bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1679: Characterization and establishment of triple negative breast cancer patient derived xenograft derived from a Nigerian woman
Authors: Okoli Uzoamaka Adaobi , Okafor Michael Tochukwu , Agu Kenneth A. , Ohayi Samuel R. , Nna Emmanuel O. , Chijioke Chioli P. , Udeniya Iroka J. 
Published: September 2020

Abstract
Extensive literature has demonstrated the use of fresh human breast tumour tissue surgically implanted in immunodeficient mice to establish patient-derived xenograft (PDX) as a therapeutic assessment tool. Unfortunately, there is a paucity of genomic research using PDX as a preclinical tool for breast cancer metastasis in Nigerian women. Previous studies of rodent models have concentrated on cell line xenograft of other tumours usually of Caucasian or African American counterpart. To overcome this limitation, Triple-negative breast cancer (TNBC) was derived from a consenting 32-year-old Nigerian woman who had neoadjuvant therapy and had undergone a mastectomy. Triple-negative breast cancer lacks expression of hormone receptors including human epidermal receptor (HER2-), estrogen receptor (ER-) and progesterone receptor (PR-) genes. TNBC xenograft was established by orthotopic surgical implantation of breast cancer tissue fragments of 2mm3 in size with cultrex in the cleared breast pads of immunosuppressed mice and a further two passages. The size of the implanted tumour was checked twice weekly. Haematology & eosin histology and immunohistochemistry analysis were used to structurally and functionally characterize the tumour xenograft and primary tumour respectively. Real-time quantitative polymerase chain reaction (RQ-PCR) was used to evaluate the genomic correlation between primary tumour and tumour xenograft. Target genes compared between the tumour xenograft and primary tumours included CXCL16; CLD10; CDC42EP3; CXCL16; EPSTI1; PALMD and ZAN. Reference genes RLP13A and GAPDH were selected as assays for endogenous controls. All tumour tissues were mechanically homogenized and lysed in guanidine isothiocyanate buffer from which RNA was extracted and converted to cDNA by random hexamer priming. RQ-PCR was performed using TaqMan chemistries. This was validated by DNA sequencing of the xenografts tumour and primary tumour using Nanopore DNA sequencing, and Ligation Sequencing ID2 chemistry. The DNA sequences were aligned with Meg Align Pro The xenografts appear to maintain characteristic human histopathology, tumour-marker production. None of the tumours showed hormone sensitivity. There was a local invasion of breast cancer in the bone. The pairwise alignment yielded significant percentage relativity.
Citation Format: Uzoamaka Adaobi Okoli, Michael Tochukwu Okafor, Kenneth A. Agu, Samuel R. Ohayi, Emmanuel O. Nna, Chioli P. Chijioke, Iroka J. Udeniya. Characterization and establishment of triple negative breast cancer patient derived xenograft derived from a Nigerian woman [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 1679.
Abstract 1714A: TGF-beta signaling on myeloid cells regulates ECM deposition in mammary carcinoma via adenosine dependent mechanisms
Authors: Vasiukov Georgii , Novitskaya Tatiana , Schwager Samantha , Moses Harold , Blackwell Timothy , Feoktistov Igor , Novitskiy Sergey 
Published: September 2020

Abstract
TGF-beta plays a crucial role in tumor microenvironment by regulating cell-cell and cell-stroma interactions. We previously demonstrated that TGF-beta signaling on myeloid cells regulates expression of CD73, a key enzyme for production of adenosine, a pro-tumorigenic metabolite implicated in regulation of tumor cell behaviors, immune response and angiogenesis. Using MMTV-PyMT mouse mammary tumor model, we discovered that deletion of TGF-beta signaling on myeloid cells (PyMT/TGFbRII-LysM) affects ECM formation in tumor tissue, specifically increases collagen and decreases fibronectin deposition, and these changes associate with mitigated tumor growth and reduced metastases. Using multiplexed five-color immunofluorescent staining and spatial analysis on a single-cell level, we discovered that reduced TGF-beta signaling on fibroblasts associates with their proximity to CD73 positive myeloid cells in tumor tissue. Consistent with these findings, in vitro gel contraction assay and Western blotting for Collagen I and pSMAD proteins confirmed that adenosine significantly downregulates TGF-beta signaling on fibroblasts. Using in vitro pharmacological approach, we found that this effect is regulated by A2a and A2b adenosine receptors. TCGA data base analysis revealed that patients with triple negative breast cancer and basal type have similar signature of adenosine and ECM profiles: high expression of A2b adenosine receptors correlates with decreased expression of Col1 and is associates with poor outcome. Taken together, our studies reveal a new role for TGF-beta signaling on myeloid cells in tumorigenesis. Discovered crosstalk between TGF-beta/CD73 on myeloid cells and TGF-beta signaling on fibroblasts can contribute to ECM remodeling and pro-tumorigenic actions of CAFs.
