selection, TP53, FOXO1, MLL3, CCND3, NFKBIZ and STAT6 emerged as top candidate genes implicated in therapeutic resistance. We observed individual examples of clonal expansions affecting genes whose mutations had not been previously associated with DLBCL including two regulators of NF-κB: NFKBIE and NFKBIZ. We detected mutations that may be affect sensitivity to novel therapeutics, such as MYD88 and CD79B mutations, in 31% and 23% of patients with activated B cell-type of rrDLBCL, respectively. We also identified recurrent STAT6 mutations affecting D419 in 36% of patients with the germinal center B (GCB) cell rrDLBCL. These were associated with activated JAK/STAT signaling, increased phospho-STAT6 protein expression and increased expression of STAT6 target genes.
Conclusions: This work improves our understanding of therapeutic resistance in rrDLBCL and has identified novel therapeutic opportunities especially for the high-risk patients with GCB-type rrDLBCL.
Citation Format: Nathalie Johnson, Sarit Assouline, Miguel Alcaide, Arezoo Mohajeri, Celia Greenwood, Yasser Riazalhosseini, Koren Mann, Ryan Morin. Genetic landscapes of relapsed and refractory diffuse large B cell lymphomas. [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 117.
Abstract 1179: Combined genetic and genealogic studies uncover a large BAP1 cancer syndrome kindred, tracing back nine generations to a common ancestor from the 1700s
Authors: Carbone Michele , Flores Erin G. , Emi Mitsuru , Gaudino Giovanni , Pastorino Sandra , Yang Haining , Johnson Todd , Tsunoda Tatsuhiko , Hesdorffer Mary , Pass Harvey I. 
Published: July 2016

Abstract
Germline BAP1 mutations cause a cancer syndrome characterized by high incidence of mesothelioma (MM), uveal melanoma and other cancers, and by very high penetrance, as all individuals carrying BAP1 mutations developed at least one, and usually several, malignancies throughout their lives. Through screening MM patients with histories of multiple cancers, we found four supposedly unrelated patients that shared an identical germline BAP1 mutation. We investigated whether this BAP1 mutation occurred in a ‘hot-spot’ for “de novo” mutations or whether these four MM patients shared a common ancestor. Using molecular genomics analyses we found that they are related. By genealogic studies we traced their ancestor to a couple that emigrated from Germany to North America in the early 1700’s; we traced the subsequent migration of their descendants, who are now living in at least three different US States. Our findings demonstrate that BAP1 mutations are transmitted among subsequent generations over the course of centuries. This knowledge and methodology is being used to identify additional branches of the family carrying BAP1 mutations. Our study shows that the application of modern genomic analyses, coupled with “classical” family histories collected by the treating physician, and with genealogical searches, offer a powerful strategy to identify high-risk germline BAP1 mutation carriers that will benefit from genetic counseling and early detection cancer screening.
Citation Format: Michele Carbone, Erin G. Flores, Mitsuru Emi, Giovanni Gaudino, Sandra Pastorino, Haining Yang, Todd Johnson, Tatsuhiko Tsunoda, Mary Hesdorffer, Harvey I. Pass. Combined genetic and genealogic studies uncover a large BAP1 cancer syndrome kindred, tracing back nine generations to a common ancestor from the 1700s. [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 1179.
Abstract 1219: Sym015, a novel antibody mixture targeting non-overlapping epitopes of MET, effectively inhibits growth of MET dependent tumors and overcomes resistance to a single monoclonal antibody
Authors: Poulsen Thomas T. , Grandal Michael M. , Jacobsen Helle J. , Hansen Dorte S. , Lindsted Trine , Pedersen Mikkel W. , Horak Ivan D. , Kragh Michael , Lantto Johan 
Published: July 2016

Abstract
The tyrosine kinase receptor MET is involved in progression of a variety of human cancers and constitutes a promising therapeutic target. Particularly, subsets of tumors originating from lung or gastric tissues appear to be truly MET dependent. MET dependency is driven by alterations, such as MET-gene amplification, MET-exon 14 deletion, kinase activating mutations, or autocrine HGF production. Furthermore, MET-amplification has been reported as a key mechanism of de novo resistance to EGFR targeting agents in lung and colorectal cancers.
