bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5519: BAP1 modulates gene-environment interaction in carcinogenesis
Authors: Carbone Michele , Bononi Angela , Giorgi Carlotta , Patergnani Simone , Pass Harvey I. , Jia Wei , Pinton Paolo , Yang Haining 
Published: August 2018

Abstract
We discovered that heterozygous germline BAP1 mutations (BAP1+/-) cause a novel cancer syndrome that we named “The BAP1 cancer syndrome” characterized by development of malignant mesothelioma (MM), uveal and cutaneous melanoma, and other cancers. We demonstrated how germline BAP1 mutations are transmitted over the centuries across generations and found that 100% of individuals who inherited germline BAP1 mutations have developed one or more malignancies in their lifetime. Very recently we demonstrated that the potent BAP1 tumor-suppressor activity is linked to its dual function in the nucleus, where it regulates DNA repair, and in the cytoplasm, where it regulates apoptosis by deubiquitylating and stabilizing the IP3R3 endoplasmic reticulum (ER) Ca2+ channel. In parallel we discovered that cells carrying heterozygous BAP1 mutations derive energy largely via aerobic glycolysis, Warburg effect. Now we have found the mechanisms regulated by BAP1 that are responsible for the changes in metabolism. We discovered that reduced BAP1 levels lead to reduced release of Ca2+ from the ER into the cytoplasm and reduced intra-mitochondrial Ca2+ levels. Reduced mitochondrial Ca2+ levels directly impair aerobic respiration and cells switch to glycolysis even in the presence of oxygen. We demonstrate that aerobic glycolysis can be induced in apparently any human cell type by reducing BAP1 levels using siRNAs or other strategies, and that in these cells glycolysis can be reverted to aerobic respiration upon re-establishing normal Ca2+ levels. In conclusion, our findings indicate how BAP1 deficiency regulates DNA repair and apoptosis and how low BAP1 levels induce the Warburg effect, an effect seen in all “normal” cell types from individuals born with inherited germline heterozygous BAP1 mutations. In these individuals aerobic glycolysis predates by many years malignant transformation.
Citation Format: Michele Carbone, Angela Bononi, Carlotta Giorgi, Simone Patergnani, Harvey I. Pass, Wei Jia, Paolo Pinton, Haining Yang. BAP1 modulates gene-environment interaction in carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5519.
Abstract 5520: Oncogenic RTK signaling inhibits Spred1/NF1 to sustain constitutive Ras/MAPK signaling
Authors: Markegard Evan , Mercado Ellen L. , Castel Pau , Silva Jillian , Galeas Jacqueline , Li Kathy , Urisman Anatoly , McCormick Frank 
Published: August 2018

Abstract
Spred proteins negatively regulate Ras/MAPK signaling following growth factor stimulation. Inhibition of Ras primary occurs through Spreds ability to bind and localize NF1, a RasGAP and major tumor suppressor, to the plasma membrane. Spred1 and NF1 loss-of-function mutations occur across multiple cancer types including non-small cell lung carcinoma, glioblastoma, melanoma, stomach carcinoma, and uterine carcinosarcoma. Here we demonstrate that oncogenic RTK signaling leads to phosphorylation of Spred1(S105) in the EVH domain, which disrupts Spred1-NF1 binding and function. Phosphomimetic Spred1 is unable to suppress Ras-GTP following growth factor stimulation and cancer cell proliferation. The Spred1(S105) kinase is likely to be a CDK based on in vitro kinase and in vivo cell line assays. Our findings provide one potential mechanism by which oncogenic RTK signaling disrupts negative feedback to sustain constitutive Ras signaling. Furthermore, this work may elucidate a novel therapeutic target for restoring NF1-mediated inhibition of Ras.
Citation Format: Evan Markegard, Ellen L. Mercado, Pau Castel, Jillian Silva, Jacqueline Galeas, Kathy Li, Anatoly Urisman, Frank McCormick. Oncogenic RTK signaling inhibits Spred1/NF1 to sustain constitutive Ras/MAPK signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5520.
Abstract 5537: Circulating tumor DNA analysis for ESR1 mutations in patients with hormone receptor-positive metastatic breast cancer
Authors: Sim Sung Hoon , Jeon Su Yeon , An Kyoung Hee , Kong Sun Young , Kwon Min Jung , Lee Keun Seok , Park In Hae 
Published: August 2018

