bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3466: The oncogenic roles of ANXA1 in gastrointestinal tract cancer
Authors: Saito Motonobu 
Published: August 2019

Abstract
Annexin A1 (ANXA1) is a calcium-dependent phospholipid-linked protein that is associated with anti-inflammatory effects, regulation of cellular proliferation, and apoptosis and, therefore, ANXA1 is associated with cancer development and metastasis. We have previously reported that ANXA1 was upregulated in gastrointestinal cancer and associated with venous invasion (P=0.023) and lymph node metastasis (P=0.042). We also performed in vitro cell experiments and revealed that elevated ANXA1 expression was induced resistance to 5-FU in the colon cancer cells. So next, we have evaluated the association between ANXA1 and cancer related genes, including p53 by immunohistochemical (IHC) staining in two independent gastric cancer cohorts (n=200 and n=220). The percentage of positive ANXA1 was significantly higher in p53 positive tumors compared with p53 negative tumors (P=0.023 and P=0.022, respectively). We also evaluated the association with ARID1A, the chromatin remodeler AT-Rich interactive 1A, that is frequently mutated in gastric cancer and is considered as a candidate therapeutic target by synthetic lethality. Although it was reported that the expression of ANXA1 was upregulated in ARID1A mutated breast cancer cases, significant association between ANXA1 and ARID1A expressions was not found in gastric cancer. We next performed IHC staining for ANXA1 and p53 in three human gastric cancer cell lines (MKN7, NUGU4, KATOIII). Positive staining for both ANXA1 and p53 was detected in cells with TP53 missense mutation. On the other hand, weak positive staining for ANXA1 and negative staining for p53 was found in NUGC4 cells with TP53 wild-type and KATOIII cells with TP53 truncating mutation. These results suggested that ANXA1 expression may be induced by aberrant p53 protein, resulting cancer progression and resistance to 5-FU. Our results also provide a possible strategy to overcome 5-FU resistance by modulating ANXA1 expression.
Note: This abstract was not presented at the meeting.
Citation Format: Motonobu Saito. The oncogenic roles of ANXA1 in gastrointestinal tract 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 3466.
Abstract 3469: CYP1B1 induces cancer progression through regulation of TRAIL pathway and uPA-uPAR system
Authors: Kwon Yeo-Jung , Chun Young-Jin 
Published: August 2019

Abstract
Human CYP1B1 is known as a major metabolizer for estrogen and shows tumor-specific hyper-expression. To explore the role of CYP1B1 on progression of human cancer cells, we studied the effects of CYP1B1 in MCF-7, MDA-MB-231, and HeLa cells. CYP1B1 significantly induced invasion of cancer cells while strongly inhibited cancer cell apoptosis. Suppression of CYP1B1 by si/shRNA or treatment with TMS, a specific inhibitor for CYP1B1, markedly increased the protein expression level along with the level of release from cells of TNF-related apoptosis inducing ligand (TRAIL), a death ligand for cancer cells, whereas significantly decreased the expression of urokinase-type plasminogen activator receptor (uPAR) as well as uPA. We also found that CYP1B1 showed to inhibit the expression of key factors in TRAIL-induced apoptotic pathway and promote the inducers in uPA-uPAR metastasis system including integrin β1 and α5. Interestingly, uPAR overexpression only caused a significant increase of integrin β1 and α5 in protein levels, indicating protein degradation may play an important role in regulating integrin protein level. Surprisingly, CYP1B1 down-regulated p53 expression through MDM2 activation and nutlin-3a, an inhibitor for MDM2, blocked the promoting effects of CYP1B1 inducer, DMBA, on uPAR, which explains that CYP1B1 induced uPAR expression through regulation of MDM2-p53 system. Furthermore, we found that CYP1B1 suppresses TRAIL-related apoptosis through not only inhibition of TRAIL expression but also induction of DNA methylation on the promoter region of DR4, a receptor for TRAIL. Taken together, our data suggest that CYP1B1 promotes cancer cell metastasis via activating uPA-uPAR pathway which is one of the targets of p53 signaling and suppresses cancer cell apoptosis through inhibition of TRAIL-induced apoptosis by suppression of TRAIL release as well as post-translational regulation on DR4.
Citation Format: Yeo-Jung Kwon, Young-Jin Chun. CYP1B1 induces cancer progression through regulation of TRAIL pathway and uPA-uPAR 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 3469.
Abstract 3470: The antagonistic functional duality of p21WAF1/CIP1 in cells derived from multicellular tumor spheroids
Authors: Das Viswanath , Annadurai Narendran , Holub Dušan , Hajdúch Marián 
Published: August 2019