Citation Format: Georgii Vasiukov, Tatiana Novitskaya, Samantha Schwager, Harold Moses, Timothy Blackwell, Igor Feoktistov, Sergey Novitskiy. TGF-beta signaling on myeloid cells regulates ECM deposition in mammary carcinoma via adenosine dependent mechanisms [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 1714A.
Abstract 1719: Drug-loaded porphyrin nanoparticles as a platform for targeted and photodynamic combination therapy
Authors: Cheung Justin M. , Baker Hanan , Li Daniel , Stor Daniel , Heller Daniel A. 
Published: September 2020

Abstract
Many traditional nanoparticle delivery mechanisms require the use of an inert vehicle to deliver single therapeutic payloads. Here, we describe a novel, dual-therapeutic, self-assembled nanoparticle class wherein both the payload and encapsulating vehicle may potentiate anti-neoplastic effects. The nanoparticles consist of photoactive porphyrin dyes encapsulating small molecule drugs. We screened 9 porphyrins with 27 small molecules for the formation of porphyrin-drug nanoparticles; a total of 243 nanoparticle candidates, of which 25 formed nanoparticles as dictated by pre-determined cutoffs for size, polydispersity, and porphyrin/drug concentrations. Logistic regression based on formation data and molecular descriptors suggested that the presence of electronegative groups positively influenced nanoparticle formation. Chemical inhibition of various uptake pathways in endothelial cells indicated that the uptake of these porphyrin-drug nanoparticles is largely mediated by clathrin and macropinocytosis. Stability testing demonstrated that porphyrin-drug nanoparticles remained stable at 37°C for at least 6 hrs. This work outlines the synthesis and characterization of a new class of porphyrin nanoparticles with the capacity to deliver targeted therapy. Furthermore, the simplicity of the self-assembly process highlights the potential for this novel nanoparticle paradigm to be easily tested in disease models.
Citation Format: Justin M. Cheung, Hanan Baker, Daniel Li, Daniel Stor, Daniel A. Heller. Drug-loaded porphyrin nanoparticles as a platform for targeted and photodynamic combination therapy [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 1719.