Abstract
Background: ESR1 mutations are known as a major mechanism of resistance to antihormonal therapy in breast cancer. ESR1 mutation frequency is high in metastatic disease when the tumor is refractory to aromatase inhibitor, in contrast to nonmetastatic setting. We tried to detect ESR1 mutations (Y537N, Y537S and D538G) in circulating tumor DNA (ctDNA).
Method: Patients who had hormone receptor-positive breast cancer were enrolled in this study. Plasma samples were collected and ctDNA was analyzed by ddPCR and digital targeted DNA panel. Primers and probes for ddPCR were designed for Y537N, Y537S and D538G mutations using sequences of wild-type normal human DNA.
Results: A total of 40 patients were enrolled. Histologic type was invasive ductal carcinoma (IDC) in 32, invasive lobular carcinoma (ILC) in 4 and others in 4. Thirty-four patients received endocrine treatment and 6 patients had no prior exposure to endocrine treatment. Using ddPCR, overall mutation rate was 52.5% (n=21). D538G was the most frequent mutation (n=16), followed by Y537N (n=9), and Y537S (n=6). Nine patients showed multiple ESR1 mutations. In patients without endocrine exposure (n=6), 2 patients showed ESR1 mutations (Y537N, Y537S). The mutation detection rate was higher in patients with prior use of aromatase inhibitor (AI) than in prior use of tamoxifen (TMX) only (prior AI, 17/29=58.6%; prior TMX, 2/5= 40%). In 9 cases, we conducted both ddPCR and targeted DNA panel assay using ctDNA at the same time. Overall concordance rate between two platforms was 55.6% (5/9). Among discordant cases (n=4), ESR1 mutations were detected by ddPCR in 3 cases, which were not found in DNA panel assay.
Conclusions: ESR1 mutations can be robustly identified with ctDNA analysis. Overall mutation detection rate was comparable to other previous reports. However, there is a significant discordance between clinically available NGS panel assay and ddPCR method in detection of ESR1 mutations. Further study will be needed for clinical implementation of ESR1 mutation analysis using ctDNA.
Citation Format: Sung Hoon Sim, Su Yeon Jeon, Kyoung Hee An, Sun Young Kong, Min Jung Kwon, Keun Seok Lee, In Hae Park. Circulating tumor DNA analysis for ESR1 mutations in patients with hormone receptor-positive metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5537.
Abstract 554: APC loss alters DNA damage repair in breast cancer cells
Authors: Batista Stephanie M. McClintock 
Published: August 2018

Abstract
Breast cancer is the second leading cause of cancer deaths in U.S. women. Many of these deaths have been attributed to the development of chemotherapeutic resistance. Thus, understanding the process of chemotherapeutic resistance will help develop new approaches to combat breast cancer and ultimately cause a decrease in breast cancer related deaths. The Adenomatous Polyposis Coli (APC) tumor suppressor is silenced or mutated in up to 70% of sporadic breast cancer; however, the possible effects of APC loss on chemoresistance has not been elucidated. Using the ApcMin/+ mouse crossed to the Polyoma middle T antigen (PyMT) transgenic model, we previously showed that APC loss decreased cisplatin and doxorubicin-induced apoptosis. We also have shown that APC loss increased mRNA expression of the multidrug resistance protein 1 (MDR1), which was augmented by doxorubicin treatment. Treatment with doxorubicin and A69, a STAT3 inhibitor, normalized MDR1 gene expression in MMTV-PyMT;ApcMin/+ cells. Here, we hypothesize that loss of APC causes an increase in doxorubicin efflux and a decrease in DNA damage. First, we show that APC loss increased MDR1 activity as measured by calcein flux. To determine whether MDR1 inhibition would restore doxorubicin induced DNA damage, a combination treatment of doxorubicin and the MDR1 inhibitor, Valspodar, was able to restore doxorubicin sensitivity in MMTV-PyMT;ApcMin/+ cells compared to the control MMTV-PyMT;Apc+/+ cells. In addition, we have shown a decrease of γH2AX, a marker of damaged DNA, in MMTV-PyMT;ApcMin/+ cells treated with doxorubicin suggesting that the MMTV-PyMT;ApcMin/+ cells either have less damage due to increased drug efflux via MDR1 or due to increased DNA damage repair. Due to APC binding to Topoisomerase IIa, we also examined the degree of Topoisomerase IIa inhibition (via doxorubicin and etoposide) in MMTV-PyMT;ApcMin/+ compared to MMTV-PyMT;Apc+/+ cells. Topoisomerase IIa activity will also be measured to determine the effect of APC loss on Topoisomerase IIa. To test the hypothesis that loss of APC affected DNA damage repair, the expression of phosphorylated H2AX was measured in MMTV-PyMT;ApcMin/+ and MMTV-PyMT;Apc+/+ cells treated with the following: doxorubicin, etoposide, Valspodar, or a combination treatment. The longevity of doxorubicin-induced double stranded breaks was observed. Future studies will measure DNA damage repair pathway efficiency via reporter plasmids. We also will measure downstream signaling of yH2AX. Overall with an understanding of the role of APC in DNA damage repair, the use of a combination therapy could be advantageous to overcome chemotherapeutic resistance.
Citation Format: Stephanie M. McClintock Batista. APC loss alters DNA damage repair in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 554.
Abstract 5549: Antitumor efficacy of the oncolytic peptide LTX-315 in genetic mouse models that resist conventional chemo- and immunotherapeutic treatments
Authors: Pittet Mikael J. , Liao Hsin-Wei , Sveinbjørnsson Baldur , Rekdal Øystein 
Published: August 2018

