bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5627: BALB/c-hCD3E transgenic mice to evaluate humanCD3-bispecific antibodies
Authors: Ju Cunxiang , Zhang Mingkun , Jia Dongjing , Mao Rui , Tang Jing , Li Shuai , Zhao Jing , Gao Xiang 
Published: September 2020

Abstract
T cell-mediated immunotherapy is an attractive strategy for treatment of various tumors. T-cell bispecific antibody (TCB) can binds tumor associated antigen (TAA) and CD3 molecule (especially epsilon chain, CD3ϵ), and directs target specific killing of cells carrying the TAA. However, there is a challenge to evaluate the therapeutic efficacy of TCB due to the lack of immune competent animal that have both human immune system and TAA. Considering that CD3ϵ plays a critical role in formation and function of the TCR-CD3 complex while human CD3ϵ (hCD3ϵ) shares only 47% homology with mouse CD3ϵ (mCD3ϵ) in the extracellular domain, we established a CD3ϵ BAC transgenic model (BALB/c-hCD3E) carrying hCD3E gene and its entire regulatory sequence to meet this need. These transgenic mice co-express human and mouse CD3ϵ in over 90% of T-cells. Besides, the expression pattern of hCD3ϵ in spleen and thymus of BALB/c-hCD3E mice are similar with mCD3ϵ in wild type mice. With a normal immune system, splenic T cells from this strain could be activated by either anti-hCD3ϵ or anti-mCD3ϵ antibodies to produce IFNγ, IL2 and TNFα in vitro. We also tested the T cell-dependment cellular cytotoxicity on BALB/c-hCD3E mice use blinatumomab (bscCD19xCD3), the results shown significant anti-tumor effect. It's worth noting that further knockout of mCd3e in BALB/c-hCD3E mice cause remarkable reduce of splenic T cells, strong tumor inhibition of anti-mCTLA4 was observed in BALB/c-hCD3E but not BALB/c-hCD3E/mCd3e-KO mice, demonstrate that mCD3ϵ is indispensable for T-cell development and function in BALB/c-hCD3E transgenic mice. Taken together, these findings indicate that BALB/c-hCD3E mice with intact mCd3e is a novel and valuable model to assessing the therapeutic efficacy of TCBs.
Citation Format: Cunxiang Ju, Mingkun Zhang, Dongjing Jia, Rui Mao, Jing Tang, Shuai Li, Jing Zhao, Xiang Gao. BALB/c-hCD3E transgenic mice to evaluate humanCD3-bispecific antibodies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5627.
Abstract 5637: Investigating tumor intrinsic PD-1/PD-L1 signaling in canine osteosarcoma cell lines as a spontaneous model for human disease
Authors: Katarzyna Dziubek , Kocikowski Mikolaj , Vojtesek Borek , Argyle David , Lisowska Malgorzata , Hupp Ted , Parys Maciej 
Published: September 2020

Abstract
There is limited advancement in osteosarcoma therapy in humans. Interestingly, dogs spontaneously develop very similar disease at higher frequency, making canines a perfect model to study OS. Recent introduction of immune checkpoint blockade has revolutionized cancer therapy. Despite huge success, immunotherapy is still not effective in some group of patients or cancer types, and largely ineffective in sarcomas. Until recently, immune-checkpoint therapy was considered to block the interaction between PD-L1 expressed by cancer cells and PD-1 receptor localized on T-cells. Surprisingly, latest studies showed that cancer cells not only express PD-L1 but also PD-1 what is associated with increased growth, proliferation and survival via mTOR pathway signalling. Our group use canine osteosarcoma cell lines to investigate the role of PD-1/PD-L1 intrinsic signalling in disease pathogenesis. Flow cytometry confirmed PD-1 spontaneous expression on many OS cell lines, which ranged between 0.26% and 33.3%. Phenotypic changes were observed in PD-1/PD-L1 transfected over-expressing cells (OE). Strikingly, when grown in 3D culture, over-expressing cells shown accelerated growth and formation of spheres. Upregulation of pS6RP in PD-1 and PD-L1 OE cell lines indicated increased mTOR pathway signaling as demonstrated by Western Blot analysis. To confirm the impact of PD-1 antibody on canine cells, cell viability assay was performed after PD-1 blocking antibody treatment. Interestingly although in many of the cell lines, the addition of the antibody did not alter the growth, in one cell line the growth accelerated, while in another the proliferation decreased. Our data implies that the PD-1/PD-L1 intrinsic signalling may be important in canine osteosarcoma and targeting it could help enhance the therapeutic effect in both dogs and humans.
Citation Format: Dziubek Katarzyna, Mikolaj Kocikowski, Borek Vojtesek, David Argyle, Malgorzata Lisowska, Ted Hupp, Maciej Parys. Investigating tumor intrinsic PD-1/PD-L1 signaling in canine osteosarcoma cell lines as a spontaneous model for human disease [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5637.
Abstract 5660: Characterisation of novel CD73 antibodies as a therapeutic method of adenosine regulation
Authors: Gernon Grainne , Grooby Suzanne , Tonkin Louise , Bitterwolf Anja-Christina , Stewart Lorna , Deken Marcel , Shah Pritom , Ewings Katherine , Johnson Zoe 
Published: September 2020

