bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2115: FOS contributes to 5-FU resistance and reversal effects of natural flavonoid GL-V9 in colon cancer
Authors: Zhao Li , Zhaohe Li , Youxiang Ding 
Published: August 2019

Abstract
5-FU is widely used in the treatment of colon cancers. Although 5-FU can improve response rates and survival, response rates for 5-FU-based chemotherapy as a first-line treatment for advanced colorectal cancer are only 10-15%. Meanwhile, cancer drug resistance often occurs, which is an important reason for poor treatment effect of 5-FU. Therefore, it is significant to uncover the mechanisms underlying 5-FU resistance and develop effective but nontoxic agent candidates for reversing cancer drug resistance. Here, we found that proto-oncogene FOS was activated in 5-FU-resistant colon cancer cells compared to parental cells. Additionally, FOS overexpression using lentivirus plasmid obviously triggered 5-FU resistance in colon cancer cells. Moreover, by analyzing two GEO datasets, we also found that FOS expression was associated with poor overall survival of colon cancer. Taken together, FOS confers 5-FU resistance to colon cancer and it is potential to be exploited as a therapeutical target. Lastly, we studied the reversal effects of natural flavonoid GL-V9 on the FOS activation and 5-FU resistance in order to develop candidates for FOS inhibitor which would be helpful for 5-FU-resistant colon cancer. Consequently, nontoxic doses of GL-V9 could significantly suppress activation of FOS and sensitize colon cancer cells to 5-FU. Therefore, the flavonoid is potential to be exploited as a synergetic agent for 5-FU-resistant colon cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Li Zhao, Li Zhaohe, Ding Youxiang. FOS contributes to 5-FU resistance and reversal effects of natural flavonoid GL-V9 in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2115.
Abstract 2125: Genetic analysis for classification and treatment of poorly differentiated sinonasal cancer
Authors: Hermsen Mario , Riobello Cristina , Cabal Virginia N. , García-Marín Rocío , Potes-Ares Sira , Suárez-Fernández Laura , Vivanco Blanca , Franchi Alessandro , Büttner Reinhard , López Fernando , Llorente José Luis 
Published: August 2019

Abstract
Introduction: The sinonasal cavities harbour a wide variety of rare tumour types, including squamous-cell carcinoma (SNSCC), intestinal-type adenocarcinoma (ITAC), olfactory neuroblastoma (ONB), neuroendocrine carcinoma (SNEC), undifferentiated carcinoma (SNUC) and malignant mucosal melanoma (MMM). Histopathological classification is related to clinical outcome, but correct diagnosis is difficult in cases with poor differentiation. Five-year overall survival ranges from 20% to 60% while therapeutic options are limited. This study aims to identify genetic alterations that may aid diagnosis and indicate targets for modern specific therapies.
Experimental procedures: DNA was extracted from 80 frozen or paraffin-embedded tumor tissues collected from three different hospital centers. Mutations were screened by next generation sequencing of a panel of 120 cancer-related genes using the SureSelect QXT Target Enrichment Kit for Ilumina Multiplexed Sequencing, and recurrent hits were confirmed by Sanger sequencing and by analyzing their effect on protein expression.
Results: Frequently mutated genes were TP53, KRAS, PI3K, NTRK1, ATM and BRCA1 and BRCA2. Several mutations were found exclusive to only one sinonasal tumor-type: APC and B-catenin in ITAC, EGFR exon 20 in SNSCC, IDH2 in SNUC and NF1 in MMM. With exception of ONB, a majority of cases showed a high mutational burden.
Conclusions: A number of tumor-specific mutations were identified that may be used for differential diagnosis. In addition, many gene mutations may serve as targets for specific antibody or small molecule inhibitors. Finally, the finding that sinonasal tumors carry a high mutational burden suggests that therapy with immune checkpoint inhibitors may be effective in clinical management.
Citation Format: Mario Hermsen, Cristina Riobello, Virginia N. Cabal, Rocío García-Marín, Sira Potes-Ares, Laura Suárez-Fernández, Blanca Vivanco, Alessandro Franchi, Reinhard Büttner, Fernando López, José Luis Llorente. Genetic analysis for classification and treatment of poorly differentiated sinonasal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2125.