Sym015, a novel antibody mixture comprising two monoclonal antibodies targeting non-overlapping epitopes on the SEMA domain of MET, was shown to effectively inhibit cell growth in vitro through effective MET degradation. In the present study, we screened a large panel of highly annotated human cancer cell lines for sensitivity to Sym015 in order to identify potential markers of response. Sym015 effectively inhibited growth of cell lines with MET-amplification, MET-exon 14 deletion, and autocrine HGF production, including MET-amplified cell lines with acquired resistance to EGFR targeting agents.
To validate the in vitro findings, a range of cell line- and patient-derived xenograft models with MET amplification or Exon 14 deletion were tested for sensitivity to Sym015 and an analogue of the clinical stage anti-MET monoclonal antibody emibetuzumab (LY2875358). Sym015 effectively inhibited growth of tumors with autocrine HGF production, MET-amplification, and/or Exon 14 deletion, and had superior activity compared to the emibetuzumab analogue in many of the models. Importantly, tumors with a partial response to the emibetuzumab analogue were strongly inhibited by subsequent treatment with Sym015 in two MET-amplified models, one of which also harbors a MET-exon 14 deletion.
In summary, our findings demonstrate a potent antitumor effect of Sym015 in MET-dependent models. The data thus strongly support initiation of clinical trials for patients with MET-amplification and Exon 14 deletions.
Citation Format: Thomas T. Poulsen, Michael M. Grandal, Helle J. Jacobsen, Dorte S. Hansen, Trine Lindsted, Mikkel W. Pedersen, Ivan D. Horak, Michael Kragh, Johan Lantto. Sym015, a novel antibody mixture targeting non-overlapping epitopes of MET, effectively inhibits growth of MET dependent tumors and overcomes resistance to a single monoclonal antibody. [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 1219.
Abstract 1225: NVP-HDM201: cellular and in vivo profile of a novel highly potent and selective PPI inhibitor of p53-Mdm2
Authors: Jeay Sébastien , Chène Patrick , Ferretti Stéphane , Furet Pascal , Gruenenfelder Bjoern , Guagnano Vito , Guerreiro Nelson , Halilovic Ensar , Hofmann Francesco , Kallen Joerg , Léonard Michelle , Mah Robert , Masuya Keiichi , Ramos Rita , Rynn Caroline , Ruetz Stephan , Stachyra-Valat Thérèse , Stutz Stefan , Vaupel Andrea , Wuerthner Jens , Holzer Philipp 
Published: July 2016

Abstract
Stabilization of p53 protein by preventing its interaction with the negative regulator Mdm2 leads to selective induction of the p53 pathway, thus offering a promising cancer therapeutic strategy in p53 wild-type tumors. In the present study, we show the identification of NVP-HDM201, a novel, highly optimized, and selective inhibitor of the p53-Mdm2 interaction. NVP-HDM201 activates p53 in human cells and induces robust p53-dependent cell cycle arrest and apoptosis, selectively in p53 wild-type tumor cells. Its activity and selectivity has been tested and confirmed across a large panel of cancer cell lines from the Cancer Cell Line Encyclopedia. In vivo, NVP-HDM201 shows a dose-proportional pharmacokinetic (PK) profile and a clear PK/PD relationship, resulting in tumor growth inhibition and regression in SJSA-1 tumor-bearing rats at well-tolerated oral (p.o.) doses. The validation and understanding of its mechanism of action, the overall favorable drug-like properties and the characterization of its on-target toxicological profile in preclinical species strongly supported the initiation of Phase I clinical trials with NVP-HDM201 in pre-selected patients with p53 wild-type tumors.
Citation Format: Sébastien Jeay, Patrick Chène, Stéphane Ferretti, Pascal Furet, Bjoern Gruenenfelder, Vito Guagnano, Nelson Guerreiro, Ensar Halilovic, Francesco Hofmann, Joerg Kallen, Michelle Léonard, Robert Mah, Keiichi Masuya, Rita Ramos, Caroline Rynn, Stephan Ruetz, Thérèse Stachyra-Valat, Stefan Stutz, Andrea Vaupel, Jens Wuerthner, Philipp Holzer. NVP-HDM201: cellular and in vivo profile of a novel highly potent and selective PPI inhibitor of p53-Mdm2. [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 1225.
