bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3816: Efficacy of CDX-1140, an agonist CD40 antibody, in preclinical tumor models
Authors: Thomas Lawrence J. , He Li-Zhen , Testa James , Wasiuk Anna , Weidlick Jeffrey , Sisson Crystal , Vitale Laura A. , O'Neill Thomas , Forsberg Eric , Pilsmaker Catherine D. , Gergel Lauren E. , Do Elizabeth Q. , Boyer James , Baronas April R. , Rocheleau Mallary , Grealish Michelle E. , Borrelli Kathleen M. , Marsh Henry C. , Keler Tibor 
Published: August 2018

Abstract
CD40 on antigen presenting cells plays a critical role in the induction of effective innate and adaptive immune responses. In contrast, CD40 signaling on certain malignant cells, particularly B cell lymphomas, inhibits proliferation or triggers apoptotic cell death. Thus, two independent mechanisms provide opportunities for the use of agonist anti-CD40 monoclonal antibodies in cancer therapy: enhancement of anti-tumor immunity, and direct inhibition of tumor growth. CDX-1140 is a human IgG2 antibody selected from a panel of fully human mAbs specific for CD40 generated by hybridoma technology from human Ig transgenic mice. We previously demonstrated the potent immune enhancing effects of CDX-1140 using in vitro models and in non-human primates. CDX-1140 was shown to activate dendritic cells and B cells in an Fc receptor independent manner. CDX-1140 does not bind to the CD40L binding site, and synergizes with CD40L in stimulation of the CD40 receptor and subsequent functional activities. Here we further characterized the anti-tumor activity of CDX-1140 on CD40 positive tumors using xenograft models in immunodeficient mice. Using the Ramos and Raji human lymphoblastoma cell lines, CDX-1140 was shown to attenuate tumor growth and prolong survival. Addition of CDX-1140 and human PBMC was highly effective at promoting complete rejection of both Ramos and Raji tumors. Importantly, the epithelial EJ138 bladder carcinoma cell line was also highly sensitive to CDX-1140 treatment. For example, in a study where mice received EJ138 cells subcutaneously, all animals that were treated with 300 µg of CDX-1140 on days 1, 8, and 15, showed suppression of tumor growth through day 60, in comparison to saline-treated animals which developed significant tumors in 7 of 8 animals. These data support the potential of CDX-1140 for direct anti-tumor effects on CD40-positive tumors (including epithelial tumors) that may supplement its activity as an immune activating agent. CDX-1140 is currently in a phase 1 dose-escalation study in patients with advanced solid tumors.
Citation Format: Lawrence J. Thomas, Li-Zhen He, James Testa, Anna Wasiuk, Jeffrey Weidlick, Crystal Sisson, Laura A. Vitale, Thomas O'Neill, Eric Forsberg, Catherine D. Pilsmaker, Lauren E. Gergel, Elizabeth Q. Do, James Boyer, April R. Baronas, Mallary Rocheleau, Michelle E. Grealish, Kathleen M. Borrelli, Henry C. Marsh, Tibor Keler. Efficacy of CDX-1140, an agonist CD40 antibody, in preclinical tumor models [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 3816.
Abstract 3819: INCAGN02385 is an antagonist antibody targeting the co-inhibitory receptor LAG-3 for the treatment of human malignancies
Authors: Savitsky David , Ward Rebecca , Riordan Christina , Mundt Cornelia , Jennings Shawn , Connolly Joe , Findeis Mark , Sanicola Michele , Underwood Dennis , Nastri Horacio , Scherle Peggy , Hollis Gregory , Huber Reid , Stein Robert , Dijk Marc van , Wilson Nicholas S. 
Published: August 2018