Abstract
LTX-315 is an oncolytic peptide that induces immunogenic cancer cell death and is currently evaluated in phase 1 clinical trials for its ability to trigger recruitment of tumor-specific T cells to tumors. Previous experimental studies identified LTX-315's ability to control cancer in mice grafted with various tumor cell lines. Here we extend our analyses to conditional genetic mouse models of both melanoma (driven by Braf and Pten alterations) and soft tissue sarcoma (driven by Kras and P53 alterations). In these genetic models, cancer cells are derived from somatic cells that are transformed in their normal tissue microenvironment and progress to high-grade tumors that are poorly infiltrated by T cells and typically resist prescribed chemo- and immunotherapeutic treatments. We report that LTX-315 not only delays tumor progression substantially in both models, but also profoundly alters the tumor microenvironment, most notably characterized with CD8+ T cell, NK cell and dendritic cell infiltration. Transition from a ‘cold' to a ‘hot' tumor microenvironment was also observed in patients with melanoma, sarcoma and breast cancer. Furthermore, CD8+ T cell depletion in mice abrogated long-term antitumor efficacy of LTX-315, indicating that these cells are required for drug-induced tumor control. Importantly, the ability to convert non-T-cell-infiltrated tumors into ones that display antitumor T cell immunity opens the possibility to prime and make unresponsive tumors sensitive for systemic immune treatments.
Citation Format: Mikael J. Pittet, Hsin-Wei Liao, Baldur Sveinbjørnsson, Øystein Rekdal. Antitumor efficacy of the oncolytic peptide LTX-315 in genetic mouse models that resist conventional chemo- and immunotherapeutic treatments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5549.
Abstract 5560: PD-1/PD-L1 blockade enhances MDM2 inhibitor activity in p53 wild-type cancers
Authors: Wang Hui Qin , Liang Jinsheng , Mulford Iain , Sharp Fiona , Gaulis Swann , Chen Yan , Trabucco Gina , Quinn David , Growney Joseph D. , Meyer Matthew J. , Williams Juliet , Hammerman Peter , Hofmann Francesco , Dranoff Glenn , Engelman Jeffrey , Mataraza Jennifer , Halilovic Ensar 
Published: August 2018