Abstract 1265: Dysregulated tyrosine kinase Tyro3 signaling in acute myeloid leukemia
Authors: Eryildiz Fatma , Tyner Jeffrey W. 
Published: July 2016

Abstract
The undesirable outcomes of classical chemotherapy approaches in the treatment of cancer pathogenesis has directed scientists to find more targeted and less toxic therapies. Numerous studies of targeted therapies in cancer have demonstrated that finding target genes that are responsible for cancer pathogenesis can lead to novel targeted cancer therapies. Among these studies, tyrosine kinases have been prominent as effective gene targets. We have employed this approach to study the hematologic malignancy, Acute Myeloid Leukemia (AML).
In this study, we aimed to understand how human tyrosine kinase members, as functional drivers of leukemogenesis, promote tumor progression by activating downstream molecules. For this purpose, an RNAi assisted silencing assay was designed in which every individual tyrosine kinase member was silenced and impact on primary AML cell viability was assessed. Bioinformatic interpretation of the data revealed that TYRO3 is one of the genes showing significant sensitivity to silencing in 7.64% of AML cases tested (n = 484). This data is compatible with previous studies showing aberrant expression of TAM family member tyrosine kinases in several human cancers. In addition, immunoblotting was performed to assess TYRO3 protein expression in several AML cell lines. Several AML lines demonstrated higher expression levels of TYRO3. In a strong correlation with this finding, TYRO3 siRNA was able to partially silence the TYRO3 expression especially in those cell lines that have higher expression levels of TYRO3 and due to this silencing we observed decreased cell viability relative to non-specific siRNA suggesting that high expression of TYRO3 provides a cell survival advantage in AML.
Even though signaling pathways of other TAM family members and their interactions are described in detail, TYRO3 downstream signaling pathway still remains quite undetermined which makes it an intriguing player in cell survival. There are not many small molecules designed to inhibit TAM tyrosine kinases, but our study shows that successful targeted inhibition of this family of receptor tyrosine kinases may represent a promising avenue to provide opportunities to improve therapeutic approaches for patients with AML.
[1] Druker, Brian J. “Imatinib as a paradigm of targeted therapies.” Advances in cancer research 91 (2004): 1-30.
Citation Format: Fatma Eryildiz, Jeffrey W. Tyner. Dysregulated tyrosine kinase Tyro3 signaling in acute myeloid leukemia. [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 1265.
Abstract 1301: Anti-invasive and antimetastatic effects of ω3-polyunsaturated fatty acids through inhibition of NF-kB/matrix metalloproteinases in ovarian cancer cells
Authors: Jeong Soyeon , Jing Kaipeng , Shin Soyeon , Kim Soyeon , Jeon Young-Joo , Heo Jun-Young , Kweon Gi-Ryang , Park Seung-Kiel , Park Jong-Il , Lim Kyu 
Published: July 2016

Abstract
Ovarian cancer is leading cause of gene cological cancer death in the United States. It is reported that about 14,000 patients will die to ovarian cancer in United States, 2015. ω3- and ω6-PUFAs are considered as essential fatty acids because they cannot be synthesized in mammals. The ω3-desaturase (fat-1) converts ω6-PUFAs to ω3-PUFAs. Cancer cells and transgenic mice stably expressing fat-1 geneare useful models to study the anti-cancer effects of ω3-PUFAs. Here, we show anti-invasive and anti-metastatic action of ω3-PUFA in ovarian cancer.DHA significantly inhibited cell invasion and wound healing activity of human ovarian PA-1 cells. DHA also abolishedthe induction of matrix-metalloproteinases (MMPs) and cyclooxygenase (COX2) as well as the transactivity of NF-κB in PA-1 cells. When ID8 cells were subcutaneously implanted into fat-1 transgenic mice, the tumor size and volume were smallin comparison to wild-type mice. The growth inhibition of tumor was also confirmed with the increase in the level of TUNEL-positive cells. Additionally, when ID8 cells were injected via tail vein of fat1 mice, the lung metastasis was remarkably inhibited in fat-1 transgenic mice. Furthermore, the proliferation of fat-1-stably expressing PA-1 (f-PA-1) cells was more attenuated than that of cells expressing control vectors. The invasion and NF-κB/MMPs promoter activities were also decreased in f-PA-1 cells. These results suggest that ω3-PUFAs inhibit invasion and metastasis of ovarian cancer cells through inhibition of NF-κB/MMPs. Therefore, ω3-PUFAs may contribute an effective and safe therapeutic approach for the chemoprevention and treatment of human ovarian cancer. [This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2007-0054932)]
Citation Format: Soyeon Jeong, Kaipeng Jing, Soyeon Shin, Soyeon Kim, Young-Joo Jeon, Jun-Young Heo, Gi-Ryang Kweon, Seung-Kiel Park, Jong-Il Park, Kyu Lim. Anti-invasive and antimetastatic effects of ω3-polyunsaturated fatty acids through inhibition of NF-kB/matrix metalloproteinases in ovarian cancer 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 1301.