Abstract
CD73 is a membrane-bound nucleotidase receptor which is frequently overexpressed in the tumour microenvironment and can be found on both tumour and immune cell types. Its function is to catalyse the conversion of adenosine monophosphate (AMP) to adenosine and phosphate and it has been proposed as a therapeutic target in cancer due to adenosines role in tumour immune suppression.
Using multiple approaches, a series of novel CD73 antibodies have been characterised for their therapeutic potential and benchmarked against agents currently undergoing clinical evaluation Inhibition of CD73 activity was evaluated using an Amplex Red-based coupled adenosine assay against both human and mouse CD73, and kinetics of antibody binding were determined using BioLayer Interferometry. Cellular assays were then utilised to further evaluate the antibodies in vitro. The ability of the CD73 antibodies to internalise was evaluated using two different methods, a Fab-ZAP killing assay and the IncuCyteTM FabFluor internalisation assay. The antibodies have also undergone functional studies, investigating the ability of the CD73 antibodies to disrupt the production of adenosine in tumour cells. We demonstrate that the novel CD73 antibodies inhibit CD73 function by two different mechanisms; direct inhibition of enzyme activity and modulation of cell surface expression, both of a which have therapeutic potential to disrupt CD73-mediated adenosine production and therefore reduce antitumor immune responses.
Ongoing studies are investigating the in vitro and in vivo efficacy of the clone selected for further development as a monotherapy and in combination with a novel small molecule inhibitor in murine models of cancer.
Citation Format: Grainne Gernon, Suzanne Grooby, Louise Tonkin, Anja-Christina Bitterwolf, Lorna Stewart, Marcel Deken, Pritom Shah, Katherine Ewings, Zoe Johnson. Characterisation of novel CD73 antibodies as a therapeutic method of adenosine regulation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5660.
Abstract 5663: Affinity tuned XmAb®2+1 PSMA x CD3 bispecific antibodies demonstrate selective activity in prostate cancer models
Authors: Nisthal Alex , Dragovich Matthew , Pong Erik W. , Zeng Veronica , Hedvat Michael , Bonzon Christine , Avery Kendra , Rashid Rumana , Ardila Connie , Muchhal Umesh S. , Moore Gregory L. , Chu Seung Y. , Desjarlais John R. 
Published: September 2020

