bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1628: A small-molecule inhibitor of WRN selectively kills MSI-H cancer cells and phenocopies WRN genetic defects
Authors: Rao Yanhua , Srivatsan Anjana , Liimatta Marya , Munoz Diana , Quirit Jeanne , Shi Jianxia , Nguyen An , Linghu Xin , Federowicz Federowicz , Jones Brian , Fleury Melissa , Newby Zach , Dillon Michael P. , Barsanti Paul A. , Lackner Mark R. , White Michael A. , Lee Yang , Landis Phil , Peng Yang , Cicchini Michelle , Cottom Josh , Nickels Leng , Brnardic Ed , DeMartino Michael , Taygerly Josh 
Published: April 2023

Abstract
Werner syndrome protein (WRN) is a RecQ-family helicase involved in the maintenance of genome integrity. Germline mutations in WRN cause premature aging and cancer predisposition. Analysis of systematic RNAi and CRISPR screening data has previously revealed that WRN is essential for the survival of cancer cell lines with high microsatellite instability (MSI-H). We have developed potent and selective small-molecule inhibitors of WRN helicase (WRNi) and showed that pharmacological inhibition of WRN causes lethality and induction of DNA damage markers selectively in MSI-H cancer cell lines compared to microsatellite-stable (MSS) cell lines. Screening of WRNi across a large panel of pooled, barcoded cell lines in the PRISM format revealed selective sensitivity in MSI-H cell lines and showed that pharmacological inhibition of WRN is highly correlated with genetic ablation of WRN across this panel, confirming selectivity for WRN. In vivo evaluation demonstrated robust and MSI-selective tumor regressions. These data provide pharmacological proof-of-concept for the WRN/MSI-H synthetic lethal relationship and support WRN inhibition as a novel therapeutic approach for the treatment of MSI-H cancers.
Citation Format: Yanhua Rao, Anjana Srivatsan, Marya Liimatta, Diana Munoz, Jeanne Quirit, Jianxia Shi, An Nguyen, Xin Linghu, Federowicz Federowicz, Brian Jones, Melissa Fleury, Zach Newby, Michael P. Dillon, Paul A. Barsanti, Mark R. Lackner, Michael A. White, Yang Lee, Phil Landis, Yang Peng, Michelle Cicchini, Josh Cottom, Leng Nickels, Ed Brnardic, Michael DeMartino, Josh Taygerly. A small-molecule inhibitor of WRN selectively kills MSI-H cancer cells and phenocopies WRN genetic defects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1628.
Abstract 163: Establishment of pancreatic ductal adenocarcinoma organoids model using endoscopic ultrasonography-guided fine needle biopsy: a new window into understanding pancreatic ductal adenocarcinoma tumor biology
Authors: Kim Hyemin , Cha Hongui , Lee Se-Hoon , Park Joo Kyung 
Published: April 2023

Abstract
Background & Aims: Tumor biology studies of pancreatic ductal adenocarcinoma (PDAC) used surgical specimens, even though most PDACs are unresectable. The aims of the study were to 1) establish PDAC organoids platform from endoscopic ultrasonography (EUS)-guided fine needle biopsy (FNB), 2) investigate clinicopathologic and genomic characterization, and 3) find out the clinical applicability of the patient-derived PDAC organoids model from PDAC diagnosis to treatment timeline.
Methods: The patients with suspected PDACs were enrolled prospectively, and PDAC minimal specimens were acquired from EUS-guided FNB at Samsung Medical Center from 2015 to 2019.
Results: Ninety-four PDAC organoids were successfully established (94/113, 83.2%) via EUS-guided FNB within 8.2±2.6 days. Clinical factors were also analyzed associated with the success rate in establishing PDAC organoids; specimens with high cellularity (&gt;10 clusters) were an independent factor in multivariate analysis. Whole exome sequencing showed the high concordance between primary PDAC and its organoid and more enriched genetic alterations in organoids. In addition, the high-throughput screening (HTS) drug test revealed that the clinical correlation with real-world data was 12 out of 15 between PDAC organoids and the chemotherapeutic response of the study patients. Whole-transcriptome sequencing identified genes and pathways associated with the drug responses.
Conclusions: We have achieved the PDAC organoid platform in a high success rate via EUS-guided FNB, and the concordance between primary PDAC and its organoid seems very high. More importantly, the HTS drug test showed that PDAC organoids may well reflect clinical chemotherapeutic response and may also be used as the “Patient Avatar Model” in clinical practice on time.
Citation Format: Hyemin Kim, Hongui Cha, Se-Hoon Lee, Joo Kyung Park. Establishment of pancreatic ductal adenocarcinoma organoids model using endoscopic ultrasonography-guided fine needle biopsy: a new window into understanding pancreatic ductal adenocarcinoma tumor biology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 163.
Abstract 176: Generation and maintenance of anaplastic thyroid cancer spheroids from human cancer cells
Authors: Hu Jiangnan , Ghosh Chandrayee , Kebebew Electron 
Published: April 2023

