bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4776: Characterizing an oncolytic adenovirus modified with the CXCL12 ligand for breast cancer therapy
Authors: O'Bryan Samia M. , Mathis J. Michael 
Published: August 2019

Abstract
Breast cancer is the most commonly diagnosed cancer in women, making up nearly 30% of all diagnosed cancer cases each year. While localized breast cancer is easily treated, advanced cases are difficult to treat resulting in poor five-year survival rates. Thus, new therapies capable of increasing treatment efficacy are needed. Oncolytic virotherapy using human adenovirus is a novel therapeutic approach capable of specifically targeting cancer cells while sparing normal tissue. The adenovirus vector is well-characterized and is uniquely suited for oncolytic virotherapy due to its systemic stability, good safety profile and the ability to infect a broad range of dividing and non-dividing cells. Replication of oncolytic adenoviruses within cancer cells causes the lysis of the cells and subsequent spread of progeny virions within the surrounding tumor stroma. One challenge in targeting cancer cells with adenovirus vectors has been the low expression of the endogenous receptor, the Coxsackie and adenovirus receptor (CXADR), prompting the search for new receptor targets. In this study, we engineered an adenovirus to contain the CXCL12 ligand to target the chemokine receptors CXCR4 and CXCR7 overexpressed in a variety of tumors. Altered expression of these receptors drives tumor progression, migration, invasion and metastasis. Previously, we developed a bispecific adaptor molecule containing the CXCL12 ligand to redirect a replication-deficient wild-type adenovirus to breast cancer cells overexpressing CXCR4. In the current study, we engineered a replication-competent oncolytic adenovirus modified with the CXCL12 ligand to target cancer cells overexpressing CXCR4 and CXCR7. A recombinant gene was constructed using the tail domain of the adenovirus fiber gene fused to the trimerization domain of the T4 fibritin gene followed by the mature CXCL12 sequence. After viral production, the presence of a modified fiber and the CXCL12 ligand were confirmed. Subsequently, the vector was tested in a panel of breast cancer cells for infection and cell killing efficacy in vitro. Receptor knock down and overexpression studies confirmed the specificity of the virus. Together, these studies address the hypothesis that constructing a retargeted oncolytic adenovirus using the CXCL12 ligand provides selective infection and killing of breast cancer cells overexpressing CXCR4 and CXCR7. These results support the rationale for further development of retargeted adenovirus vectors for oncolytic virotherapy in patients. Future experiments will be conducted to assess tumor targeting using a xenograft mouse model of human breast cancer.
Citation Format: Samia M. O'Bryan, J. Michael Mathis. Characterizing an oncolytic adenovirus modified with the CXCL12 ligand for breast cancer therapy [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 4776.
Abstract 4777: Anti-tumor effect of adenovirus encoding APE1/Ref-1 in breast cancer xenografts: anti-inflammation and apoptotic cell death
Authors: Choi Sunga , Lee Yu Ran , Kim Yeon Hyang , Kim Ki Mo , Park Myoung Soo , Jeon Byeong Hwa 
Published: August 2019

Abstract
In persistent inflammatory state involving the chronic activation of the immune system, the interplay between breast cancer and stromal cells is closely associated. We have previously shown that APE1/Ref-1 which could inhibit inflammatory signaling by reductive conformational change of cytokines receptors. In response to hyperacetylation, stimulation by secreted Ac-APE1/Ref-1 binding to RAGE initiated apoptotic cell death in TNBC models, in vitro and in vivo. In the present study, we used Ad-APE1/Ref-1 adenovirus, which can be overexpressed and be secreted into the blood of xenografts. We investigated how the Ad-APE1/Ref-1 influences growth retardation and apoptotic cell death of inflammation associated TNBC in vivo. The Ad-APE1/Ref-1-injection in MDA-MB 231 orthotopic xenografts caused a decrease in the volume and weight of tumors as shown in IVIS images. The treatment of Ad-APE1/Ref-1 also induced an inhibition of tumor growth and development, leading to apoptotic cell death, accompanied by generation of reactive oxygen species. Tumor tissues derived from Ad-APE1/Ref-1 exhibited apoptotic bodies compared with tumors of control or Adβ-galactosidase-injected mice. Moreover, level of inflammatory cytokines was evaluated in plasma of the xenografts; ratio of anti- to pro inflammatory cytokines was comparable with one of normal mice. The PAK1-STAT-3-NFkB axis in inflammatory signaling of tumor tissues derived from AdAPE1/Ref-1 injected mice was significantly inhibited compared to those of control or Adβ-galactosidase-injected mice. These results suggest that regulation of inflammatory signaling with adenoviral mediated APE1/Ref-1 in tumors of MDA-MB-231 xenografts modulates cytokine secretion, thereby inhibiting cancer cell growth.