Abstract 1722: Nanoparticle pro-drug to overcome the stromal barrier in pancreatic ductal adenocarcinoma
Authors: Alzhrani Rami , Sau Samaresh , Aboukameel Amro , Alsaab Hashem , Azmi Asfar , Iyer Arun 
Published: September 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third-highest cause of cancer-related death in the United States. The heterogenicity of the PDAC is a major challenge in the success of anti-PDAC therapy. PDAC is comprised of &gt;90 % dense desmoplastic tumor stroma that impedes the delivery of drugs into the core of the tumor, resulting development of drug resistance. Thus, we developed a nanoparticle pro-drug to overcome the stromal barrier of PDAC. We utilized nanoengineering to target dual CD44 and c-Met biomarkers that have a significant role in developing drug resistance on PDAC. Western blot analysis in various PDAC cell lines, such as PANC-1, AsPc-1, and BxPc3 revealed a high abundance of CD44 and cMet, strongly supporting our hypothesis. Therefore, targeting the CD44 and c-Met biomarker and selectively delivering anti-PDAC drug is a smart strategy to improve the anti-PDAC outcome. We developed dual CD44/c-Met targeted nanoparticle, called D44M that can efficiently penetrate the core of tumor as well as home into CD44 and cMet biomarker. We evaluated tumor selectivity of the near infrared (NIR) fluorescent dye conjugated D44M, D44M-NIR in the orthotopic PDAC model. The biodistribution of D44M-NIR in orthotopic animal model proved superior tumor penetration of D44M-NIR with 7-fold higher than the control NIR dye treatment. Moreover, D44M-NIR treated showed minimum liver accumulation, suggesting an outstanding approach of overcoming nanoparticle mediated liver toxicity. Finally, the D44M was chemically conjugated with gemcitabine (GEM), namely D44M-GEM pro-drug that showed excellent PDAC killing. The PDAC cell killing study of D44M-GEM in combination with Everolimus revealed high synergistic combination effect with CI value of 0.2-0.5. The anti-PDAC therapy in ASPC-1 xenograft model demonstrated significant tumor growth inhibition for treatment of D44M-GEM and D44M-GEM+Everolimus as compared to control. Supported with data, our work provides a perspective towards the implementation of nanotherapeutic to overcome the bottleneck barrier of therapeutic delivery and efficacy of PDAC management.
Citation Format: Rami Alzhrani, Samaresh Sau, Amro Aboukameel, Hashem Alsaab, Asfar Azmi, Arun Iyer. Nanoparticle pro-drug to overcome the stromal barrier in pancreatic ductal adenocarcinoma [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 1722.
Abstract 174: Genomic cytometry characterization of preclinical models for development of immune-oncology therapeutics
Authors: Lee Joon Sang , McGrath Shannon , Wang Emma , Rogers-Grazado Maximilian , Zhang Yu-an , Malkova Natalia , Pollard Jack , Protopopov Alexei 
Published: September 2020

Abstract
Single cell characterization of protein epitopes is usually associated with fluorescent Flow Cytometry, which can be both costly and time consuming to optimize for multiple epitopes. To overcome the limitations of this method, we introduce Genomic Cytometry that utilizes cellular indexing of transcriptomes and protein epitopes by next-generation sequencing (CITE-seq) technology instead of flow. Genomic Cytometry is based on staining cells with antibodies conjugated to unique 15-bp DNA barcodes instead of fluorophores. After sequencing and data analysis the barcode read number can be linked to protein abundance. We utilized Genomic Cytometry to simultaneously analyze over 50 different protein biomarkers in a single scalable workflow. The application is ideal for characterization of heterogeneous cell populations such as tumors including their immune content. In addition to profiling a number cell surface protein markers that exceeds capabilities of traditional flow cytometry the technology allows for assessment of single cell gene expression data to link protein and genomic data sets.
Corresponding pre-analytical and 10X Genomics-based analytical workflows were established for human PBMC samples, as well as for solid tissue including tumor specimens derived from mouse syngeneic tumor models. Data analysis pipelines were developed and validated that includes custom scripts. We ran a number of cross-platform validation studies (mouse and human cells) and found that the Genomic Cytometry is highly correlative to fluorescent flow. Multiplex methods were implemented to allow pooling of samples to reduce biases related to sample manipulation. The method enables large-scale single-cell sequencing experiments. In proof of concept experiments, a number of preclinical models, such as MC38 and H22, were deeply analyzed using CITE-seq approach. Genomic Cytometry enables rapid and cost effective characterization of both immune-oncology (I-O) models and modes of action of new I-O molecules in order to develop more differentiated therapeutics.
Citation Format: Joon Sang Lee, Shannon McGrath, Emma Wang, Maximilian Rogers-Grazado, Yu-an Zhang, Natalia Malkova, Jack Pollard, Alexei Protopopov. Genomic cytometry characterization of preclinical models for development of immune-oncology therapeutics [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 174.