Abstract 2129: CPTAC: Biospecimen accrual for proteogenomics
Authors: Thiagarajan Mathangi 
Published: August 2019

Abstract
The Clinical Proteomics Tumor Analysis Consortium (CPTAC) is a National Cancer Institute initiative that seeks to uncover the molecular basis of cancer using a proteogenomic approach to study prospective cancer specimens from treatment naïve patients. Leidos Biomed provides an infrastructure for supporting the collection of high quality biospecimens specific to proteogenomics and the corresponding clinical data, in addition to project and subcontract management for the program. The proportion of biospecimens so far from racial and ethnic minority patients are underrepresented, which preclude equitable research across all patient groups for cancer treatment. CPTAC program seeks diversity in the accrual cohort and an effort is ongoing to encourage the participation of tissue source sites serving racial and ethnic minorities that can contribute high quality biospecimens towards the collection. CPTAC applies the understanding of the molecular basis of cancer to identify biomarker candidates. CPTAC Phase II completed in 2016, collecting over 350 cases from breast, colon and ovarian patients. CPTAC Phase III that is in progress began to collect and analyze 200 cases from each of ten additional cancers. Analysis is close to completion for uterine corpus endometrial carcinoma, kidney clear cell renal cell carcinoma and lung adenocarcinoma while accruals are ongoing for 7 other cancer types. The study entails collection and pathology evaluation of biospecimens, high-quality clinical data and images from clinical sites from around the world. A biorepository evaluates and processes the biospecimens, sending nucleic acids to a sequencing center and tissues to proteomics groups. Data are combined and analyzed by analysis and translational centers. Genomic data are made available to the research community through the NCI Genomic Data Commons(GDC). Proteomic data are made available through CPTAC’s Data Coordinating Center(DCC). Imaging data are made available through The Cancer Imaging Archive (TCIA). The program is expanding and initiating biospecimen collection for proteogenomic analysis of ten additional rare tumor types.
Citation Format: Mathangi Thiagarajan. CPTAC: Biospecimen accrual for proteogenomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2129.
Abstract 2134: Niraparib combined with abiraterone acetate inhibits the growth of BRCA2wt prostate tumors
Authors: Damle Rajendra N. , Hawkins Rebecca , Hosbach Jennifer , Ndikuyeze Georges Habineza , Driscoll Jenny , Fulton Natalie L. , Derosa David , Hughes Anna , Chu Gerald , Calara-Nielsen Karl , Smirnov Denis , Shen Dong , Snyder Linda A. 
Published: August 2019

Abstract
Patients with metastatic prostate cancer may initially respond well to first- and second-generation androgen receptor (AR)-targeted therapies, but many will experience disease progression, indicating a need for alternative therapies. A subset of these patients bears prostate tumors that harbor deleterious mutations in DNA damage repair (DDR) pathway genes, such as BRCA2. These DDR mutations render the tumors sensitive to drugs that inhibit poly (ADP-ribose) [PAR] polymerase-1 (PARP1), inducing synthetic lethality. Studies indicate that there are interactions between AR signaling pathways and DDR pathways in prostate cancer cells, supporting the hypothesis that dual AR/PARP inhibition could inhibit prostate tumor growth more potently than single agents, regardless of the DDR status of the tumor. This hypothesis was tested using well-known human and mouse prostate tumor models that are sensitive to androgen deprivation. Genotyping of the models confirmed that none of them carried homozygous pathogenic mutations in DDR genes, including BRCA1, BRCA2, and ATM. When the cell lines were incubated in vitro with niraparib, a potent and highly selective PARP1/2 inhibitor, PAR formation was significantly inhibited, and there was induction of γH2AX in treated cells, indicating the drug induced DNA double-stranded breaks. In addition, the cytotoxicity IC50 values for niraparib were in the range of 1-10 µM, as expected for cells that are DDRwt. In vivo efficacy studies demonstrated that the VCaP and Myc-CaP tumor models were insensitive or modestly sensitive to single agent treatment with niraparib or abiraterone acetate (AA). In contrast, the combination treatment of niraparib plus AA significantly reduced tumor growth and increased survival (p&lt;0.05) as compared with control or single agent arms. Studies are ongoing to understand the mechanisms of tumor growth control mediated by the combination of these two agents. The results support the hypothesis that prostate tumors may respond to a combination treatment with niraparib, a PARP inhibitor, and AA, an androgen synthesis inhibitor, even in the absence of DDR anomalies. A Phase 3 study is planned to evaluate this hypothesis and the safety and efficacy of this combination in humans.