Abstract 1315: Nanoparticles targeting RAF/ERK-driven cell-autonomous resistance to sorafenib for effective treatment of hepatocellular carcinoma
Authors: Chen Yunching , Liu Ya-Chi , Lin Ts-Ting , Ramjiawan Rakesh , Duda Dan 
Published: July 2016

Abstract
Sorafenib is the only systemic therapy approved for advanced hepatocellular carcinoma (HCC). Sorafenib's efficacy has been attributed in part to inhibition of cancer cell proliferation due to B- and CRAF targeting in HCC cells. However, cell autonomous mechanisms promote evasion from sorafenib treatment, leading to moderate survival benefit. Herein, we demonstrated that the effects of sorafenib on HCC cell viability were initially independent of RAF kinase inhibition and were mediated in part by p38MAPK inhibition. Moreover, sorafenib treatment led to RAF heterodimerization (BRAF/CRAF) and subsequent ERK activation and thus converted HCC cell dependence for survival signaling to the RAF/ERK pathway. Inhibition of ERK pathway by the MEK inhibitor AZD6244 significantly enhanced the therapeutic efficacy of sorafenib efficacy on HCC in vitro and in vivo. Furthermore, we developed HCC-targeted nanoparticles (NPs) to efficiently co-deliver both sorafenib and AZD6244 into HCC, downregulate RAF/ERK pathway, suppress angiogenesis and enhance anti-cancer effect in the orthotopic HCC model. In conclusion, sorafenib treatment leads to rapid MAPK activation due to BRAF heterodimerization as a cell-autonomous mechanism of treatment resistance. Co-delivery of sorafenib and MEK inhibitor AZD6244 using HCC targeted NPs downregulates the compensatory activated RAF/ERK pathway and overcomes resistance to sorafenib in HCC.
Citation Format: Yunching Chen, Ya-Chi Liu, Ts-Ting Lin, Rakesh Ramjiawan, Dan Duda. Nanoparticles targeting RAF/ERK-driven cell-autonomous resistance to sorafenib for effective treatment of 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 1315.
Abstract 1327: Gold nanorods based hypoxia-targeted photothermal cancer therapy
Authors: Xie Huan , Krishnan Sunil 
Published: July 2016

Abstract
PURPOSE: Tumor hypoxia is a well-recognized driver of resistance to traditional cancer therapies such as chemotherapy and radiation therapy. Gold nanorods (GNR), with unique dimension and optical properties, have shown superior capability for tumor photothermal ablation. This study aimed to develop a new nanoconstruct composed of gold nanorods (GNRs) conjugate to anti-carbonic anhydrase IX (CAIX) antibody that specifically binds to CAIX, a biomarker of hypoxia, to facilitate targeting tumor hypoxic areas for focused photothermal ablation. METHODS: GNR were synthesized according to the seed-mediated growth method with modification. Transmission electron microscopy (TEM) were used to characterize the size and shape of the particles. The GNR/anti-CAIX conjugates were prepared through a bifunctional polyethylene glycol (PEG). The conjugates were characterized by UV-Vis spectra, particle sizes and zeta potentials. The binding affinity and specificity of the GNR/anti-CAIX were evaluated with ELISA, cell adhesion assay and cell photothermal treatment. HT29 colon cancer cell line (overexpressing CAIX) and NIH3T3 cell line (no expressing CAIX) were used in our study. Near-infrared (NIR) ablation was performed on HT29 tumors in mice that treated with PBS, GNR-PEG and GNR/anti-CAIX. Biodistribution were conducted on the latter two groups. RESULTS: TEM images showed that the synthesized GNR had an aspect ratio of about 3 (8 × 24 nm). The changes of UV-vis spectra, particle sizes and zeta potentials confirmed the success of the conjugation. ELISA suggested that the number of anti-CAIX per GNR was 4.8 ± 0.3. In the cell binding assay, GNR/anti-CAIX only showed specific and high degree binding to HT29 cells but not to NIH3T3 cells. NIR laser treatment of HT29 cells resulted in significantly higher killing of GNR/anti-CAIX-targeted cells than of controls. NIR ablation of HT29 tumors in mice showed no tumor regression in the sham-treated group, regression but recurrence in the non-targeted-GNR group, and complete tumor regression in the targeted-GNR group. Biodistribution study showed significant higher accumulation in tumor in the targeted-GNR group. CONCLUSIONS: GNR/anti-CAIX nanoconstructs show promise as highly efficient targeting and photothermal ablation agents for cancer treatment.