Abstract 1762: Dual HDAC-BET proteins inhibition by TW9 hold promise for breast cancer
Authors: Xavier Pedro Luiz P. , Lucas Romain , Weiser Tim , Knapp Stefan , Fukumasu Heidge , Müller Susanne 
Published: September 2020

Abstract
Epigenetic proteins play a key role in gene expression regulation and cellular states and, consequently, abnormalities in these mechanisms result in the development and progression of several types of cancer. Thus, inhibitors against epigenetic targets have recently entered clinical trials as potential and innovative therapies against this disease. Both histone deacetylases (HDACs) and bromodomain and extraterminal proteins (BET) inhibitors have been shown to be efficient against several different cancer types, including breast cancer. Although synergistic effects of HDAC and BET inhibitors have been observed in different cancer types, few studies have been performed in breast cancer. However, combination studies often result in increased toxicity, thus new strategies are necessary to overcome these limitations. Therefore, we designed and synthesized a dual HDAC-BET inhibitor, TW9. In this study, we determined the effects of TW9 on two HR-positive cell lines MCF7 and T-47D and two triple-negative breast cancer cell lines, MDA-MB-231 and HCC1806 in 2D and 3D in vitro models. To determine the cytotoxic effects, cells were treated with (+)-JQ1 (BET inhibitor), CI994 (HDAC inhibitor) and TW9 (dual HDAC-BET inhibitor). After 72h, cell viability was tested using XTT assay. Primary and secondary tumorspheres were grown in ultra-low attachment multiwell plates and were treated with DMSO (control) or different concentrations of TW9. The triple-negative cell lines were more resistant to all inhibitors and TW9 was more potent compared to (+)-JQ1 or CI994 in all the breast cancer cells (p&lt;0.05). Tumorspheres of MCF7 cells were treated with TW9 ranging from 100 nM to 500 nM. Significant decrease of primary and secondary tumorspheres was observed at all doses (p&lt;0.0001). In addition, TW9 was able to inhibit the formation of secondary tumorspheres, even after removal of the treatment during dissociation of primary tumorspheres (p&lt;0.0001), pointing to an epigenetic effect. In summary, our findings showed that dual HDAC-BET inhibition by TW9 shows positive effects regarding tumorigenicity and self-renewal of cancer cells and thus may provide a promising treatment against breast cancer, in particular for the more resistant triple-negative cells.
Citation Format: Pedro Luiz P. Xavier, Romain Lucas, Tim Weiser, Stefan Knapp, Heidge Fukumasu, Susanne Müller. Dual HDAC-BET proteins inhibition by TW9 hold promise for 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 1762.
Abstract 1768: Identification of a potent, orally-available SMARCA2/4 inhibitor with in vitro and in vivo activity in preclinical models of SMARCA4-mutant NSCLC
Authors: Drew Allison E. , Jacques Suzanne L. , Eichinger Lindsey W. , Pantano Chloe , Motwani Vinny , Tang Cuyue , Tang Cuyue , Farrow Neil , Brach Dorothy , Howe Selene , Raimondi Alejandra , Dransfield Daniel T. , Duncan Kenneth W. , Stickland Kim , Huang Liyue , Lampe John 
Published: September 2020

Abstract
SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily A member 2 (SMARCA2) is an ATP-dependent DNA helicase and a catalytic component of the SWI/SNF complex. SWI/SNF-mediated nucleosome remodeling is a critical regulator of chromatin accessibility resulting in transcriptional regulation of gene sets that determine and maintain cell state. The role of SMARCA2 as the catalytic driver of SWI/SNF activity is mutually exclusive with that of its close paralog, SMARCA4. Loss of functional SMARCA4, as is reported in a subset of NSCLC and other cancer types generally confers a dependency on SMARCA2. Cancers lacking functional SMARCA4 have been shown to be sensitive to loss of SMARCA2 function either through genetic ablation or the use of a small molecule SMARCA2/4 inhibitor. We describe the identification and characterization of a small molecule SMARCA2/4 inhibitor Compound 1 and its selective activity in the SMARCA4-mutant setting both in in vitro and in vivo model systems. The compound demonstrates inhibition of SMARCA2 and SMARCA4 enzymatic activity in biochemical assays and broad selectivity against other helicases. Selective sensitivity in anti-proliferative assays of 15-fold was observed in NSCLC cell lines with SMARCA4 protein loss compared to those harboring WT SMARCA4 protein. Oral dosing demonstrates dose-dependent in vivo SMARCA2 inhibition and anti-tumor activity in SMARCA4-mutant NSCLC xenograft models. This compound is suitable for further exploration of the role of SMARCA2/4 and SWI/SNF in vitro and in vivo in cancer and other indications.