Citation Format: Rajendra N. Damle, Rebecca Hawkins, Jennifer Hosbach, Georges Habineza Ndikuyeze, Jenny Driscoll, Natalie L. Fulton, David Derosa, Anna Hughes, Gerald Chu, Karl Calara-Nielsen, Denis Smirnov, Dong Shen, Linda A. Snyder. Niraparib combined with abiraterone acetate inhibits the growth of BRCA2wt prostate tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2134.
Abstract 2136: Doublecortin-like Kinase 1 (DCLK1) correlates with the cell proliferation in malignant pleural mesothelioma
Authors: Miura Akihiro , Yamamoto Hiromasa , Tao Hiroyuki , Suzawa Ken , Miyauchi Syunsaku , Araki Kota , Takahashi Yuta , Kurihara Eisuke , Ogoshi Yusuke , Shien Kazuhiko , Soh Junichi , Okabe Kazunori , Tomida Shuta , Sakaguchi Masakiyo , Toyooka Shinichi 
Published: August 2019

Abstract
Background: Malignant pleural mesothelioma (MPM) is a refractory disease with poor prognosis despite multimodality therapy. Because standard therapy is unsatisfactory, it is expected to establish a novel strategy such as molecular-targeting therapy for MPM. Doublecortin-like kinase 1 (DCLK1), a microtubule-associated protein, is one of the tumor-specific stem cell marker and is revealed that the cell survival is reduced by inhibiting this protein in pancreatic and colorectal cancers. DCLK1 is known to have several isoforms named as isoform #1-#4, although the significance of them in MPM has not been clarified. We hypothesized that DCLK1 was a potential therapeutic target for MPM.&lt;Materials and
Methods: Immunohistochemical staining was performed using surgically resected formalin-fixed paraffin-embedded tissue of MPM to evaluate the expression of DCLK1. Additionally, MPM cell lines were analyzed to characterize the protein and mRNA expression of DCLK1 by western blotting and RT-PCR. The expression of DCLK1 isoforms were selectively knocked down by small interfering RNA (siRNA) and cell viability was analyzed by colony formation and cell count assays.
Results: Immunohistochemical staining demonstrated that the expression of DCLK1 in MPM specimens was positive in 24 out of 27 samples (89%). Western blotting and RT-PCR revealed that DCLK1 was expressed in seven out of nine MPM cell lines. The results of RT-PCR revealed that isoform #2 and isoform #4 of DCLK1 were expressed in H2052, isoform #4 was expressed in H28, and isoform #2 was expressed in YUMC44 cell lines. Expressions of DCLK1 isoforms were selectively suppressed by isoform-specific siRNAs. Colony formation and cell count assays revealed that siRNA-mediated knockdown of both isoforms #2 and #4 suppressed cell growth compared to knockdown by negative control siRNA and knockdown of only isoform #2 or #4.
Conclusion: Our results demonstrate that simultaneous knockdown of both isoforms #2 and #4of DCLK1 results in the inhibition of cell growth and suggest its potential as a therapeutic target in MPM.
Citation Format: Akihiro Miura, Hiromasa Yamamoto, Hiroyuki Tao, Ken Suzawa, Syunsaku Miyauchi, Kota Araki, Yuta Takahashi, Eisuke Kurihara, Yusuke Ogoshi, Kazuhiko Shien, Junichi Soh, Kazunori Okabe, Shuta Tomida, Masakiyo Sakaguchi, Shinichi Toyooka. Doublecortin-like Kinase 1 (DCLK1) correlates with the cell proliferation in malignant pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2136.