Abstract
Bispecific antibodies enable therapeutic modalities inaccessible to traditional mAbs, such as T cell engagers that bind both CD3 on T cells and a target antigen on tumor cells. These agents provide synthetic immunity by expanding, activating, and redirecting T cells against a target of interest. While targeting lineage-restricted antigens such as CD19 or CD20 have found clinical success in hematopoietic cancers, targeting solid tumors requires high expressing tumor associated antigens (TAAs) with minimal normal tissue expression. Prostate cancer (PC) is one of the most prevalent cancers in men, and end stage (castration-resistant prostate cancer) has no curative treatment option. Prostate specific membrane antigen (PSMA), a type II transmembrane protein with a large extracellular domain, has long generated interest as a therapeutic target. It is highly overexpressed in PC compared to normal tissue, and its expression has been shown to correlate with malignancy. Previous attempts to target PSMA include antibody-based radiotherapy and antibody drug conjugates, which have shown some success but can be hampered by the inherent toxicity of the modality. Building upon the XmAb® heterodimeric Fc platform, we generated bispecific antibodies in an XmAb 2+1 Fab2-scFv-Fc format that are bivalent for PSMA and monovalent for CD3. Reducing the affinity of both specificities encouraged avid binding and strong activity on high PSMA expressing cell lines while minimizing reactivity on low expressing cell lines, matching PSMA's differential expression pattern. To ensure biologically valid antigen densities were being considered, IHC was conducted on paraffin embedded arrays of tumor tissue, normal tissue, and cell lines. Upon matching the staining intensity between the three sample types, we identified cell lines with corresponding PSMA antigen density that could serve as proxies of tumor and normal tissue. In vitro T cell-dependent cellular cytotoxicity (TDCC) assays on the relevant cell lines confirmed selective potency on high versus low expressing cells.
Citation Format: Alex Nisthal, Matthew Dragovich, Erik W. Pong, Veronica Zeng, Michael Hedvat, Christine Bonzon, Kendra Avery, Rumana Rashid, Connie Ardila, Umesh S. Muchhal, Gregory L. Moore, Seung Y. Chu, John R. Desjarlais. Affinity tuned XmAb®2+1 PSMA x CD3 bispecific antibodies demonstrate selective activity in prostate cancer models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5663.
Abstract 5706: Identifying regulators of cancer heterogeneity with phenotypic sorting and single cell sequencing
Authors: Chen Kevin , Fraley Stephanie Irene 
Published: September 2020

Abstract
Intratumoral heterogeneity is a major challenge to the effective treatment of cancer. The genomic, transcriptomic, and epigenetic differences among tumor cells give rise to diverse phenotypes, some of which can persist in dysregulated environmental conditions and survive therapeutic attempts. Single cell sequencing (scSeq) technologies have improved our understanding of the transcriptional variation among tumor cells. However, it remains unclear how cell behavior is related to these alterations. Here, we link genotype to phenotype by employing a method of fluorescently labeling and isolating tumor cell subpopulations based on user-defined phenotypic characteristics from within a biologically relevant three-dimensional (3D) environment for subsequent scSeq and molecular analyses (Pheno-scSeq). We compare this Pheno-scSeq technique to traditional agnostic clustering of scSeq data and find significant differences. We then use Pheno-scSeq to guide our dissection of the mechanistic basis of heterogeneity in the invasive capacity of triple negative breast cancer cells. After seeding cells in 3D collagen and photoconverting based on invasion phenotype, we find that cells undergoing collective invasion are defined by a transcriptional program of migration, anabolism, and proliferation, suggesting a “go and grow” state contrasting with the “go or grow” hypothesis. Cells that do not invade form acini and are defined by a transcriptional program enriched for catabolism, senescence, and immune regulation. Functional assessment of the gene sets validates the relevance of the transcriptional program and reveals differential Human Leukocyte Antigen localization associated with differential migration phenotypes. Treatment with doxorubicin and paclitaxel reveals that acini cells are resistant to drug-induced death, while collectively invasive cells are more susceptible. Modulation of cell-matrix adhesion is explored to determine the potential for reprogramming between the two phenotypes and to identify couplings between migration, immune, and metabolic phenotypes. This study lends deeper insight into the mechanisms underlying phenotypic heterogeneity and may inform the success of precision oncology initiatives.
Citation Format: Kevin Chen, Stephanie Irene Fraley. Identifying regulators of cancer heterogeneity with phenotypic sorting and single cell sequencing [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5706.
Abstract 5714: Targeting serine metabolism impairs tumor growth in preclinical models of Ewing sarcoma
Authors: Issaq Sameer , Mendoza Arnulfo , Rosales Tracy , Heske Christine , Thomas Craig , DeBerardinis Ralph , Helman Lee 
Published: September 2020