Abstract
Background: Anaplastic thyroid cancer (ATC) is the most aggressive thyroid cancer. Despite advances in tissue culture techniques, a robust model for thyroid cancer spheroid culture is yet to be developed. Here, we described a protocol to generate tumor spheroids from human ATC cells and excising cell lines.
Methods: Using four established ATC cell lines (8505C, SW1736, C643 and THJ-16T) and one clinical tumor sample derived ATC cells, we created an efficient and cost-effective 3D culture system that can enhance our understanding of ex vivo treatment response.
Results: We found that all four cell lines can readily form spheroids in culture with unique morphology, size, and cytoskeletal organization. We observed both cohesive (dense and solid structures) and dis-cohesive (irregularly shaped structures) spheroids within the same culture condition across different cell lines. BRAFWT ATC spheroids grew in a cohesive pattern, while BRAFV600E- mutant ATC spheroids show dis-cohesive organization. In the patient-derived spheroids (BRAFV600E- mutant ATC), we observed both growth patterns with mostly the dis-cohesive type. Phase-contrast images taken over time suggest that the cohesive ATC spheroids seem to be clonally derived, allowing the study of tumor heterogeneity. Furthermore, the ATC spheroids we established can maintain the 3D structures in the culture medium.
Conclusion: Our study describes the development of a robust spheroid system from established ATC cell lines and freshly acquired patient tumor samples. We show that combining 3D culture with traditional 2D methods provides a complementary and powerful approach to the future drug screening and mechanism studies in the ATC.
Citation Format: Jiangnan Hu, Chandrayee Ghosh, Electron Kebebew. Generation and maintenance of anaplastic thyroid cancer spheroids from human cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 176.
Abstract 1760: ADI-PEG20 and GC7 as a novel anti-metabolite strategy for the treatment of malignant pleural mesothelioma
Authors: Carpentier Joséphine , Szlosarek Peter W. , Martin Sarah Anne 
Published: April 2023

Abstract
Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with less than 10% of patients surviving 5-years from diagnosis. Arginine deprivation using pegylated arginine deiminase (ADI-PEG20) is a novel treatment for mesothelioma deficient in the arginine biosynthetic enzyme ASS1. However, resistance to ADI-PEG20 in MPM is a significant problem and is characterized in part by reprogramming of the urea and polyamine metabolism pathway (Locke et al., 2016). We sought to identify a targeted metabolism-based therapy to overcome the emerging resistance and increase the efficiency of ADI-PEG20 treatment for patients with MPM.
New models of ADI-PEG20 resistance were generated by constant exposure of MPM cell lines to arginine deprivation for 6 months. ADI-PEG20 resistant and sensitive MPM cell lines were treated with a panel of polyamine targeting molecules. Metabolome alterations were studied by targeted metabolomics and glucose flux analyses.
Our results confirmed the up-regulation of ASS1 expression from (50 to 3000-fold) alongside upregulation of polyamine catabolism and upon generation of ADI-PEG20 resistance. Treatment of ADI-PEG20 resistant cell lines with a range of different polyamine inhibitors demonstrated that ADI-PEG20 resistant cell lines were significantly more sensitive to the spermidine-analogue GC7 than their respective ASS1-ve parental cell lines. Moreover, the combination of GC7 and ADI-PEG20 prevented the emergence of resistant cells in vitro. We observed a significant synergistic effect of GC7 and ADI-PEG20 in both ASS1-ve and ASS1+ve cell lines in 2D and 3D cell culture models as well as in our mice in vivo model. Metabolomics analysis revealed that GC7 treatment significantly impaired the TCA cycle. We hypothesize that GC7 is repurposing the fate of Acetyl-CoA to polyamine catabolism therefore shutting down the TCA cycle. Our findings provide novel insights into a polyamine targeted therapy that may prevent resistance to ADI-PEG20 treatment in MPM and related arginine-auxotrophic cancers.
Citation Format: Joséphine Carpentier, Peter W. Szlosarek, Sarah Anne Martin. ADI-PEG20 and GC7 as a novel anti-metabolite strategy for the treatment of malignant pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1760.
Abstract 1887: Preclinical development of BB-1701, a HER2-tageting eribulin-containing ADC with potent bystander effect and ICD activity
Authors: Wang Yang , Xia Bing , Cao Lixia , Yang Jianfeng , Feng Cui , Jiang Fangdun , Li Chen , Gu Lixia , Yang Yifan , Tian Jing , Cheng Cindy , Furuuchi Keiji , Fulmer James , Verdi Arielle , Rybinski Katherine , Soto Allis , Albone Earl , Uenaka Toshimitsu , Gong Likun , Liu Tingting , Qin Qiuping , Wei Ziping , Zhou Yuhong 
Published: April 2023

