bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 652: Mutational profile of papillary thyroid microcarcinoma with extensive lymph node metastasis: Comparison of primary thyroid cancer and metastatic lymph nodes
Authors: Jeon Min Ji , Kim Won Gu , Chun Sung Min , Song Dong Eun , Kim Tae Yong , Shong Young Kee , Kim Won Bae 
Published: August 2018

Abstract
Introduction: Papillary thyroid microcarcinoma (PTMC) has excellent clinical outcomes, but distant metastasis of PTMC can be fatal. We previously reported that change to an aggressive pathologic subtype of metastatic lymph nodes (LNs) were associated with distant metastasis of PTMC. This study aimed to evaluate and compare the mutational profile of primary tumor and metastatic LNs of PTMC. Method: We included 16 PTMC patients with lateral cervical LN metastases. One of them has distant metastases. DNAs from formalin-fixed, paraffin-embedded archival samples of 16 sets of the normal thyroid tissue, primary PTMC, and the largest metastatic LN were used for targeted next-generation sequencing by Oncopanel AMC version 2.0. Results: A total of 7 somatic variants were confirmed in primary PTMC compared to normal thyroid tissue. BRAF V600E mutation was the most common and seen in 12 primary PTMCs (75%) and 11 metastatic LNs (69%). Missense mutation of KMT2A, RAF1, and ROS1 was detected only in one primary PTMC (6.3%), respectively. Frame-shift mutation of JAK2, inframe deletion of ACVR2A and nonsense mutation of AR was detected one primary PTMC (6.3%) with its metastatic LN, respectively. When we compare the mutational profile of primary tumor and metastatic LNs, there were no newly developed somatic mutations in metastatic LNs. We also found ALK/STRN rearrangement in one PTMC with its metastatic LN (6.3%). CCDC6/RET rearrangement and RET intergenic rearrangement was detected only in 2 metastatic LNs (12.5%) and one metastatic LN (6.3%), respectively. BARD1 deletion was detected in one primary PTMC with its metastatic LNS (6.3%) and FLT4 deletion was detected only in one primary PTMC (6.3%). We also found JAK1, AURKC, and TP53 deletions, which were detected only in one metastatic LN, respectively (6.3%). Conclusion: The mutation frequency of PTMC was really low even in patients with extensive LN metastasis. The mutational status of primary tumor and their regional metastatic LNs were not significantly different and this suggests the minor role of genetic mutations in the process of LN metastases.
Citation Format: Min Ji Jeon, Won Gu Kim, Sung Min Chun, Dong Eun Song, Tae Yong Kim, Young Kee Shong, Won Bae Kim. Mutational profile of papillary thyroid microcarcinoma with extensive lymph node metastasis: Comparison of primary thyroid cancer and metastatic lymph nodes [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 652.
Abstract 700: Characterization of new AML PDX models: Engraftment kinetics and mutational profile
Authors: Kaur Pali , Sachs Victoria , Christie Amanda L. , Weinstock David M. , Keck James G. 
Published: August 2018

Abstract
Acute myeloid leukemia (AML) is a genetically heterogeneous cancer of progenitor cells in myeloid hematopoiesis. Due to heterogeneity, most of AMLs are not responsive to targeted therapy. In addition, treatment outcome varies greatly depending upon patient age, disease etiology and mutational status. Previously, a large repository of well-characterized patient-derived- xenografts (PDXs) of hematologic malignancies was established (Townsend et al., 2016). This repository was generated by injecting primary bone marrow and blood samples from patients with leukemia into NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice. An average success rate of 23.2% engraftment was observed in first passage (P0). In this study, we have characterized ten AML PDX models in NSG-SGM3 mice by serial transplantation. NSG-SGM3 (NOD.Cg-Prkdcscid Il2rgtm1Wjl Tg(CMV-IL3,CSF2,KITLG)1Eav/MloySzJ) mice have been found to have increased proliferation and survival of engrafted AML cells along with decreased disease latency (Wunderlich et al., 2010). Leukemic engraftment in these models was confirmed by flow analysis for hCD45+ hCD33+ in the peripheral blood, bone marrow and spleen of engrafted mice. Kinetics of engraftment varied from one model to another; and ranged from 10% - 80% of hCD33+ in peripheral blood 8 week post AML cell injection (1X106 cells/mouse). Four models displayed positive response to Cytarabine (Ara-C) treatment with reduction in levels of human CD33+ cells following a 5-day treatment cycle. Data will be presented on model characterization to show distinct engraftment kinetics, correlation with disease mutations and response to AML standard of care drug Cytarabine. These models have varying mutational profiles and treatment histories. Mutations include FLT3, FLT3-ITD, NPM1, TP53, DNMT3A and CUX1 alone or in combination. Treatment phases at the time of collection varied from untreated to relapse post-chemotherapy. These AML PDX models are useful tools for testing new experimental therapeutics. Diversity of these AML PDX models will facilitate focus on specific AML targets, thus providing an invaluable tool set to support drug discovery.
Citation Format: Pali Kaur, Victoria Sachs, Amanda L. Christie, David M. Weinstock, James G. Keck. Characterization of new AML PDX models: Engraftment kinetics and mutational profile [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 700.
Abstract 710: CD73 inhibitors (CD73i) reverse the AMP/adenosine-mediated impairment of immune effector cell activation by immune checkpoint inhibitors (ICI)
Authors: Becker Annette , Narasappa Nell , Yin Fangfang , Zhang Kristen , DiRenzo Daniel , Park Timothy , Kalisiak Jaroslaw , Lawson Ken , Jeffrey Jenna , Powers Jay P. , Schindler Ulrike , Walters Matthew J. , Tan Joanne B. 
Published: August 2018