Abstract
The cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21) is a key mediator of p53-dependent cell cycle arrest after DNA damage, in addition to p53-independent mechanisms. Being one of the major transcriptional targets of p53 and due to its anti-cell proliferative activity, p21 was considered initially as a potent tumor suppressor. However, emerging studies now show the anti-apoptotic and pro-cell proliferative effects of p21, highlighting the oncogenic role of p21 in cancer. In particular, p21 results in genomic instability and the development of aggressive and chemo-resistant traits in a subset of highly proliferating tumor cells through p53-independent pathways. The cellular localization of p21 has been proposed to be critical either in promoting cell survival or in inhibiting cell growth. Herein, using a combination of gene knockout, cytotoxicity assay, immunofluorescence, immunoprecipitation, and mass spectrometry techniques, we study the consequence of nuclear and cytoplasmic localization of p21 on cell survival and drug response in cells derived from multicellular spheroids of multiple human cancer cell lines. Our study shows that cells derived from multicellular spheroids show an increased induction of p21 despite the reversal from three-dimensional to two-dimensional cultures. The p21-overexpressing, highly proliferative cells are significantly resistant to a number of standard anti-cancer agents. Further analysis shows that the majority of p21 in this subset of spheroid-derived cells is localized in the cytoplasm and forms a potential 'anti-apoptosome'-like complex with mitochondrial apoptosis-associated proteins. These findings add to the shifting paradigm on the oncogenic role p21 due to cellular mislocalization in tumor cells.
Citation Format: Viswanath Das, Narendran Annadurai, Dušan Holub, Marián Hajdúch. The antagonistic functional duality of p21WAF1/CIP1 in cells derived from multicellular tumor spheroids [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 3470.
Abstract 348: ABI-009 (nab-Sirolimus) improves tumor accumulation and antitumor activity over oral mTOR inhibitors
Authors: Hou Shihe , Schmid Anita , Desai Neil 
Published: August 2019

Abstract
Background: mTOR pathway has been implicated in cell survival and proliferation and is an attractive target for cancer therapy. ABI-009 (nab-sirolimus) is an injectable nanoparticle form of human albumin-bound sirolimus with a mean particle size of approximately 100 nm developed with a proprietary nanoparticle albumin-bound (nab®) technology. ABI-009 is currently in phase 1 and 2 clinical studies for the treatment of multiple cancer types, including bladder cancer, soft-tissue sarcomas, neuroendocrine tumors, colorectal cancer, glioblastoma, and various childhood cancers, and a registrational phase 2 study for malignant perivascular epithelioid cell carcinoma (PEComa). In nonclinical and clinical studies, ABI-009 demonstrated a PK profile distinct from oral mTOR inhibitors. This study compared the antitumor activity, tissue penetration, and pharmacodynamics of ABI-009 with equal doses of oral mTOR inhibitors at clinically relevant doses in a mouse tumor xenograft model.
Methods: Athymic mice bearing subcutaneous UMUC3 bladder cancer xenografts were treated with saline, ABI-009 (IV, 7.5 mg/kg, 2x/wk), sirolimus and everolimus (PO, 3 mg/kg/day, 5 days/wk). Body weights, tumor measurements, and clinical signs were recorded 3x/wk for up to 5 wks. Tumor and blood sirolimus concentrations were also obtained (tumor: D1 1h and 24h, D4 1h, D7; blood: D4 1h, D7). Markers for mTOR pathway activation (pS6, p4EBP1) will also be analyzed.
Results: Overall, all treatments were well tolerated with no significant body weight loss in any group. ABI-009 IV resulted in significantly higher sirolimus concentrations in the tumor compared with oral mTOR inhibitors at all time points tested. Tumor AUC with ABI-009 IV over 1 week were significantly higher vs equal weekly dose of oral sirolimus (43 fold) and everolimus (12 fold) (p &lt; 0.0001). The enhanced tumor drug delivery by ABI-009 corresponded with significantly greater tumor growth inhibition (TGI: ABI-009 69.6% vs oral sirolimus 24.3%, p &lt; 0.00001; vs oral everolimus 36.2%, p = 0.0023) and longer animal survival (median OS: ABI-009 not reached vs oral sirolimus 21 days, p &lt; 0.05; vs oral everolimus 19 days, p &lt; 0.05). mTOR pathway inhibition in tissues is being assessed.
Conclusions: Compared with equal weekly dose of oral mTOR inhibitors, ABI-009 at clinically relevant dose of administered IV demonstrated significantly greater tumor drug delivery, stronger antitumor activity, and prolonged animal survival. These advantages observed in this nonclinical study support the clinical investigation of ABI-009 in numerous oncology indications.
Citation Format: Shihe Hou, Anita Schmid, Neil Desai. ABI-009 (nab-Sirolimus) improves tumor accumulation and antitumor activity over oral mTOR inhibitors [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 348.
Abstract 3494: Centrobin is involved in the cellular response to DNA damage
Authors: Ryu Na-mi , Jung Jin Ki , Jang Seok Won , Kim Jung Min 
Published: August 2019