GRANT SUPPORT: This work was performed under funding from NIH/NIGMS grant (1SC3GM102018-01) and NIH/NIMHD/RCMI grant (5G12RR003045-21).
Citation Format: Huan Xie, Sunil Krishnan. Gold nanorods based hypoxia-targeted photothermal cancer therapy. [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 1327.
Abstract 1408: Tumor-targeting Salmonella typhimurium A1-R promotes CD8+ T cell infiltration in pancreatic cancer in an orthotopic syngeneic mouse model
Authors: Murakami Takashi , Hiroshima Yukihiko , Zhang Yong , Zhao Ming , Kiyuna Tasuku , Matsuyama Ryusei , Chishima Takashi , Tanaka Kuniya , Bouvet Michael , Endo Itaru , Hoffman Robert M. 
Published: July 2016

Abstract
The effect of tumor-targeting Salmonella typhimurium A1-R on CD8+ cell infiltration was determined on Pan02 murine pancreatic adenocarcinoma cells implanted orthotopically on the pancreatic tail of C57BL/6 mice. Three weeks after orthotopic implantation, mice were randomized into G1: untreated control group (n = 8); and G2: Salmonella typhimurium A1-R treatment group (n = 8, 1 × 107 CFU/body, iv, weekly, 3 weeks). On the 22nd day from initial treatment, all mice were sacrificed and tumors were harvested. The tumor volume ratio was defined as ratio of tumor volume at the 1st day to the 22nd day. H&E staining was performed to evaluate tumor destruction which was classified into 4 categories according to the Evans grading system: Grade I; 0-9% destruction, Grade IIA; 10-50% destruction, Grade IIB; 51-90% destruction, Grade III; few (&lt;10%) viable cancer cells. Immunohistochemical staining using anti-mouse CD8+ antibody was performed to count tumor infiltrating CD8+ cells. The tumor volume ratio was significantly lower in G2 (3.0 ± 2.8) than G1 (39.9 ± 30.7, p &lt; 0.01). Six mice in G1 had peritoneal dissemination whereas no mice showed peritoneal dissemination in G2 (p &lt; 0.01). Significant tumor destruction was observed in G2 (Grade I: 0, Grade IIA: 1, Grade IIB: 6, Grade III: 1) compared to G1 (Grade I: 5, Grade IIA: 3, Grade IIB: 0, Grade III: 0, p &lt; 0.01). Tumor infiltrating CD8+ cells per high-magnification field were significantly higher in G2 (133.5 ± 32.2) than G1 (45.1 ± 19.4, p &lt; 0.001). Strong tumor destruction correlated with higher numbers of tumor-infiltrating CD8+ cells per high-magnification field (Grade I: 35.5 ± 18.3, Grade IIA: 77.3 ± 32.8 Grade IIB and III: 134.7 ± 34.8). The present study demonstrates that Salmonella typhimurium A1-R promotes CD8+ T cell infiltration in a syngeneic pancreatic cancer mouse model.
Citation Format: Takashi Murakami, Yukihiko Hiroshima, Yong Zhang, Ming Zhao, Tasuku Kiyuna, Ryusei Matsuyama, Takashi Chishima, Kuniya Tanaka, Michael Bouvet, Itaru Endo, Robert M. Hoffman. Tumor-targeting Salmonella typhimurium A1-R promotes CD8+ T cell infiltration in pancreatic cancer in an orthotopic syngeneic mouse model. [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 1408.