Abstract
Several HER2-targeting antibody-drug conjugates (ADC) have gained market approval for the treatment of HER2-expressing metastasis. However, these ADC drugs still face challenges of acquired resistance and/or severe adverse effects associate with their payload toxins. Eribulin, a market approval agent for the treatment of metastatic breast cancer and liposarcoma , is a new choice of ADC payload with distinct mechanism of action (MOA). Here we report preclinical studies of BB-1701, a novel HER2-tageting eribulin-containing ADC. BB-1701 exhibited potent and specific cytotoxicity activities to various types of cancer cells where HER2-exprssing levels vary in large ranges. BB-1701 induced tumor-growth suppression, even regression in in vivo models with a single dose of 1-5 mg/kg dosage. In comparison with other HER2-targeting ADCs with different toxin payloads (DM1, MMAE and Dxd), eribulin-containing ADC demonstrated higher potency to cancer cell lines with low HER2 expressing levels (with lower IC50). BB-1701 also showed effective tumor suppression in models insensitive to T-DM1 or T-Dxd. Mode of action studies revealed significant bystander cytotoxicity of BB-1701 to HER2-low cells when co-cultured with HER2-high cells. Additionally, BB-1701 treatment increased ATP releasing and Calreticulin expression, both were deemed immunogenic cell death (ICD) markers. Lastly, repeat dose pharmacokinetic and toxicology studies in nonhuman primates revealed favorable PK and safety profiles of BB-1701 in the clinical intend dosage route and schedule. In conclusion, these comprehensive preclinical data have strongly supported BB-1701 as a potent antitumor agent to cancers including HER2-low expressing and/or cancers insensitive to other HER2-targeting ADCs. A phase I clinical study of BB-1701 in those patients is ongoing.
Citation Format: Yang Wang, Bing Xia, Lixia Cao, Jianfeng Yang, Cui Feng, Fangdun Jiang, Chen Li, Lixia Gu, Yifan Yang, Jing Tian, Cindy Cheng, Keiji Furuuchi, James Fulmer, Arielle Verdi, Katherine Rybinski, Allis Soto, Earl Albone, Toshimitsu Uenaka, Likun Gong, Tingting Liu, Qiuping Qin, Ziping Wei, Yuhong Zhou. Preclinical development of BB-1701, a HER2-tageting eribulin-containing ADC with potent bystander effect and ICD activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1887.
Abstract 1890: Bispecific T cell engagers targeting TrkB
Authors: Bijlsma Jetta , Desikan Srinidhi , Miller Timothy , Thom Allie , Bath Jennifer , Roodink Ilse 
Published: April 2023

Abstract
Tropomyosin kinase B (TrkB) plays an important role in survival, differentiation, and proliferation of neural cells. It belongs to the family of receptor tyrosine kinases and its specific ligands are NT-4/5 and BDNF. The (over)expression of TrkB and (over)activation of the BDNF/TrkB signaling pathway is implicated in various solid malignancies and associated with poor prognosis due to the role of TrkB in suppressing anoikis and promoting epithelial-mesenchymal transition. Here we present the development and characterization of novel T cell engagers targeting TrkB. A panel of 41 sequence unique antibodies were selected from human phage display libraries and B cells of TrkB-ECD immunized chicken. Following recombinant expression, the panel of antibodies was analyzed for off-rate, binding reactivity to plate-immobilized and cell-expressed TrkB, cross-reactivity to other tropomyosin kinase family members, and competition with BDNF. Based on their characteristics, two targeting arms were prioritized for the generation of T cell engagers using a standard bispecific knob-into-hole approach. Apart from a commercial CD3 targeting arm, three proprietary CD3 targeting arms were also analyzed. After successful production of the bispecifics , the molecules were validated to bind to plate-immobilized TrkB and CD3 separately and cell-associated TrkB and CD3 simultaneously. In addition, our TrkB T cell engagers were able to induce varying levels of T cell activation in vitro. Our data suggests that these TrkB/CD3 bispecific molecules could be interesting candidates for further development into immuno-oncology therapeutics.
Citation Format: Jetta Bijlsma, Srinidhi Desikan, Timothy Miller, Allie Thom, Jennifer Bath, Ilse Roodink. Bispecific T cell engagers targeting TrkB [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1890.
Abstract 190: Personalized identification of cancer treatments in real-time: TumOC - a tumor organoid-on-chip platform for online cell vitality measurements
Authors: Flechner Marie , Loskutov Juergen , Nadolny Madeleine , Pfohl Ulrike , Regenbrecht Christian R. , Uhlig Katja , Wedeken Lena 
Published: April 2023