Abstract
Despite a growing body of knowledge about the genomic landscape of Ewing sarcoma (ES), translation of basic discoveries into targeted therapies and significant clinical gains has remained elusive. Recent insights have revealed that the oncogenic transcription factor EWS-FLI1 can impact ES cellular metabolism, raising the possibility of targeting metabolic dependencies as a novel therapeutic strategy. Here, we show that 3-phosphoglycerate dehydrogenase (PHGDH), the first enzyme in de novo serine synthesis, is highly expressed in human ES cells and that EWS-FLI1 regulates PHGDH expression and de novo serine synthesis. PHGDH knockdown resulted in decreased ES cell proliferation, especially under serine limitation, and significantly inhibited xenograft tumorigenesis in preclinical orthotopic models of ES. Additionally, the PHGDH inhibitor NCT-503 caused a dose-dependent decrease in cellular proliferation. Moreover, we report a novel drug combination in which nicotinamide phosphoribosyltransferase (NAMPT) inhibition, which blocks production of the PHGDH substrate NAD+, synergized with NCT-503 to abolish ES cellular proliferation and tumor growth. Furthermore, we show that serine deprivation inhibited ES cell proliferation and tumorigenesis, indicating that ES cells depend on exogenous serine in addition to de novo serine synthesis. Our findings suggest that serine metabolism is critical for ES tumorigenesis, and that targeting serine metabolism should be further investigated as a potential therapeutic strategy for ES.
Citation Format: Sameer Issaq, Arnulfo Mendoza, Tracy Rosales, Christine Heske, Craig Thomas, Ralph DeBerardinis, Lee Helman. Targeting serine metabolism impairs tumor growth in preclinical models of Ewing sarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5714.
Abstract 5726: A-to-I RNA deaminase deregulation in pre-leukemia stem cell evolution
Authors: Jiang Qingfei , Holm Frida , Isquith Jane , Mark Adam , Mason Cayla , Reynoso Eduardo , Morris Isabella , Ma Wenxue , Diep Raymond , Pham Jessica , Nasamran Chanond , Xu Guorong , Sasik Roman , Rosenthal Sara Brin , Birmingham Amanda , Crews Leslie , Pineda Gabriel , Whisenant Thomas , Fisch Kathleen , Jamieson Catriona 
Published: September 2020

Abstract
While inflammation induced ADAR1 RNA deaminases protect the human genome from retroviral integration, deregulation promotes therapeutic resistance in many malignancies. However, the combinatorial role of these deaminases in pre-leukemia stem cell (pre-LSC) evolution to therapy resistant LSC had not been elucidated. Thus, we performed whole genome sequencing (WGS) analysis of 43 CD34+pre-leukemic myeloproliferative neoplasm (MPN) samples compared with matched saliva and non-MPN controls andwhole transcriptome sequencing (RNA-seq) analysis of 113 FACS-purified hematopoietic stem cells (HSC) and hematopoietic progenitor cells (HPC) from MPN, acute myeloid leukemia (AML) and healthy young and aged samples. During MPN progression, inflammation-driven ADAR1 isoform p150 upregulation corresponded with increased Adenosine-to-Inosine (A-to-I) transitions in both MPN stem and progenitor populations. We identified unique A-to-I editing events in coding regions that are associated with either normal stem progenitors or with MPN progenitors. In addition, STAT3 transcript hyper-editing leads to STAT3beta splice isoform expression. Moreover, lentiviral ADAR1p150 overexpression enhanced replating as well as beta-catenin activation, which was reversed by lentiviral shRNA ADAR1 knockdown. In summary, innate immune deaminase deregulation fuels pre-LSC evolution to LSC and may represent a vital LSC therapeutic vulnerability.
Citation Format: Qingfei Jiang, Frida Holm, Jane Isquith, Adam Mark, Cayla Mason, Eduardo Reynoso, Isabella Morris, Wenxue Ma, Raymond Diep, Jessica Pham, Chanond Nasamran, Guorong Xu, Roman Sasik, Sara Brin Rosenthal, Amanda Birmingham, Leslie Crews, Gabriel Pineda, Thomas Whisenant, Kathleen Fisch, Catriona Jamieson. A-to-I RNA deaminase deregulation in pre-leukemia stem cell evolution [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5726.
Abstract 5749: The association between physical health-related quality of life, physical functioning and risk of contralateral breast cancer
Authors: Mukand Nita , Nabulsi Nadia , Alobaidi Ali , Asfaw Alemseged , Chiu Brian C. , Ko Naomi Y. , Calip Gregory S. 
Published: September 2020