Note: This abstract was not presented at the meeting.
Citation Format: Sunga Choi, Yu Ran Lee, Yeon Hyang Kim, Ki Mo Kim, Myoung Soo Park, Byeong Hwa Jeon. Anti-tumor effect of adenovirus encoding APE1/Ref-1 in breast cancer xenografts: anti-inflammation and apoptotic cell death [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 4777.
Abstract 4781: Preclinical assessment of efficacy and safety of novel oncolytic adenovirus for therapy of disseminated lung cancer
Authors: Atasheva Svetlana , Yao Jia , Young Cedrick , Paolo Nelson C. Di , Wyche Henry , Shayakhmetov Dmitry M. 
Published: August 2019

Abstract
The majority of lung cancer patients do not respond to current immune-oncology drugs due to low PD1 and PD-L1 expression on immune and cancer cells. Oncolytic viruses are being actively explored as an alternate modality for cancer therapy due to their natural ability to kill infected cells through viral replication. In this study, we analyzed the anti-tumor efficacy and safety profile of AVID-317 oncolytic virus in pre-clinical mouse models of disseminated lung cancer. AVID-317 is a novel oncolytic adenovirus possessing a set of mutations in the virus capsid, which ablate virus interactions with cellular b3 integrins on macrophages and hepatic cells, resulting in virus de-targeting from the liver after intravenous administration. In vitro studies demonstrated that 70% of tested human non-small cell lung cancer (NSCLC)-derived cell lines (N=16) are sensitive to AVID-317 infection, and 85% of AVID-317-sensitive NSCLC lines express no or low PD-L1. Intravenous injection of control parental human adenovirus type 5 (HAdv5) at a dose of 1e11 v.p. per mouse into wild-type mice resulted in release of pro-inflammatory cytokines IL-1b, IL-6, IL-16, and G-CSF into the bloodstream at 6 hours post virus administration. Furthermore, this dose of HAdv5 was lethal due to severe hepatotoxicity within 48 h post virus injection. In contrast, intravenous administration of AVID-317 in the range of doses up to 1e12 v. p. per mouse resulted in no detectible IL-6 and significantly reduced IL-1b, IL-16, G-CSF amounts in the blood. Importantly, AVID-317 administration did not result in mortality. Next, we grafted PD-L1-low human adenocarcinoma A549-Luc-C8 cells into lungs of NCr nude mice to establish an orthotopic model of disseminated lung cancer. When tumor burden reached between 2xe6 to 8e6 RLU, mice were enrolled in four cohorts and treated with AVID-317 at doses of 5e10, 1e11, or 3e11 v.p. per mouse or administered with saline only (control group; N=&gt;10 in each cohort). Mice were euthanized upon detection of 20% weight loss compared to baseline. The median survival in saline-treated group was 57 days post treatment. However, median survival has not be reached for AVID-317-treated groups for the duration of the study (80 days). Taken together, our study demonstrates feasibility of using AVID-317 oncolytic adenovirus for systemic therapy of disseminated lung cancer and its greatly improved safety profile observed upon intravenous virus delivery.
Citation Format: Svetlana Atasheva, Jia Yao, Cedrick Young, Nelson C. Di Paolo, Henry Wyche, Dmitry M. Shayakhmetov. Preclinical assessment of efficacy and safety of novel oncolytic adenovirus for therapy of disseminated lung 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 4781.