Abstract
p53 is a transcription factor that plays a central role in guarding genomic stability of the cell through cell cycle arrest or induction of apoptosis. It has also been reported that p53 participates in the regulation of tumor immunity and in homeostatic regulation of immune responses. However, the immunomodulatory effect of p53 in tumor and the tumor microenvironment is not well understood. From gene expression and immunohistochemical analysis of pre- and post-treatment biopsies from patients treated with the MDM2 inhibitor NVP-CGM097, we observed upregulation of immune checkpoint transcripts (PD1 and PDL1), and an increase in the number of CD8+ tumor infiltrating lymphocytes. To investigate the immunomodulatory effect of p53 in more detail, we studied murine syngeneic models treated with NVP-HDM201, a potent and selective second generation MDM2 inhibitor. We performed multi-color FACS analysis on tumors and tumor draining lymph nodes. With NVP-HDM201 treatment, we observed increase in numbers of CD103+ DC cells, capable of antigen cross-presentation. Furthermore, NVP-HDM201 increased the percentage of Tbet+EOMES-T cells in tumors as well as tumor draining lymph nodes and also resulted in increased ratios of CD8+ Tcells/Treg in tumor. In addition, levels of both PD-L1 on CD45- cells and PD-1 on CD4+ T cells were increased. Importantly, PD-1 and PD-L1 blockade enhanced HDM201 activity in p53 WT syngeneic mouse models but not in p53 mutated models. The rate of complete tumor regressions (CR) was significantly increased with combination treatment as compared to either treatment alone. The animals that
achieved complete regressions also developed long lasting anti-tumor memory against the specific tumor cells as evidenced by re-challenge experiments. Taken together, these results demonstrate that MDM2 inhibition triggered adaptive immunity which was further enhanced by blockade of PD-1/PD-L1 pathway, thereby providing a rationale for combining MDM2 inhibitors and checkpoint blocking antibodies in cancer patients with wildtype p53.
Citation Format: Hui Qin Wang, Jinsheng Liang, Iain Mulford, Fiona Sharp, Swann Gaulis, Yan Chen, Gina Trabucco, David Quinn, Joseph D. Growney, Matthew J. Meyer, Juliet Williams, Peter Hammerman, Francesco Hofmann, Glenn Dranoff, Jeffrey Engelman, Jennifer Mataraza, Ensar Halilovic. PD-1/PD-L1 blockade enhances MDM2 inhibitor activity in p53 wild-type cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5560.
Abstract 5562: A 3D image-based quantification of T cell-mediated killing of CRC organoids in the presence of immuno-modulators
Authors: Goverse Gera , Daszkiewicz Lidia , Yan Kuan , Tleis Mohamed , Madej Mariusz , Salinaro Lucia , Price Leo 
Published: August 2018

Abstract
BACKGROUND
Cancer immunotherapy has already yielded promising clinical results but most patients still do not respond. The mechanisms of action of these treatment modalities are also not fully understood and the progress in this direction is hampered by a lack of appropriate pre-clinical testing models. To investigate the role of novel therapeutics targeting the immune cell compartment to kill tumor cells, we developed an in vitro assay based on 3D cultures and image based analysis in a 384-wells plate format. Immune cells are added to recapitulate the tumor micro-environment and its complex interactions between different cellular players. Specifically, infiltration of immune cells into the tumoroids and their killing are visualized and measured, enabling a better understanding of the immune-modulatory profile of different treatments.
METHODS
Autologous patient derived colon organoids from normal and tumor tissue from several patients were cultured in a 3D environment. HLA-matched PBMCs with and without activation were added and immune-cell infiltration and killing of the CRC organoids was visualized in 3D using automated microscopy. Quantification of immune cell effects was achieved with morphometric analysis with OMinerTM software.
RESULTS
3D image data analysis enabled the discrimination of immune-tumor cell interactions and revealed a higher immune cell infiltration and tumoroid killing upon activation. In addition, we were able to compare both normal and tumor colon tissue from the same patient and compare between patients, demonstrating patient related differences and elucidating the effect of immune cell targeting on normal colon tissue.
CONCLUSIONS
The 3D assay presented here allows the analysis of different cell types that engage in a more realistic setting than when culturing them in traditional 2D cultures. Using image-based analysis, immune-tumor interactions can be visualized and quantified. The 3D environment, both for the cell culture and image analysis, allows for measurement of spatially resolved information, not accessible by monolayer cultures or biochemical assays. This new and innovative platform can empower immunotherapy drug developers to select the most promising candidates and better understand their mechanism of action.
Citation Format: Gera Goverse, Lidia Daszkiewicz, Kuan Yan, Mohamed Tleis, Mariusz Madej, Lucia Salinaro, Leo Price. A 3D image-based quantification of T cell-mediated killing of CRC organoids in the presence of immuno-modulators [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5562.
Abstract 557A: The clinicopathoogical significance of FBXW7 expression in GIST
Authors: Koga Yuki , Iwatsuki Masaaki , Yamashita Kouhei , Kiyozumi Yuki , Sawayama Hiroshi , Hiyoshi Yukiharu , Baba Yoshihfumi , Miyamoto Yuji , Yoshida Naoya , Baba Hideo 
Published: August 2018