Abstract
Lymphocyte activation gene 3 (LAG-3) is a cell surface receptor that negatively regulates antigen-specific T cell responses. LAG-3 expression is generally restricted to populations of recently activated and chronically stimulated exhausted T cells, and is often correlated with general T cell dysfunction across several human malignancies. Accordingly, the LAG-3 pathway has been identified as a potential barrier to productive tumor-specific T cell immunity generated by PD-1/PD-L1 blockade. The antitumor activity from targeting the LAG-3 pathway in preclinical models has provided further rationale for pharmacologic modulation of the LAG-3 axis in cancer patients. INCAGN02385 is an Fc-engineered IgG1κ antibody chosen for development based on its high-affinity binding to human LAG-3, cross-reactivity with cynomolgus monkey LAG-3, and ability to potently block LAG-3 binding with its MHC class II ligand. INCAGN02385 also enhances T cell responsiveness to TCR stimulation alone or in combination with PD-1/PD-L1 axis blockade. Evaluation of INCAGN02385 in cynomolgus monkeys was well-tolerated and demonstrated the expected pharmacokinetic profile. Altogether, these data support assessment of INCAGN02385 in patients with advanced or metastatic solid tumors.
Citation Format: David Savitsky, Rebecca Ward, Christina Riordan, Cornelia Mundt, Shawn Jennings, Joe Connolly, Mark Findeis, Michele Sanicola, Dennis Underwood, Horacio Nastri, Peggy Scherle, Gregory Hollis, Reid Huber, Robert Stein, Marc van Dijk, Nicholas S. Wilson. INCAGN02385 is an antagonist antibody targeting the co-inhibitory receptor LAG-3 for the treatment of human malignancies [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 3819.
Abstract 3823: Bat4306f, an anti-CD20 antibody devoid of fucose modification, demonstrates enhanced ADCC effect and potent in vivo efficacy
Authors: Yu Jin-Chen , Qin Chao , Li Shengfeng 
Published: August 2018

Abstract
Depletion of malignant B cells using anti-CD20 antibodies is one of the most effective approaches for CD20-positive non-Hodgkin lymphoma therapy. Anti-CD20 antibodies can activate several pathways including antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), or programmed cell death to kill tumor cells. ADCC is mediated via Fc region of antibody binding to FcγRIIIa receptor on effector cells, such as NK cells. Previous studies have shown that non-fucosylated antibody binds to FcγRIIIa with increased affinity and can thus trigger FcγRIIIa-mediated effector functions more efficiently than native, fucosylated antibody. Obinutuzumab, an FDA-approved anti-CD20 antibody with approximate 30% fucose level of a normal antibody, has demonstrated better efficacy than fucosylated rituximab. We generated BAT4306F, which has the same sequence as obinutuzumab yet is completely devoid of fucose modification. BAT4306F induced higher level of ADCC effect compared with rituximab and obinutuzumab in vitro. BAT4306F also showed significantly superior activity on depleting B cells in whole blood compared to rituximab, and superior activity compared to obinutuzumab. In monkeys dosed once with these antibodies, BAT4306F demonstrated much stronger B-cell depletion activity than that of obinutuzumab and rituximab, whether detected in serum, spleen, or lymph node. The residual B cells detected in spleen of monkey treated with BAT4306F were 8-fold less than that of obinutuzumab, and 10-fold less than that of rituximab. Furthermore, BAT4306F demonstrated stronger tumor-inhibition activity than rituximab in a DLBCL tumor cell xenograft mouse model. Preclinical acute and long-term toxicity studies in monkey reveal that BAT4306F is well tolerated. Together these data demonstrate that BAT4306F is more potent than obinutuzumab and rituximab due to a complete defucosylation. The result warrants further clinical development of BAT4306F.
Citation Format: Jin-Chen Yu, Chao Qin, Shengfeng Li. Bat4306f, an anti-CD20 antibody devoid of fucose modification, demonstrates enhanced ADCC effect and potent in vivo efficacy [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 3823.
Abstract 385: HIF1A can regulate Wnt signaling in human colon cancer cells
Authors: Lyou Yung , Chen George , Waterman Marian 
Published: August 2018