Abstract 4787: New and potent small molecule as EF2K inhibitor: A novel EF2K inhibitor
Authors: Onder Ferah Comert , Ay Mehmet , Durdagi Serdar , Ozpolat Bulent , Kantarcioglu isik 
Published: August 2019

Abstract
Triple-negative breast cancer (TNBC) which constitutes 15-20% of breast cancers, is the most aggressive and chemo-resistant subtype of breast cancer and associated with the highest mortality rates of mortality among all breast cancer subtypes. TNBC is characterized by a lack of molecular targets (e.g., estrogen, progesterone, and HER2 receptors. Current treatment options for TNBC are still limited to conventional chemotherapies such as anthracyclines (e.g., doxorubicin) and taxane-based therapeutics. Identification of new molecular targets is critical for development of novel targeted treatments to improve poor patient prognosis and survival. We recently found that expression of eukaryotic elongation factor-2 kinase (EF2K), an unusual alpha kinase, is commonly upregulated in the majority of TNBC patients and associated with poor prognosis. We showed that EF2K is a potential molecular driver by promoting cell proliferation motility and invasion and drug resistance and validated it as a molecular target by RNA based therapeutic (i.e, siRNA and microRNA) in various TNBC models in mice (Tekedereli 2012, Hamurcu 2017, Bayraktar 2017). Several inhibitors of eEF2K have been described in the previous studies. However, these inhibitors have been neither specific nor potent. Small molecule inhibitor was synthesized in many steps by using different synthesis methods and also performed all of the structural analysis (FT-IR, 1H-NMR, 13C-NMR and LC-MS-MS). Computational studies were performed by using Schrödinger 2015 programme to investigate of in vitro activity of the compounds. By performing in vitro assays we identified a potent inhibitor of EF2K which inhibited p-EF2 at 1 μM (2 hours) detected by Western blots. Treatment of TNBC cells with this compound starts to inhibits cell proliferation and colony formation at 5-10 μM concentrations. The further studies are still ongoing. In conclusion, our results suggest that our newly designed small molecule may be potent EF2K inhibitor and can be used for targeting EF2K in TNBC.
Note: This abstract was not presented at the meeting.
Citation Format: Ferah Comert Onder, Mehmet Ay, Serdar Durdagi, Bulent Ozpolat, isik Kantarcioglu. New and potent small molecule as EF2K inhibitor: A novel EF2K inhibitor [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 4787.
Abstract 479: BRAF and KRAS mutation define distinct subtypes of the CpG island methylator phenotype in colorectal cancers
Authors: Whitehall Vicki L. , Fennell Lochlan , Dumenil Troy , Hartel Gunter , Nones Katia , Bond Catherine , McKeone Diane , Patch Ann-Marie , Kazakoff Stephen , Pearson John , Waddell Nicola , Wirapati Pratyaksha , Lochead Paul , Ogino Shuji , Tejpar Sabine , Leggett Barbara 
Published: August 2019

Abstract
BACKGROUND AND AIMS: Colorectal cancer is an epigenetically heterogeneous disease, however the extent and spectrum of the CpG Island Methylator Phenotype (CIMP) is not clear.METHODS: Genome scale methylation and transcript expression were measured using the Illumina HM450 DNA methylation and HT12 V3 expression microarrays in 216 unselected colorectal cancers. Mutations in epigenetic regulators were assessed using CIMP-classified Cancer Genome Atlas exomes.RESULTS: CIMP-High cancers dichotomised into CIMP-H1 and CIMP-H2 based on methylation profile, which was supported by over-representation of BRAF (74%, P&lt;0.0001) or KRAS (55%, P&lt;0.0001) mutation. Congruent with increasing methylation, there was a stepwise increase in patient age from 62 years in the CIMP-Negative subgroup to 75 years in the CIMP-H1 subgroup (P&lt;0.0001). CIMP-H1 were predominantly comprised of consensus molecular subtype 1 (CMS1) cancers (70%) whilst CMS3 was over-represented in the CIMP-H2 subgroup (55%). PRC2-marked loci were subjected to significant gene body methylation in CIMP cancers (P&lt;1.6x10-78). We identified oncogenes susceptible to gene body methylation and Wnt pathway antagonists resistant to gene body methylation. CIMP cluster specific mutations were observed for in chromatin remodeling genes, such as in the SWI/SNF and NuRD complexes, suggesting synthetic lethality.CONCLUSION: There are five clinically and molecularly distinct subgroups of colorectal cancer. We show a striking association between CIMP and age, gender and tumor location and identify an unidentified role for gene body methylation in progression of serrated neoplasia. These data support our recent findings that CIMP is uncommon in young patients and that BRAF mutant polyps in young patients may have limited potential for malignant progression.