Abstract
DNA-repair proteins have been found to localize to the centrosomes and defects in these proteins cause centrosome over-duplication. Centrobin is a centriole-associated protein that is required for centriole duplication. In the present study, we investigated a possible role of centrobin in DNA damage response. Centrobin was phosphorylated in response to UV radiation and its phosphorylated form was detected only in the detergent / DNase 1-resistant fraction. UV-induced phosphorylation of centrobin was significantly decreased by ATR inhibition, but not by ATM inhibition. In addition, centrobin-depleted cells showed reduced survival rate after UV exposure compared with control cells. Moreover, centrobin knockdown in DR-GFP/U2OS cells had a significant reduction in DNA repair efficiency of homologous recombination (HR) and this defect was recovered by expression of wild-type centrobin, but not by a mutant form of centrobin. Taken together, these results suggest that centrobin may play a critical role in DDR and that ATR dependent phosphorylation of centrobin may be at least partially responsible for this function.
Citation Format: Na-mi Ryu, Jin Ki Jung, Seok Won Jang, Jung Min Kim. Centrobin is involved in the cellular response to DNA damage [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 3494.
Abstract 3496: Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors
Authors: Ratnaparkhe Manasi , Wong John K. , Wei Pei-Chi , Hlevnjak Mario , Kolb Thorsten , Simovic Milena , Haag Daniel , Paul Yashna , Devens Frauke , Northcott Paul , Jones David T. , Kool Marcel , Jauch Anna , Pastorczak Agata , Mlynarski Wojciech , Korshunov Andrey , Kumar Rajiv , Downing Susanna M. , Pfister Stefan M. , Zapatka Marc , McKinnon Peter J. , Alt Frederick W. , Lichter Peter , Ernst Aurelie 
Published: August 2019

Abstract
Chromothripsis and chromoanasynthesis are catastrophic events leading to clustered genomic rearrangements. Whole-genome sequencing revealed frequent complex genomic rearrangements (n= 16/26) in brain tumors developing in mice deficient for factors involved in homologous recombination repair or non-homologous end-joining. Catastrophic events were tightly linked to Myc/Mycn amplification, with increased DNA damage and inefficient apoptotic response already observable at early postnatal stages. Inhibition of repair processes and comparison of the mouse tumors with human medulloblastomas (n=68) and glioblastomas (n=32) identified chromothripsis as associated with MYC/MYCN gains and with DNA repair deficiencies, pointing towards therapeutic opportunities to target DNA repair defects in tumors with complex genomic rearrangements.
Citation Format: Manasi Ratnaparkhe, John K. Wong, Pei-Chi Wei, Mario Hlevnjak, Thorsten Kolb, Milena Simovic, Daniel Haag, Yashna Paul, Frauke Devens, Paul Northcott, David T. Jones, Marcel Kool, Anna Jauch, Agata Pastorczak, Wojciech Mlynarski, Andrey Korshunov, Rajiv Kumar, Susanna M. Downing, Stefan M. Pfister, Marc Zapatka, Peter J. McKinnon, Frederick W. Alt, Peter Lichter, Aurelie Ernst. Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human 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 3496.
Abstract 350: Investigating the mechanisms of cellular uptake and metabolism of ICT2588, an MT-MMP-activated prodrug
Authors: Barnieh Francis Mprah , Race Amanda D. , Shnyder Steven D. , Loadman Paul M. , Falconer Robert A. 
Published: August 2019