Abstract
Objective: Gastrointestinal stromal tumor (GIST) is a rare mesenchymal tumor originated from the interstitial cells of Cajal in the gastrointestinal tract. A significant breakthrough was achieved with the identification of the expression of the c-kit (CD117) antigen in GISTs. However, alternate oncogenic pathways have not sufficiently been understood. FBXW7 is a ubiquitin ligase that mediates ubiquitylation of oncoproteins, which is known as tumor-suppressor gene in various malignancies. Previous reports showed that FBXW7 is associated with tumor progression by regulating some oncoprotein such as c-myc and c-jun. The aim of this study is to elucidate the clinicopathological significance of FBXW7 in GIST.
Methodology: (i) We examined the FBXW7 expression in GIST cells by immunostaining and correlation clinicopathological characteristics. (ii) We examined cell proliferation by Cytotoxicity assays in GIST-T1 cells suppressed by FBXW7-specific siRNA.
Results: (i) In 90 cases of GIST samples with surgical resection, high FBXW7 and observed are 47 cases and low expression are 43 cases. There are significantly more large size, located small intestine, high mitotic index in low FBXW7 cases (P=0.05, P=0.01, P=0.04). There are significantly more high risk cases in modified-Fletcher classification in low FBXW7 expression cases (P=0.0008). There are significantly higher value of SUV max in high risk cases of modified-Fletcher
classification and low FBXW7 expression cases (P=0.007, P=0.02). In GIST cases with distant metastasis, there are significantly more low FBXW7 expression cases than GIST cases without distant metastasis (P=0.009). FBXW7 expression is significantly inversely correlated with C-MYC expression (P=0.0004). (ii) The GIST cells suppressed FBXW7 expression by siRNA have higher proliferation rate compared to control GIST cells (P=0.02).
Conclusion: We demonstrated that FBXW7 expression is correlated with modified-Fletcher classification, SUV max value, c-myc expression and cell proliferation in GIST. These results are suggesting that FBXW7 may be associated with tumor progression. These findings suggest that it is possible that FBXW7 can be a promising biomarker for disease progression of GIST.
Citation Format: Yuki Koga, Masaaki Iwatsuki, Kouhei Yamashita, Yuki Kiyozumi, Hiroshi Sawayama, Yukiharu Hiyoshi, Yoshihfumi Baba, Yuji Miyamoto, Naoya Yoshida, Hideo Baba. The clinicopathoogical significance of FBXW7 expression in GIST [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 557A.
Abstract 5584: Circulating tumor cells in the peripheral blood and leukapheresis product of non-small cell lung cancer patients
Authors: Andree Kiki C. , Tamminga Menno , Mentink Anouk , Hilterman T Jeroen , Groen Harry J. , Terstappen Leon W. 
Published: August 2018

Abstract
Introduction The number of circulating tumor cells (CTC) isolated by the FDA approved CellSearch (CS) system in 7.5 mL of blood of metastatic and non-metastatic non-small cell lung cancer (NSCLC) patients is low or absent. Processing a larger blood volume could yield a greater amount of CTC from these patients. An approach to probe larger volumes is using diagnostic leukapheresis (DLA) where the blood can be split into its components after which selective harvesting of mononuclear cells (MNC) including CTC can take place.
Methods Patients with histologically proven NSCLC who either have been recently diagnosed or are eligible for new therapy can participate in this ongoing study. Patients had DLA for MNC collection derived from one total body blood volume. Before and after DLA, whole blood was drawn in a CellSave blood collection tube and analyzed by CS. The obtained DLA product was divided for analysis. 2x108 cells (on average 2mL of DLA product, representing ~100mL of blood) was diluted in 7.5 mL buffer, and analyzed by CS. 9 mL of the DLA product (on average 1x109 cells) was fixed and depleted of leukocytes using the RosetteSep CD45 depletion kit (Stemcell Technologies), allowing processing of a larger volume, followed by CS analysis. Results of molecular characterization of the detected CTC is pending.
Results So far, a total of 8 DLA's were performed in 7 stage 4 NSCLC patients. Sample collection took place before (t=0) and/or after (t=1) treatment. Patients underwent DLA in about 110 minutes, at this time an average of 4860 mL of blood was processed. No complications occurred, no post-procedure complaints were recorded. Similar DLA products with an average of 95 mL were obtained. CTC counts for these patient samples are shown in the table below.
CTC counts blood and DLAPatientt=#CTC pre blood#CTC post blood#CTC DLA (~2mL, 200x106 cells)#CTC depleted DLA (~9mL, 900x106 cells)101n/a114113020203514602031000040n/a04495000166000029020114
Conclusion DLA is a novel method to collect CTC from the blood. DLA can result in the detection of CTC where the use of 7.5mL of blood is not sufficient. Additionally, DLA shows an increase of CTC yield in patients with CTC detected in 7.5 mL of blood.
Citation Format: Kiki C. Andree, Menno Tamminga, Anouk Mentink, T Jeroen Hilterman, Harry J. Groen, Leon W. Terstappen. Circulating tumor cells in the peripheral blood and leukapheresis product of non-small cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5584.