Abstract 214: Preclinical evaluation of a novel MET antibody-drug conjugate in uveal melanoma models
Authors: Surriga Oliver , DaSilva John , Schwartz Gary K. 
Published: August 2019

Abstract
Uveal melanoma is the most common primary intraocular malignant tumor in adults. These tumors are characterized by mutations in G-proteins (GNAQ and GNA11) and high expression of MET, a receptor tyrosine kinase. While inhibition of MET signaling delays the development of uveal melanoma metastases in preclinical models (possibly by inhibiting cell migration), primary tumor growth is not inhibited, indicating a lack of dependence on the MET pathway. Thus, treatment of established metastatic uveal melanoma with MET signal blockers is unlikely to be effective. However, the high expression of MET protein in metastatic uveal melanoma presents an opportunity to directly kill tumor cells with a MET-targeted antibody drug conjugate (ADC). METxMET-ADC is a novel bispecific antibody that binds to two distinct epitopes on MET and is conjugated to a maytansinoid payload via a cleavable linker. The METxMET-ADC potently induces receptor internalization and mitotic arrest of cancer cells. Our in vitro studies show that the METxMET-ADC significantly and specifically decreases the viability of MET expressing uveal melanoma cell lines in a dose-dependent manner with an IC50 of less than 1 nM. A longer 7-day cell viability assay shows significantly enhanced inhibition of proliferation of several MET expressing cell lines (Mel270, Mel202, OMM1.3 and MP65) but not of OCM3 cells which express low levels of MET. Apoptosis is also induced up to 40% in the MET-expressing cell lines when treated with 10 nM of the METxMET-ADC for 48 hours. Cell cycle analysis shows a significant increase of OMM1.3 and Mel202 cells in mitosis after 6-24 hours of treatment and appearance of a sub-G1 population after 24-48 hours. Western blots confirm a decrease of MET protein levels, presumably due to receptor internalization and trafficking to lysosomes. Finally, treatment with the METxMET ADC is associated with induction of PARP cleavage and phosphorylation of histone H3 after 24 hours in OMM1.3 and Mel202 cells, but not in OCM3 cells. In summary, conjugation of a METxMET bispecific antibody with a cytotoxic payload allows for potent and selective killing of MET-expressing uveal melanoma cells. The METxMET-ADC demonstrates promising therapeutic potential for the treatment of uveal melanoma.
Citation Format: Oliver Surriga, John DaSilva, Gary K. Schwartz. Preclinical evaluation of a novel MET antibody-drug conjugate in uveal melanoma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 214.
Abstract 2146: High expression of Olfactomedin-4 correlates with chemoresistance and poor prognosis for pancreatic cancer
Authors: Ohkuma Ryotaro , Yada Erica , Kubota Yutaro , Hamada Kazuyuki , Ishida Hiroo , Hirasawa Yuya , Ariizumi Hirotsugu , Satoh Etsuko , Tsurutani Junji , Yoshimura Kiyoshi , Sasada Tetsuro , Aoki Takeshi , Murakami Masahiko , Norose Tomoko , Ohike Nobuyuki , Takimoto Masafumi , Tsunoda Takuya , Wada Satoshi 
Published: August 2019

Abstract
Background: Pancreatic cancer has an extremely poor prognosis and novel therapeutic strategies are desperately needed. It is considered that suitable molecules as therapeutic targets are resistant to chemotherapy and correlate with poor prognosis. In this experiment, we aimed to identify the optimal therapeutic targets in pancreatic cancer.
Materials and Methods: We established 10 lines of patient derived xenografts (PDXs) for pancreatic cancer. Next generation sequencer (NGS) analysis was performed for PDXs which were administered chemotherapy and untreated PDXs as a control. Furthermore, we performed immunohistochemistry (IHC) analysis for the protein expression of identified molecules from PDXs and post-operative pathologic specimens from 80 patients with pancreatic cancer. When chemotherapy was added on tumor cell lines forcibly expressing the molecule, antitumor effect was compared with the control.