Citation Format: Allison E. Drew, Suzanne L. Jacques, Lindsey W. Eichinger, Chloe Pantano, Vinny Motwani, Cuyue Tang, Cuyue Tang, Neil Farrow, Dorothy Brach, Selene Howe, Alejandra Raimondi, Daniel T. Dransfield, Kenneth W. Duncan, Kim Stickland, Liyue Huang, John Lampe. Identification of a potent, orally-available SMARCA2/4 inhibitor with in vitro and in vivo activity in preclinical models of SMARCA4-mutant NSCLC [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 1768.
Abstract 1776: Exploring anetumab ravtansine in a preclinical model of thymic carcinoma
Authors: Chen Vincent , Sommer Anette , Schatz Christoph , Zitzmann-Kolbe Sabine , Kim In-Kyu , Giaccone Giuseppe 
Published: September 2020

Abstract
Thymic epithelial tumors (TETs) are a group of rare tumors (0.13 per 100,000 persons), comprised of thymomas and thymic carcinoma, arising from the epithelial cells of the thymus. The biology of these tumors is not well understood, and there are no approved targeted therapies against TETs. One promising drug target is mesothelin (MSLN), which is a surface glycoprotein that is cleaved to produce two proteins: mature MSLN (mMSLN) and megakaryocyte potentiating factor (MPF). In normal physiology, expression of MSLN is limited to mesothelial cells lining the pleura, pericardium, and peritoneum. Its expression is also present in various cancers, including thymic carcinoma, where it is expressed in 79% of cases. In this study, we investigate the ability of the MSLN targeting, fully human monoclonal antibody-drug conjugate (ADC) anetumab ravtansine (ARav) to inhibit growth of thymic carcinoma in in-vitro and in-vivo models.
We utilized immunoblotting and RT-qPCR to characterize MSLN expression in human thymoma and thymic carcinoma derived cell lines. Binding of anetumab, the antibody moiety in ARav, to thymoma and thymic carcinoma cell lines was assessed by flow cytometry. In-vitro, ARav's effect on cell proliferation was tested against MP57 cells (thymic carcinoma), stably transfected with MSLN, utilizing CellTiter-Glo. ARav's activity in-vivo as a monotherapy, and as a combination therapy with cisplatin, was tested against MSLN expressing T1889 xenograft tumors in athymic nude mice and compared to vehicle, isotype control ADC, and standard-of-care (SoC) cisplatin.
Using the anetumab antibody, thymoma (T1682) and thymic carcinoma (T1889) cell lines were shown to express MSLN on the cell surface. In-vitro, ARav was effective at inhibiting growth of MP57 cells stably transfected with mMSLN. In-vivo, 15 mg/kg ARav inhibited T1889 xenograft tumor growth more efficaciously than vehicle, the isotype control ADC (all given every 2 weeks), and 4 mg/kg cisplatin (given every week). Combining ARav at a dose of 7.5 mg/kg with 4 mg/kg cisplatin yielded an additive effect on inhibiting tumor growth.
MSLN is expressed in thymoma and thymic carcinoma derived cell lines. Anetumab ravtansine inhibits growth of MSLN positive thymic carcinoma in our preclinical model; when combined with SoC cisplatin, ARav confers enhanced tumor growth inhibition.
Citation Format: Vincent Chen, Anette Sommer, Christoph Schatz, Sabine Zitzmann-Kolbe, In-Kyu Kim, Giuseppe Giaccone. Exploring anetumab ravtansine in a preclinical model of thymic 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 1776.