Citation Format: Vicki L. Whitehall, Lochlan Fennell, Troy Dumenil, Gunter Hartel, Katia Nones, Catherine Bond, Diane McKeone, Ann-Marie Patch, Stephen Kazakoff, John Pearson, Nicola Waddell, Pratyaksha Wirapati, Paul Lochead, Shuji Ogino, Sabine Tejpar, Barbara Leggett. BRAF and KRAS mutation define distinct subtypes of the CpG island methylator phenotype in colorectal cancers [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 479.
Abstract 48: Cellular dynamics and heterogeneity of active Kras induced-gastric pre-neoplasia in mouse
Authors: Choi Eunyoung , Vega Paige N. , Min Jimin , Engevik Amy C. , Williams janice A. , Yang Qing , Patterson Loraine M. , Simmons Alan J. , Lau Ken S. , Magness Scott T. , Goldenring James R. 
Published: August 2019

Abstract
Cellular heterogeneity in cancer development is considered as a source of cancer cell generation and drug resistance. However, cellular heterogeneity has not been fully eluciated during metaplasia progression to gastric pre-neoplasia and neoplasia in gastric carcinogenesis. Recent investigations have suggested that Ras activation, rather than Ras mutation, may promote the gastric carcinogenesis. We have recently established several in vitro metaplastic/pre-neoplastic organoid lines; Meta3-metaplasia and Meta4-pre-neoplasia, derived from mouse stomachs induced active Kras expression in chief cells and investigated cellular heterogeneity and plasticity that may lead to the progression of metaplasia to gastric neoplasia. While both Meta3 and Meta4 initially formed spherical or spheroidal structures and generated complicated budding or cyst-like structures between 2 and 4 weeks, Meta4 cells displayed more disorganized structures and aggressive behaviors than Meta3. We also examined altered cellular behaviors, structural changes and survival of Meta4 organoids after MEK inhibition which is a downstream mediator of Kras signaling pathway. The Meta4 treated with Selumetinib for 3 days died or did not show an increase in size at various concentrations. However, some Meta4 organoids showed an ability to survive and retained a spheroidal structure despite the Selumetinib treatment. Single cell-RNA sequencing (scRNA-seq) data analysis demonstrated distinct characteristics of Meta4 cells as pre-neoplastic cells and a signature of presence and heterogeneity of pre-neoplasia stem cell (PNSC) populations. The scRNA-seq data analysis also revealed that cellular behavior and dynamics of pre-neoplastic cells can be controlled by MEK inhibition, but the PNSC populations still maintain the niche for stem-like cells in gastric pre-neoplasia. The isolated two PNSC populations showed functional differences and the stemness of the PNSCs in pre-neoplastic stage through high-throughput functional analysis. Therefore, our study concludes that putative gastric cancer stem cells in gastric pre-neoplasia might be the source for maintenance of heterogeneity and contribute to the progression of gastric pre-neoplasia to cancer.
Citation Format: Eunyoung Choi, Paige N. Vega, Jimin Min, Amy C. Engevik, janice A. Williams, Qing Yang, Loraine M. Patterson, Alan J. Simmons, Ken S. Lau, Scott T. Magness, James R. Goldenring. Cellular dynamics and heterogeneity of active Kras induced-gastric pre-neoplasia in mouse [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 48.
Abstract 482: Recurrent glioma with lineage conversion from oligodendroglioma to astrocytoma: Another facet of glioma evolution during recurrence
Authors: Lee Kyung-Hwa , Jung Tae-Young , Jung Shin , Lee Jae-Hyuk , Kim Kyung-Keun , Kim Hangun , Moon Kyung-Sub 
Published: August 2019

Abstract
Background: Following the introduction of the molecular classification of gliomas by the WHO in 2016, molecularly-proven lineage conversion during glioma recurrence has never been reported.
Methods: We analyzed two cases of recurrent glioma that began as oligodendroglioma, both histologically and molecularly, but converted to astrocytoma over episodes of recurrence.