Results: As a result of NGS analysis, we identified Olfactomedin-4 (OLFM4) molecule which was commonly shown high expression in chemotherapy administered PDXs. In IHC analysis, OLFM4 molecule expression was shown high expression with chemotherapy administered PDXs compared to untreated PDXs. For the analysis to use tumor cell lines forcedly expressing OLFM4 in vitro, the reduction rate of the tumor cell numbers was significantly lower than control vector, even if the concentration of the chemotherapy agent was increased. In a study using tissue specimens of 80 pancreatic cancer patients, Kaplan-Meier analysis showed that low expression of OLFM4 had a better survival rate than patients with high expression (p=0.0926, log-rank test). In multivariate analysis, it was shown that the high expression of OLFM4 was an independent poor prognostic factor with a statistically significant difference (p=0.044, Cox proportional hazards).
Conclusions: It was demonstrated that high expression of OLFM4 was involved in chemoresistance and was an independent prognostic factor for pancreatic cancer. This molecule might be a candidate of therapeutic target in pancreatic cancer.
Citation Format: Ryotaro Ohkuma, Erica Yada, Yutaro Kubota, Kazuyuki Hamada, Hiroo Ishida, Yuya Hirasawa, Hirotsugu Ariizumi, Etsuko Satoh, Junji Tsurutani, Kiyoshi Yoshimura, Tetsuro Sasada, Takeshi Aoki, Masahiko Murakami, Tomoko Norose, Nobuyuki Ohike, Masafumi Takimoto, Takuya Tsunoda, Satoshi Wada. High expression of Olfactomedin-4 correlates with chemoresistance and poor prognosis for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2146.
Abstract 215: Generation of site-specific DARPin® drug conjugates using EGFR as a model system
Authors: Laviolette Laura A. , Guidi Cynthia J. , Reichen Christian , Qiu Qifeng , Harris Luke , Schildknecht Patricia , Fischer Stefanie , Arany Zita , Hospodarsch Tanja , Skaletskaya Anna , Fuller Megan , Abbott Stephen , McCarthy Rebecca , Lee Jenny , Francisco Katherine , Sinkevicius Kerstin , Adams Sharlene , Espelin Christopher , Reid Emily , Li Wei , Marashio Carla , Donahue Kerry , Hicks Stuart , Snell Dan 
Published: August 2019

Abstract
DARPin® molecules are small engineered proteins, derived from natural ankyrin repeat proteins that are selected to bind to specific targets with high affinity. Individual DARPin® molecules can be linked together genetically in order to create multi-specific drug molecules. This versatility of DARPin® molecules makes them an attractive alternative to antibodies for the development of drug conjugates. We have developed DARPin® drug conjugates (DDCs) using a model EGFR multi-specific DARPin® molecule, consisting of four DARPin® domains linked together. DARPin® constructs were conjugated to the indolinobenzodiazepine mono-imine DGN549, a potent DNA alkylating payload. Biophysical characterization showed the DDCs to be well behaved in stability and solubility assays. The in vitro binding and cytotoxicity of these DDCs were evaluated. The DARPin® conjugates displayed in vitro potency in direct cytotoxicity assays across a panel of cell lines expressing EGFR. The impact of conjugation on PK parameters and in vivo efficacy is currently under evaluation. DARPin® drug conjugates combine the potency observed with antibody drug conjugates and the modular design of DARPin® molecules to create designer therapeutics.
Citation Format: Laura A. Laviolette, Cynthia J. Guidi, Christian Reichen, Qifeng Qiu, Luke Harris, Patricia Schildknecht, Stefanie Fischer, Zita Arany, Tanja Hospodarsch, Anna Skaletskaya, Megan Fuller, Stephen Abbott, Rebecca McCarthy, Jenny Lee, Katherine Francisco, Kerstin Sinkevicius, Sharlene Adams, Christopher Espelin, Emily Reid, Wei Li, Carla Marashio, Kerry Donahue, Stuart Hicks, Dan Snell. Generation of site-specific DARPin® drug conjugates using EGFR as a model system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 215.