Abstract
Standard-of-care treatment for KRAS mutant metastatic colorectal cancer (mCRC) combines a cytotoxic chemotherapy backbone (FOLFOX) with an antiangiogenesis biologic agent (i.e., bevacizumab). Despite significant efforts to improve treatment, the prognosis for this type of cancer remains poor with an average 5-year overall survival of ~11%. Oncogenic KRAS mutations lead to the overactivation of RAS/ERK/MAPK pathwa,y driving many hallmarks of cancer such as cell proliferation, growth, and altered metabolism. In particular, several studies have shown that oncogenic activation of KRAS leads to normoxic stabilization of HIF1A protein, which can then reprogram cellular metabolism towards aerobic glycolysis. Our studies have discovered that overactive Wnt signaling can also reprogram cancer cell metabolism towards aerobic glycolysis. Of note, KRAS (~40%) and Wnt signaling (~90%) are very frequently coactivated in colorectal cancer. Interestingly, an important, key metabolic gene targeted by Wnt signaling, Pyruvate Dehydrogenase Kinase I (PDK1), is also directly regulated by HIF1A, suggesting there may be crosstalk between the HIF1A and Wnt pathways. Indeed, several published studies support the idea that HIF1A can influence Wnt signaling, and our data show this may occur through regulation of the Wnt mediating transcription factors LEF1 and TCF1 (TCF7 gene). Using luciferase reporters driven by LEF/TCF promoters, we observed significantly increased LEF1/TCF7 promoter activity in hypoxic colon cancer cells but not for other TCF family members (TCF7L1/TCF7L2). We identified putative hypoxia responsive elements (HREs) in the human LEF1 promoter, and deletion of these HREs reduced responsiveness to hypoxia. Furthermore, we have found that targeting glycolysis and Wnt can be synergistic in inhibiting colon cancer cell colony growth. We find that HIF1A and LEF/TCF/beta-catenin complexes coregulate gene expression of metabolic targets as well as Wnt signaling components (e.g., LEF1 and TCF7). These data suggest that cross-regulation between the HIF1A and Wnt signaling pathway is important and may be a potential Achilles heel for novel therapeutics in targeting KRAS mutant colon cancer. Current studies are under way to further investigate the mechanisms of crosstalk and joint regulation of metabolic reprogramming in KRAS mutant colon cancer cells.
Citation Format: Yung Lyou, George Chen, Marian Waterman. HIF1A can regulate Wnt signaling in human colon 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 385.
Abstract 3913: Selective targeting of circulating tumor cells with agonistic EphA2 ligand
Authors: Salem Ahmed F. , Wang Si , Billet Sandrine , Chen Jie-Fu , Udompholkul Parima , Gambini Luca , Baggio Carlo , Posadas Edwin M. , Bhowmick Neil A. , Pellecchia Maurizio 
Published: August 2018

Abstract
EphA2 is a tyrosine kinase receptor that is overexpressed in many cancer types like pancreatic, colon and breast cancers. Targeting cancer cells with an EphA2-targeting molecule conjugated with cytotoxic agents can spare normal cells from chemotherapy side effects. Here, we developed (123B9)2, a novel, potent ligand for the EphA2 receptor that binds to EphA2 ligand-binding domain and causes receptor activation at a sub micromolar concentration as evident in biochemical and cell-based assays. Furthermore, our molecule showed enhanced resistance to degradation, making it suitable for in vivo studies. Subsequently, we conjugated (123B9)2 with paclitaxel, a mitotic spindle inhibitor, and administered it in nude mice bearing breast cancer cells MDA-MD-231 in mammary glands. Remarkably, (123B9)2 paclitaxel-conjugate showed significant inhibition of breast cancer circulating tumor cells (CTC)s in orthotropic mice compared to paclitaxel alone. Finally, we are planning to use our molecule as a single agent to target cancer cells.
Citation Format: Ahmed F. Salem, Si Wang, Sandrine Billet, Jie-Fu Chen, Parima Udompholkul, Luca Gambini, Carlo Baggio, Edwin M. Posadas, Neil A. Bhowmick, Maurizio Pellecchia. Selective targeting of circulating tumor cells with agonistic EphA2 ligand [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 3913.
Abstract 3954: Anti-cancer agent P306 restores p53 pathway through PUMA
Authors: Tian Xiaobing , Lulla Amriti R. , Zhang Shengling , Lev Avital , Abbosh Philip , Sikder Rahmat , Dicker David T. , El-Deiry Wafik S. 
Published: August 2018