Results: The cases were initially diagnosed as oligodendroglioma with 1p/19q-codeletion and mutation of isocitrate dehydrogenase 1 (IDH1)-R132H. The recurrent tumors showed loss of alpha-thalassemia/mental retardation X-linked (ATRX) expression, strong P53 positivity, and 1p/19q-nondeletion. Next generation sequencing (NGS) analysis performed on the first case confirmed the transition of molecular traits from oligodendroglioma to astrocytoma. An IDH mutation of R132H was preserved in the episodes of recurrence, but ATRX and TP53 mutations were newly acquired and TERT promoter mutation C228T was lost at the most recent recurrence.
Conclusions: The issue in question for the presented cases is whether the original tumors were pure oligodendrogliomas that then transdifferentiated into astrocytomas, or whether the original tumor was an oligoastrocytoma having oligodendroglioma cells that outnumbered the astrocytoma cells and where the astrocytoma cells becoming more dominant over the episodes of recurrence. With the recognition of the possibility of lineage conversion, our study suggests that molecular examination should be performed to adjust therapeutic strategies in recurrent gliomas. Indeed, our observation of lineage conversion in glioma recurrence calls into question the current distinction drawn between oligodendroglioma, astrocytoma and oligoastrocytoma, rather than simply bidding “farewell to oligoastrocytoma”.
Citation Format: Kyung-Hwa Lee, Tae-Young Jung, Shin Jung, Jae-Hyuk Lee, Kyung-Keun Kim, Hangun Kim, Kyung-Sub Moon. Recurrent glioma with lineage conversion from oligodendroglioma to astrocytoma: Another facet of glioma evolution during recurrence [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 482.
Abstract 4853: M6123 is an ADCC-enhanced and selective monovalent antagonist of FGFR1 showing antitumor activity in preclinical lung cancer models
Authors: Esdar Christina , Iffland Christel , Zimmermann Astrid , Lim Angela , Sanderson Michael , Blaukat Andree 
Published: August 2019

Abstract
Despite the considerable progress made with immunotherapies and targeted therapies, lung cancer remains a devastating disease with a high medical need for more effective and safer therapeutic options. Targeted therapies have delivered meaningful benefit to subsets of lung adenocarcinoma patients harboring specific oncogenic driver alterations but have not yet been extensively explored in other lung cancer subtypes. In the case of lung squamous carcinoma and small-cell lung cancer, amplification and overexpression of FGFR1 have been described as potential oncogenic drivers.Several small molecule tyrosine kinase inhibitors of the FGFR family are in clinical development but initial reports have suggested limited therapeutic benefit of these agents when applied as monotherapy in FGFR1-amplified lung cancer patients. To overcome toxicities associated with pan-FGFR inhibition, such as dysregulation of FGF23-mediated phosphate homeostasis, M6123 was developed as an FGFR1-selective biological antagonist. An immunization campaign in OmniRats® led to the identification of the fully human, potent and highly selective FGFR1 antibody A08 which was converted into the monovalent FGFR1 antagonist M6123 based on the proprietary SEED platform. Furthermore, M6123 was engineered for enhanced ADCC effector function. In contrast to bivalent FGFR1 antibodies, M6123 was well tolerated in mice, with no signs of body weight loss. Of note, M6123 did not interfere with hormonal FGF23 signaling in mice, a severe side effect of FGFR kinase inhibitors. Concentration-dependent inhibition of FGFR1 auto-phosphorylation was demonstrated in FGFR1-overexpressing lung cancer cells both in vitro and in vivo. Moreover, M6123 monotherapy had strong antitumor activity in specific FGFR1-expressing cell line- and patient-derived xenograft models, whilst combination with chemotherapy significantly enhanced efficacy. In summary, M6123 is a unique and clearly differentiated selective FGFR1 antagonist which warrants further testing in preclinical models to refine a predictive biomarker strategy for selection of potentially sensitive lung cancer patients.
Citation Format: Christina Esdar, Christel Iffland, Astrid Zimmermann, Angela Lim, Michael Sanderson, Andree Blaukat. M6123 is an ADCC-enhanced and selective monovalent antagonist of FGFR1 showing antitumor activity in preclinical lung cancer 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 4853.