Abstract
ICT2588 is a non-toxic MT1-MMP-activated peptide prodrug of the potent vascular disrupting agent (VDA) azademethylcolchicine [1]. ICT2588 produces significant tumor-selective delivery (≥10-fold) of the toxic and potent azademethylcolchicine, as compared to the administration of azademethylcolchicine alone, in murine models of human colorectal, breast, lung and prostate cancers. In addition, ICT2588 exhibited reduced potential for toxicity, and cardiotoxicity in particular (a phenomenon associated with most VDAs) as a result of its metabolic stability in plasma and normal tissues [2]. ICT2588 is progressing towards clinical evaluation in the UK in 2019. In this study we aim to further investigate the cellular uptake and metabolism of ICT2588 and related compounds in MT1-MMP positive (HT1080) and MT1-MMP negative (MCF-7) cells in vitro. ICT2588 and related compounds were synthesized in-house and purified by preparative HPLC in excellent yield and purity. Activation of ICT2588 by recombinant MT1-MMP and its preferential metabolism in MT1-MMP positive tumor xenograft homogenates has been shown previously [1]. We are currently studying the mechanism of cellular uptake and metabolism of these peptide prodrugs by incubating these compounds in HT1080 and MCF-7 cell cultures. Cellular concentrations of ICT2588 and all metabolites identified were determined using RP-HPLC, mass spectrometry and immunofluorescent microscopy. We describe the first data on the cellular mechanism of uptake and metabolism of ICT2588 and related peptide prodrugs in cancer cells. Our findings have important implications in the future design of effective peptide-based tumor-targeted prodrugs. Reference: [1] Atkinson, J.M et al “Development of a tumor-targeted vascular disrupting agent activated by Membrane-type Matrix Metalloproteinases (MT-MMPs).” Cancer Research, 2010, 70, 6902-12. [2] Gill, J.H et al “Tumor-targeted prodrug ICT2588 demonstrates therapeutic activity against solid tumors and reduced potential for cardiovascular toxicity”. Mol Pharm. 2014,11:1294-300.
Citation Format: Francis Mprah Barnieh, Amanda D. Race, Steven D. Shnyder, Paul M. Loadman, Robert A. Falconer. Investigating the mechanisms of cellular uptake and metabolism of ICT2588, an MT-MMP-activated prodrug [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 350.
Abstract 3501: Entinostat enhances the efficacy of olaparib in preclinical models of ovarian cancer
Authors: Gupta Vijayalaxmi G. , Fernandez Yoskaly Lazo , Roby Katherine , Pathak Harsh , Hirst Jeff , Wilson Andrew J. , Godwin Andrew , Khabele Dineo 
Published: August 2019