Abstract
Background: Physical limitations and disability among older cancer patients can lead to suboptimal treatment and surveillance for secondary cancers. Our objective was to evaluate the effects of poor physical health-related quality of life (PQOL) and physical functioning (PF) on contralateral breast cancer (CBC) risk among older women diagnosed with unilateral breast cancer (UBC).
Methods: We performed a nested case-control study within a cohort from the Surveillance, Epidemiology and End Results Medicare Health Outcomes Survey (MHOS) database. Women were required to have first primary UBC without prophylactic contralateral mastectomy. Among 2,938 women ages 65 years and older with stages I-III UBC between 1997 and 2011, we identified 100 subsequent CBC cases and 915 controls using incidence density sampling without replacement matched on age, race, and quarter-year of diagnosis. PQOL and PF were determined from survey responses to the Medical Outcomes Trust Short Form 36 component scores. Conditional logistic regression models were used to estimate relative risks (RR) and 95% confidence intervals (CI) for metachronous CBC.
Results: Cases and controls were similar with respect to comorbidities, stage, surgery and radiation treatments but differed by hormone receptor status (ER/PR-negative, cases 23% and controls 11%). Cases had lower mean PQOL (-1.8; 95% CI -4.3, 0.7) and PF (-2.2, 95% CI -4.9, 0.5) component scores, but these differences were not statistically significant. In multivariable models, estimates suggest increased CBC risk for women in the lowest quartile of PQOL compared to those in the upper quartile (RR=1.8; 95% CI 0.8, 4.3). Compared to women in the upper quartile of physical functioning scores, women in the lower three quartiles had a 2.6-fold (95% CI 1.2, 5.9) increased risk of CBC.
Conclusions: Our findings indicate that low physical health-related quality of life is common among older women diagnosed with breast cancer, and poor physical functioning is related to risk of CBC. Efforts to understand and minimize declines in physical functioning post-breast cancer diagnosis may help optimize treatment strategies to reduce the risk of this adverse outcome.
Citation Format: Nita Mukand, Nadia Nabulsi, Ali Alobaidi, Alemseged Asfaw, Brian C. Chiu, Naomi Y. Ko, Gregory S. Calip. The association between physical health-related quality of life, physical functioning and risk of contralateral breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5749.
Abstract 575: Disulfiram plus copper synergizes with etoposide for the treatment of Merkel cell carcinoma
Authors: Hill Natasha Tremayne , Gelb Tara , Urban Dan , Kellenberger Tyler , Hall Matthew , Brownell Isaac 
Published: September 2020

Abstract
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with limited treatment options. Currently two immunotherapies are approved for the treatment of MCC, the PD-L1 inhibitor avelumab and the PD-1 inhibitor pembrolizumab. Unfortunately, these treatments only have durable benefit for less than half of patients that can be treated with immunotherapy. Therefore, new and effective treatments are needed for MCC. To address this, we conducted a high-throughput drug screening of ~4,000 small molecules. Our drug screen identified disulfiram (DSF), an aldehyde dehydrogenase inhibitor used in the treatment of alcoholism, as an agent that selectively reduced MCC cell viability. Recent studies suggest that DSF complexed with copper can have anti-cancer effects. Consistent with this, the addition copper at physiological levels increased the potency of DSF in MCC cells lines. Next, we demonstrated that disulfiram combined with copper synergized with the topoisomerase II inhibitor etoposide, lowering the effective dose of etoposide required to reduce MCC cell viability. Mechanistically, combining DSF, copper and etoposide was cytotoxic but did not induce apoptosis in MCC cell lines. This combination increased the formation of double stranded DNA breaks while disulfiram plus copper induced autophagy, which could mechanistically be an indication of immunogenic cell death signaling. Taken together, our data suggest that disulfiram combined with copper and etoposide could be repurposed for the effective treatment of advanced MCC. One strong advantage of this combination is that all agents can be given orally and at dosages with minimal adverse effects.
Citation Format: Natasha Tremayne Hill, Tara Gelb, Dan Urban, Tyler Kellenberger, Matthew Hall, Isaac Brownell. Disulfiram plus copper synergizes with etoposide for the treatment of Merkel cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 575.