Abstract
INTRODUCTION: CD73 catalyzes the extracellular generation of adenosine (ADO) from adenosine monophosphate (AMP). ADO suppresses immune responses, including those of T cells, NK cells and dendritic cells through activation of A2aR and A2bR receptors. Exhausted T cells and NK cells express high levels of several immune checkpoint proteins, including PD-1 and TIGIT. We present here preclinical data on the ability of CD73i to reverse effector cell suppression from exposure to ADO even in the presence of ICI.
METHODS: CD73i effects in a monotherapeutic setting were assessed by CD3/CD28/CD2 T cell stimulation and cytolytic assays. Combinatorial settings were assessed using mixed lymphocyte reactions (MLRs). In vivo effects of CD73i + ICI were determined using syngeneic tumor models.
RESULTS: CD73 is expressed across a wide range of tumor types, including those with limited response to anti-PD-1 therapy. CD73i completely rescued AMP-mediated inhibition of T cell proliferation and effector function as well as NK cell cytolytic function. AMP abrogated the enhanced allogeneic CD4+ T cell activation and IFN-γ production mediated by blocking PD-1/PD-L1 and TIGIT, an effect that was reversed by CD73i. Mechanistically, addition of AMP in MLRs repressed expression of activation markers and immune checkpoint proteins. Thus, activation of the adenosinergic pathway may limit the efficacy of ICI. TCGA data from anti-PD-1-treated melanoma patients identified CD73 expression as a negative prognostic factor. Finally, co-administration of a CD73i with an anti-PD-1 mAb resulted in significant reduction of tumor volume associated with increases in immune cell infiltration.
CONCLUSIONS: CD73 inhibition, alone or in combination with anti-PD-1 and anti-TIGIT antibodies, translates into potent enhancement of immune cell activation in a variety of studies. These data provide a rationale for CD73i + ICI combinations.
Citation Format: Annette Becker, Nell Narasappa, Fangfang Yin, Kristen Zhang, Daniel DiRenzo, Timothy Park, Jaroslaw Kalisiak, Ken Lawson, Jenna Jeffrey, Jay P. Powers, Ulrike Schindler, Matthew J. Walters, Joanne B. Tan. CD73 inhibitors (CD73i) reverse the AMP/adenosine-mediated impairment of immune effector cell activation by immune checkpoint inhibitors (ICI) [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 710.
Abstract 719: A tumor mitochondria vaccine protects against experimental renal cell carcinoma
Authors: Pierini Stefano , Facciabene Andrea , Uribe-Herranz Mireia , Rafail Stavros , Fang Chongyun , Tanyi Janos 
Published: August 2018