Abstract
The tumor-suppressor p53 prevents cancer development via initiating cell-cycle arrest, cell death, repair, or anti-angiogenesis processes. Over 50% of human cancers harbor cancer-causing mutations in p53. p53 mutations not only abrogate its tumor-suppressor function, but also endow mutant p53 with a gain of function (GOF), creating a proto-oncogene that contributes to tumorigenesis, tumor progression, and chemo- or radiotherapy resistance. Thus, targeting mutant p53 and/or restoring a wild-type p53 signaling pathway provides an attractive strategy for cancer therapy. We previously showed that P01, a natural product, has potent anti-cancer activity against tumors with mutated p53. Based on the structure of the pharmacophore of the P01 family, we designed and synthesized new analogues. The novel synthetic analogue, P306, is potent in reducing both short-term and long-term proliferation in a broad panel of mutant p53 cell lines, including HT29, SW480, DLD-1, MDA-MB-231, MDA-MB-468, U251, FaDu, CAL-27, PANC-1, ASPC-1 and H1975, with IC50 values in the range of 33.9 to 242 nM. In this study, we have characterized a distinct mechanism of P306 that engages the apoptosis pathway by upregulating pro-apoptotic proteins including PUMA in a time-and dose-dependent manner in colorectal cancer cell lines. PUMA is necessary for the apoptotic effects of P306 in colorectal cancer cells with PUMA-mediated caspase 8 activation mediating P306-induced apoptosis. P306 not only restores p53 pathway but also depletes mutant p53 protein in various mutant p53-expressing cancer cells regardless of what kinds of mutation. P306 treatment potently downregulates c-Myc protein level, and apoptosis induced by P306 is dependent on the c-Myc-PUMA pathway. Our results provide novel mechanistic insights into the tumor cell death promoting activity of a candidate therapeutic agent for cancer.
Citation Format: Xiaobing Tian, Amriti R. Lulla, Shengling Zhang, Avital Lev, Philip Abbosh, Rahmat Sikder, David T. Dicker, Wafik S. El-Deiry. Anti-cancer agent P306 restores p53 pathway through PUMA [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 3954.
Abstract 4337: Identification of novel fusion gene, PUM1-TRAF3, as potent biomarker in bile duct cancer
Authors: Jung Dawoon E. , Kim Kahee , Kim Chanyang , Park Soo Been , Jo Jung Hyun , Lee Hee Seung , Song Si Young 
Published: August 2018

Abstract
Background: Gene fusion occurs when a part of one gene fuses with a part of another gene by genome rearrangement and may possess oncogenic properties. Bile duct cancer (BDC) are one of the most lethal malignancy, but lack of proper diagnostic or prognostic markers. Our aim was to investigate BDC specific fusion genes found in patient's specimens and its clinical significance. Method : We extracted total RNA from five BDC tissues and normal tissues from the same patients. RNA sequencing was performed and the result data was analyzed using ChimeraScan, Jaffa or FusionCatcher softwares to detect gene fusion. The expression of the detected novel fusion gene was confirmed by ddPCR using tissues from the operated BDC patients and its clinical significance was analyzed with medical information of the patients. Result : We found 52 BDC specific fusion genes by RNA sequencing and we identified novel BDC specific fusion gene, PUM1-TRAF3 by bioinformatics analysis. Total 55 patients with BDC who underwent curative surgery were evaluated to investigate clinical significance of PUM1-TRAF3. There were 28 patients (50.1%) who expressed PUM1-TRAF3 by ddPCR. Patients with PUM1-TRAF3 presented higher rate of female gender (57.1 vs. 25.9, p=0.019), advanced stage (25% vs. 3.7%, p=0.025) and recurrence rate (64.7 vs. 48.1%, p=0.080) compared to patients without PUM1-TRAF3. Disease free survival (DFS) was 12.1 vs. 29.8 (p=0.078) and overall survival was 26.1 vs. 36.6 (p=0.239) between the patients with PUM1-TRAF3 and without PUM1-TRAF3. In multivariated analysis by cox-regression, expression of PUM1-TRAF3 (HR 2.86, p=0.023), advanced stage (HR 2.69, p=0.041), higher CA19-9 (HR 1.00, p=0.011) and positive resection margin (HR 4.57, p=0.002) were significantly associated with short DFS.Conclusion : In this study, we identified novel BDC-specific fusion gene, PUM1-TRAF3. Expression of PUM1-TRAF3 was confirmed in patient's tissues and associated with short DFS in operated BDC patients. PUM1-TRAF3 can be a potent biomarker in BDC.
Citation Format: Dawoon E. Jung, Kahee Kim, Chanyang Kim, Soo Been Park, Jung Hyun Jo, Hee Seung Lee, Si Young Song. Identification of novel fusion gene, PUM1-TRAF3, as potent biomarker in bile duct 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 4337.
Abstract 4349: Higher level of tumor mutational burden and 11q13 amplification in Chinese hepatocellular carcinoma patients
Authors: Tang Xiaofeng , Fan Le , Chen Gang , Guo Weidong , Qiu Fabo , Wang Jun , Guo Jun , Chen Lijuan , Zhang Peng , Shi Weiwei , Wang Kai , Wang Weifeng 
Published: August 2018