Abstract
Introduction: Ovarian cancer is a rare but often fatal disease and a leading cause of gynecologic cancer death, in the United States. Poly ADP ribose polymerase inhibitors (PARPi) are promising new drugs that are most effective in patients with tumors with altered homologous recombination (HR) DNA repair genes, particularly BRCA1/2. To expand their clinical utility, PARPi are being tested in combination with other drugs. Our group has published that histone deacetylase inhibitors (HDACi) sensitize HR proficient BRCA wild-type ovarian cancer cells to PARPi. We have developed an investigator-initiated phase 1/2 clinical trial of the PARPi olaparib combined with the HDACi entinostat in patients with recurrent, HR proficient/BRCA wild-type ovarian cancer.
Objective: To test the effects of a novel combination of olaparib and entinostat in preclinical models of BRCA wild-type ovarian cancer.
Methods: HR proficient BRCA wild-type SKOV3 and ID8 ovarian cells were treated with Entinostat followed by Olaparib alone or the combination of Entinostat and Olaparib. Treated and control cells were analyzed for cell proliferation by sulforhodamine B assays, clonogenicity, and DNA damage by Comet assays. SKOV-3-luciferase cells were injected intraperitoneally into NOD-SCID mice. Mice were randomized into 4 treatment groups and treated with vehicle, entinostat, olaparib, or the combination. The mice were monitored for toxicity and by bioluminescence imaging (BLI). At sacrifice, tumor burden was quantified.
Results: In cell culture assays, entinostat significantly enhanced the sensitivity of SKOV3 and ID8 cells to Olaparib. Entinostat combined with olaparib led to synergistic reductions in cell proliferation and clonogenicity in SKOV-3 and ID8 ovarian cancer cells, compared to each drug alone. Evidence of DNA damage was enhanced by the drug combination. In the SKOV3-luc xenograft mouse model, a significant reduction in tumor burden in the group of mice treated with the combination of entinostat and olaparib, compared to each drug alone. There was no significant toxicity with drug treatment.
Conclusion: Entinostat sensitizes ovarian cancer cells to Olaparib in vitro and in vivo. Experiments in ID-luciferase and patient-derived xenograft models are ongoing. These preclinical models are powerful tools that will be used to discover markers and mechanisms of sensitivity and resistance to inform the parallel clinical trial.
Citation Format: Vijayalaxmi G. Gupta, Yoskaly Lazo Fernandez, Katherine Roby, Harsh Pathak, Jeff Hirst, Andrew J. Wilson, Andrew Godwin, Dineo Khabele. Entinostat enhances the efficacy of olaparib in preclinical models of ovarian 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 3501.
Abstract 3515: Functional antigen presentation is required to interpret the tumor mutation burden (TMB) test
Authors: Cerqueira Gustavo C. , Keefer Laurel A. , Nichol Donna , Meyer Julie R. , Dracopoli Nicholas C. 
Published: August 2019

Abstract
Therapeutic response to checkpoint inhibitors requires a prior, suppressed immune response that is released by a monoclonal antibody blocking the interaction of the checkpoint receptors with their cognate ligands. The presence of this suppressed immune response can be detected by a variety of tests including tumor mutation burden (TMB), tumor infiltrating leukocytes, T-cell receptor clonality, circulating interferons and cytokines, and upregulation of the expression of the checkpoint ligands. Today, TMB has proven to be the most predictive biomarker of response to immunotherapy.
TMB is a surrogate marker of immune response. The test works by sampling a small region of the cancer genome to estimate the number of mutations/Mb of the cancer exome. A high TMB score is associated with better response to immunotherapy because it carries more somatic mutations and a higher chance of presenting an immunogenic neoepitope that will lead to CD-8+ T-cell mediated destruction. Restriction or loss of antigen presentation caused by mutations and loss of heterozygosity (LOH) of the beta-2-microglobulin (B2M) and HLA Class I genes has been shown to be a common means of evading CD-8+ T-Cell destruction. Consequently, the outcome for high TMB tumors will be dependent on their ability to present antigens, so that the mutation count will not matter in cells that are unable to present antigens in their HLA Class I/B2M complex.
We propose that TMB should be considered together with the ability of the tumor to present these putative neoantigens. To test this hypothesis, we used the PGDx elio™ Tissue Complete test (507 genes in 1.3 Mb) to measure TMB and antigen presentation in the same assay. We tested 212 cancer patients and showed that in FFPET samples with &gt;20% tumor content, we could detect LOH of the MHC Class I and B2M genes with &gt;90% accuracy compared to whole exome data from the same sample. These data confirmed our hypothesis that it was possible to measure TMB and evaluate the genes involved in antigen presentation in the same in silico analysis of a 507 gene next-generation sequencing (NGS) panel. We are currently using this combined analysis to measure TMB and somatic alterations of the antigen presentation complex in several different cancers and to test the hypothesis that adding neoantigen presentation capability to TMB scores will significantly improve prediction of response to a variety of immunotherapies.
Citation Format: Gustavo C. Cerqueira, Laurel A. Keefer, Donna Nichol, Julie R. Meyer, Nicholas C. Dracopoli. Functional antigen presentation is required to interpret the tumor mutation burden (TMB) test [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 3515.