Abstract
Mitochondria provide energy for cells via oxidative phosphorylation. Reactive oxygen species, a byproduct of this mitochondrial respiration, can damage mitochondrial DNA (mtDNA), and somatic mtDNA mutations have been found in all colorectal, ovarian, breast, urinary bladder, kidney, lung, and pancreatic tumors studied. The resulting altered mitochondrial proteins or tumor-associated mitochondrial Ags (TAMAs) are potentially immunogenic, suggesting that they may be targetable Ags for cancer immunotherapy. In this article, we show that the RENCA tumor cell line harbors TAMAs that can drive an antitumor immune response. We generated a cellular tumor vaccine by pulsing dendritic cells with enriched mitochondrial proteins from RENCA cells. Our dendritic cell-based RENCA mitochondrial lysate vaccine elicited a cytotoxic T cell response in vivo and conferred durable protection against challenge with RENCA cells when used in a prophylactic or therapeutic setting. By sequencing mtDNA from RENCA cells, we identified two mutated molecules: COX1 and ND5. Peptide vaccines generated from mitochondrial-encoded COX1 but not from ND5 had therapeutic properties similar to RENCA mitochondrial protein preparation. Thus, TAMAs can elicit effective antitumor immune responses, potentially providing a new immunotherapeutic strategy to treat cancer.
Citation Format: Stefano Pierini, Andrea Facciabene, Mireia Uribe-Herranz, Stavros Rafail, Chongyun Fang, Janos Tanyi. A tumor mitochondria vaccine protects against experimental renal cell carcinoma [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 719.
Abstract 743: ABT-806-derived antibody-drug conjugates (ADCs) inhibit growth of malignant mesothelioma in vivo
Authors: Chia Puey Ling , Cao Diana , Rigopoulos Angela , Gan Hui , Reilly Ed , Phillips Andrew , John Thomas , Scott Andrew M. 
Published: August 2018

Abstract
Introduction: Malignant mesothelioma (MM) is an aggressive malignancy of the pleura with limited therapeutic options, and is associated with a poor prognosis. EGFR is known to be highly over-expressed in mesothelioma with reported EGFR overexpression between 44 to 97%. We have developed an anti-EGFR antibody (ABT-806), which is tumour specific and robustly inhibits EGFR-expressing tumours. We aimed to establish the validity and feasibility of targeting tumour expressed EGFR in MM using ABT-806 novel ADCs (ABT-414 and ABBV-221).
Methods: We evaluated EGFR and mAb 806 immunohistochemistry in 4 MM cell lines (MSTO-211H, NCI-H2052, NCI-H28, NCI-H2452) and performed in-vitro cell proliferation assays (CPA) to evaluate the antineoplastic potential of mAb806-related ADCs. In-vivo therapeutic studies using the biphasic mesothelioma cell line (MSTO-211H) were conducted with treatment groups involving ABT-414, ABBV-221, ADC control, cisplatin chemotherapy. We also performed quantitative biodistribution and imaging of mAb806 ADC uptake (89Zr mAb806 ADC) to allow correlation of mAb806 ADC concentration in tumours.
Results: mAb806 elicited strong binding to three of four MM cell lines (MSTO-211H, NCI-H2052 and NCI-H28). CPAs also demonstrated ABT-414 and ABBV- 221 had significant cell growth inhibition demonstrated in the range between 1 to 10ug/ml for MM cell lines. In MSTO-211H xenograft model significant anti-tumour response to both ABT-414 and ABBV-221 (p&lt;0.01), was demonstrated. High, specific targeting of 89Zr-ch806 to MM tumour in-vivo was also shown.
Conclusion: ABT-806 ADCs show potent anti-tumour activity in MM model, and warrant further exploration as a potential therapy for MM.
Citation Format: Puey Ling Chia, Diana Cao, Angela Rigopoulos, Hui Gan, Ed Reilly, Andrew Phillips, Thomas John, Andrew M. Scott. ABT-806-derived antibody-drug conjugates (ADCs) inhibit growth of malignant mesothelioma in vivo [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 743.
Abstract 752: CovisoLinK: New bacterial transglutaminase Q-Tag substrate for the development of site specific antibody-drug conjugates
Authors: Sivado Eva , Thomas Vincent , Alaoui Meddy El , Jallas Anne-Catherine , Dyson Mike R. , McCafferty John , Alaoui Said El , Valsesia-Wittmann Sandrine 
Published: August 2018