Abstract
Introduction: The approval of immune checkpoint inhibitor (ICPI) for hepatocellular cancer (HCC) has changed the landscape of HCC treatment, which is the second most common and lethal malignancy in China. Several genomic features associated with ICPI efficacy in various types of cancers has been reported as potential predictive biomarkers. The application of comprehensive genomic profiling (CGP) on HCC might be useful in identifying ICPI responders or avoiding adverse effect. Experimental procedure: Comprehensive genomic profiling of 107 advanced HCC was performed on the FFPE tumor samples and matched blood by using a 450-gene next generation sequencing assay. The cohort of HCC patients comprises 86 males (median age = 56) and 21 females (median age = 52) whose gender disparity is in the normal range of HCC epidemiological statistic study from Asia-Pacific region. The ICPI therapy related genomic alterations such as tumor mutational burden (TMB) and 11q13 amplification were subsequently analyzed. Result: CGP revealed signature genomic alterations in HCC as previously reported but with exceptional higher frequency of TP53 mutations at 66.3% of the pts and relatively low rate of TERT variants at 32.7%. Higher level of TMB high values (&gt;20 muts/Mb) was found in a significantly larger portion of the Chinese HCC patients (N=10, 9.3%), compared to only 1% in Western population (p-value 1.5E-05). The median TMB of the Chinese HCC cohort was 7.2 muts/Mb. In addition, 11q13 amplifications (FGF3, FGF4, FGF19 and CCND1) were detected in 6.5% of the Chinese HCC patients, which was associated with ICPI hyper-progression in a variety of cancers. The 7 patients with 11q13 amplifications had a median age of 65 yrs (range 52-78) which is significantly higher than the median age of the rest cohort at 55 yrs (range 28-79, p=0.02). The median TMB was 8 muts/Mb. Conclusion: Our preliminary results found that TMB high values were more commonly detected in Chinese HCC patients compared to Western population. It may indicate that more Chinese HCC patients could benefit from ICPI treatments. However, the high incidence of 11q13 amplifications related to hyper-progression response in the same cohort was observed. Therefore, the application of comprehensive genomic profiling companion diagnosis might be necessary in guiding the regimen and ICPI treatments.
Citation Format: Xiaofeng Tang, Le Fan, Gang Chen, Weidong Guo, Fabo Qiu, Jun Wang, Jun Guo, Lijuan Chen, Peng Zhang, Weiwei Shi, Kai Wang, Weifeng Wang. Higher level of tumor mutational burden and 11q13 amplification in Chinese hepatocellular carcinoma 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 4349.
Abstract 4484: Synthetic essentiality of chromatin remodeling factor CHD1 in PTEN-deficient cancer
Authors: Zhao Di 
Published: August 2018

Abstract
Background: Prostate cancer (PCa) is the second leading cause of cancer death for men in the United States. Up to 70% of primary prostate tumors show loss of heterozygosity (LOH) at the PTEN locus, and loss of PTEN is a key initiation event in PCa development. Synthetic and collateral lethality have provided conceptual frameworks to identify cancer-specific vulnerabilities. Here, we explored an approach to identify potential synthetic lethal interactions through screening mutually exclusive deletion patterns in cancer genomes.
Methods: We sought to identify ‘synthetic essential' genes, which might be occasionally deleted in some cancers but almost always retained in the context of a specific tumor suppressor deficiency, and posited that such synthetic essential genes would be therapeutic targets in cancers harboring specific tumor suppressor deficiencies.
Results: In addition to known synthetic lethal interactions, this approach uncovered the chromatin helicase DNA-binding factor CHD1 as a putative synthetic essential gene in PTEN-deleted cancers. In PTEN-deleted prostate and breast cancers, the functional analysis showed that CHD1 depletion profoundly and specifically suppressed cell proliferation, survival, and tumorigenic potential. Mechanistically, functional PTEN stimulates GSK3β-mediated phosphorylation of CHD1 degron domains, which promotes CHD1 degradation via β-TrCP-mediated ubiquitination-proteasome pathway. Conversely, PTEN deficiency results in CHD1 protein stabilization, which in turn engages the H3K4me3 mark to activate transcription of the pro-tumorigenic TNFα/NF-κB gene network. In addition, we found CHD1 depletion significantly inhibits the progression of Pten-deficient prostate cancer genetic engineered mouse model.
Conclusions: Together, this study identifies CHD1 as a novel downstream effector in PTEN pathway, and verifies CHD1 as a novel therapeutic target in PTEN deficient prostate cancer and breast cancer. Additionally, this study provides a framework for the discovery of trackable targets in cancers harboring specific tumor suppressor deficiencies.
Citation Format: Di Zhao. Synthetic essentiality of chromatin remodeling factor CHD1 in PTEN-deficient 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 4484.