Abstract
CovIsoLink™ (Covalently Isopeptide crosslinking) relates to methods for enzymatic covalently coupling drugs and other compounds through transglutaminase site specific generated in the targeted proteins including, polypeptides, proteins and immunoglobulins (patent pending1). Transglutaminases (TGases) catalyze covalent cross- linking of specific glutamine residues to the primary amine of peptide-bound lysine residues or primary amines of other compounds such as polyamines2. Using an in house peptide library and the transglutaminase colorometric assay3, we identified several amino acid sequences that were recognized as glutamine donor substrates. The optimum peptide sequences were selected and we further confirmed that these sequences have improved affinity compared with the conventional small peptides Z-QG. In different experiments we engineered Fc-containing polypeptide at the C-terminal domain and showed that mTG incorporates with high efficiency several types of amine donors to the engineered antibodies. CovIsoLink™ is now used to develop new antibody drug conjugates (ADCs) since the major advantage of this method is to obtain a homogenous immunoconjugate with uniform stoichiometry. We developed and characterized different recombinant anti Her2 IgG1 Mab carrying optimized enzymatic substrates (tag) by genetic insertion in the coding sequence of MAb. We then evaluated the best linkers and conformation to incorporate different compounds through bacterial Transglutaminase (mTG) enzymatic reaction. We set up experimental conditions, production, purification, HPLC/MS analysis and control of the immunoreactivity of CovIsoLink™ Her2-ADC. Using mTG, we obtained site specific conjugation of different modified drugs with optimized linker on the anti Her2 IgG1 antibody. By HIC analysis, we validated a specific and reproducible DAR reaching DAR2 depending on drugs and experimental conditions. In vitro and In vivo characterization and dose response studies of CovIsolink-ADC specificity and reactivity are currently performed in Her2 positive models demonstrating an improved efficacy by comparison with Kadcyla (T-DM1).1) PCT/EP2014/0792278, 2) El Alaoui S et al, Int J Cancer, 1991; 3) Perez AM et al, Anal Biochem, 2009.
Citation Format: Eva Sivado, Vincent Thomas, Meddy El Alaoui, Anne-Catherine Jallas, Mike R. Dyson, John McCafferty, Said El Alaoui, Sandrine Valsesia-Wittmann. CovisoLinK: New bacterial transglutaminase Q-Tag substrate for the development of site specific antibody-drug conjugates [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 752.
Abstract 758: Head-to-head comparison of ADC and SMDC products, alone and in combination with antibody-IL2 fusion proteins
Authors: Cazzamalli Samuele , Corso Alberto Dal , Widmayer Fontaine , Neri Dario 
Published: August 2018

Abstract
In an attempt to improve the therapeutic index of cancer chemotherapy, monoclonal antibodies and small organic ligands have been proposed as delivery vehicles, allowing the construction of antibody-drug conjugates (ADCs) and of small molecule-drug conjugates (SMDCs). Four ADC products have gained marketing authorization for cancer therapy, while SMDCs are still being investigated in clinical trials. SMDCs could in principle offer certain advantages compared to ADCs, such as a more rapid and uniform diffusion into the tumor mass, lower cost-of-goods and lack of immunogenicity, but a direct head-to-head comparison has not yet been reported.
Here we describe a novel small molecule-drug conjugate, based on a high-affinity ligand specific to carbonic anhydrase IX. The product features a peptide linker, suitable for cleavage in the tumor extracellular environment, and monomethyl auristatin E as cytotoxic payload. We compared the therapeutic efficacy of the novel SMDC and of an anti-CAIX ADC, which were injected at equimolar doses in nude mice bearing SKRC-52 renal cell carcinoma xenografts. Both products showed a potent anti-cancer activity, although no complete tumor eradication was observed. Instead, when the SMDC was administered together with L19-IL2 (a clinical-stage fusion protein capable of delivering interleukin-2 to the tumor neo-vasculature), all treated mice in the combination group could be rendered tumor-free, in a process which favored the influx of natural killer cells into the tumor mass. The combination of L19-IL2 and the new small molecule-drug conjugate also eradicated cancer in 100% of immunocompetent mice, bearing subcutaneously-grafted CT26 colorectal cancer cells, which stably expressed carbonic anhydrase IX. These findings may be of clinical significance, since carbonic anhydrase IX is over-expressed in the majority of clear-cell renal cell carcinomas and in approximately 30% of colorectal cancers. The targeted delivery of interleukin-2 helps potentiate the action of targeted cytotoxics leading to cancer eradication in models that cannot be cured by conventional chemotherapy.
Citation Format: Samuele Cazzamalli, Alberto Dal Corso, Fontaine Widmayer, Dario Neri. Head-to-head comparison of ADC and SMDC products, alone and in combination with antibody-IL2 fusion proteins [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 758.
Abstract 772: High MDC1 expression in cervical cancer cells can affect the chemo- and radiotherapeutic response as its depletion leads to increased cell death
Authors: Singh Neeru , Bhakuni Rashmi , Kirubakaran Sivapriya 
Published: August 2018

Abstract
Cervical cancer is the third most frequent cancer and common cause of death in women worldwide. The work presented identifies mediator of DNA damage checkpoint 1 (MDC1) as an important molecular target to increase sensitivity of cervical cancer cells to chemo or radiotherapy. MDC1 functions as an adaptor protein for recruitment and retention of many other DNA damage repair proteins in ataxia telangiectasia mutated (ATM) pathway for double-stranded DNA damage repair. It is reported to be highly expressed in cervical cancer cells. Also, its expression tends to increase with increase in malignancy. We have studied in detail MDC1 mRNA expression in three cervical cancer cell lines, HeLa, SiHa and CasKi, in response to various genotoxic stresses including some known inhibitors, UV exposure or gamma irradiation through quantitative PCR. The cellular response to the DNA damage resulted in increase in MDC1 expression, which declined with increase in treatment time period. Protein expression and activation by Western blotting with anti-MDC1 and anti-phosphoMDC1 antibody indicated a higher level of phosphorylated as compared to unphosphorylated MDC1. The significance of this increase in MDC1 expression was studied by generating stable cell lines knocked down for MDC1 expression. The modified cell lines were assessed for apoptosis through various assays, including flow cytometry, and showed greater cell death in response to DNA damage. In summary, high MDC1 expression can significantly affect chemo or radiotherapeutic response and its inhibition can improve sensitivity to these treatments.
Citation Format: Neeru Singh, Rashmi Bhakuni, Sivapriya Kirubakaran. High MDC1 expression in cervical cancer cells can affect the chemo- and radiotherapeutic response as its depletion leads to increased cell death [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 772.
Abstract 779: Integrative analysis reveals therapeutic targets to the DNA methyltransferase inhibitor SGI-110 in hepatocellular carcinoma
Authors: Liu Minmin , Hinoue Toshinori , Zhou Wanding , Ohtani Hitoshi , El-Khoueiry Anthony , Daniels John , O'Connell Casey , Dorff Tanya B. , Weisenberger Daniel J. , Liang Gangning 
Published: August 2018

Abstract
Objective There is an urgent need for developing more effective therapies for Hepatocellular carcinoma (HCC) because of its aggressiveness. Guadecitabine (SGI-110) is a second-generation DNA methyltransferase inhibitor (DNMTi) currently in clinical trials for HCC and shows greater stability and performance over first generation DNMTi. The aim of this study is to identify potential therapeutic targets of SGI-110 for clinical trials.
Design HCC cell lines (SNU398, HepG2 and SNU475) were used to evaluate effects of SGI-110 by an integrative analysis of DNA methylation, nucleosome accessibility and gene expression profiles following the transient SGI-110 treatment and its clinic relevant by comparing HCC clinic data from TCGA.
Results These HCC cell lines represent the three DNA methylation subtypes of primary HCC tumors based on TCGA data. After SGI-110 treatment, all cell lines were sensitive to SGI-110 with prolonged anti-proliferation effects. Up-regulated genes including tumor suppressors were positively correlated with nucleosome accessibility and negatively correlated with gene promoter DNA methylation, while the down-regulated genes, such as oncogenes, were negatively correlated with nucleosome accessibility and positively correlated with gene body DNA methylation. Furthermore, SGI-110 down-regulated PRC2 complex genes by demethylating their gene bodies, resulting in re-activation of PRC2 repressed gene promoters which are independent on DNA methylation. In addition, SGI-110 up-regulated endogenous retroviruses (ERVs) to reactivate immune pathways. Finally, about 45% of frequently altered genes in primary HCC tumors can be re-shaped into a “normal like” expression status through the treatment.
Conclusion Our integrative analysis has successfully linked the anti-tumor effects of SGI-110 to detailed epigenetic alterations in HCC cells and identified potential therapeutic targets. We also provide rationale of combination treatment with immune checkpoint therapies.
Citation Format: Minmin Liu, Toshinori Hinoue, Wanding Zhou, Hitoshi Ohtani, Anthony El-Khoueiry, John Daniels, Casey O'Connell, Tanya B. Dorff, Daniel J. Weisenberger, Gangning Liang. Integrative analysis reveals therapeutic targets to the DNA methyltransferase inhibitor SGI-110 in hepatocellular carcinoma [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 779.