Abstract
Enhanced, physiologically relevant in-vitro tumor models significantly increase the success rate in new drug development, reduce the number of animal experiments and result finally in better therapies for cancer patients. Furthermore, they have the potential to offer new approaches to personalized oncology. In recent years, 3D cell cultures were established as relevant preclinical cancer models, suitable for high-throughput-screening. However, their capacity to model and/or measure physiological processes can still be enhanced. Colorectal carcinomas (CRC) are one of the most common malignant tumors. Due to its heterogeneity and high probability to metastasize, the disease is often incurable and novel, improved therapies are urgently needed. In this project, we developed a tumor organoid-on-chip platform (TumOC) by combining most recent technological advances: We integrated CRC patient-derived 3D cell cultures (organoids) and microsensor particles that enable assessment of cell vitality in real time by measuring oxygen concentration in a microfluidic system. The resulting TumOC platform allows for defined exposition of cytostatic drugs including dynamic and combination treatments. Measurements of cell vitality in real time enables analysis of not only the final effect of a drug treatment, but also the kinetics of drug response. At the same time, utilizing organoids allows for recapitulating tumor architecture and heterogeneity. Using the TumOC platform, we measured the cell vitality in real time over several days during treatment with classic chemotherapeutics or targeted cancer drugs and compared the results to end-point measurements on the same organoids in a static system. We assessed the effect of intra- and intertumoral heterogeneity and developed a protocol for treatment with clinically used combination regimes. In conclusion, our TumOC platform with its ability to recapitulate tumor heterogeneity in combination with dynamic treatments and real-time cell vitality assessment is an in-vitro tumor model closely recapitulating the physiological situation in a patient. TumOC provides an impressive opportunity to test and, consequently, predict the effectiveness of anti-cancer therapies. Therefore, this system is of interest not only for pre-clinical drug development but also for personalized oncology.
Citation Format: Marie Flechner, Juergen Loskutov, Madeleine Nadolny, Ulrike Pfohl, Christian R. Regenbrecht, Katja Uhlig, Lena Wedeken. Personalized identification of cancer treatments in real-time: TumOC - a tumor organoid-on-chip platform for online cell vitality measurements [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 190.
Abstract 192: A novel and rapid patient-derived organoid breast cancer platform for precision medicine
Authors: Graham David M. , Rupprecht Gabrielle , Bankaitis Eric D. , Force Jeremy M. , Watlington Wylie , Metzger Steven W. , Shen Xiling , Hsu David 
Published: April 2023

Abstract
An increasing number of studies performing correlative drug screens on patient-derived organoids (PDO) are revealing enormous potential for these models in predicting patient response to therapy. Despite this, their future use in a clinical setting is hindered by intrinsic limitations of PDO models, namely low success rates in establishing growing cell cultures from tumor tissue samples and long return times for drug response data that fall outside timescales of clinical actionability. To address these limitations, we leveraged technological advances in emulsion-based microfluidics and droplet generators to develop MicroOrganoSpheres (MOS) - microscale environments containing tumorspheres that retain structural, cellular, and genetic properties of an individual patient’s diseased tissue. Here, we focused on generating MOS from breast cancer tissue biopsies and resections across different subtypes of breast cancer. We established over 30 unique patients’ breast MOS samples at an average of 80% success, with the majority of these samples being hormone receptor positive (ER+/PR+) - the most clinically lethal and challenging subtype to establish. We evaluated MOS dose-responses across several first line standard of care chemotherapies for breast cancer. For this, we created a semi-automated workflow paired with high-content imaging for quantifying dose responses and tracking longitudinal cell dynamics during dosing. We generated dose response data for MOS samples, being able to move from primary tissue samples to MOS to drug dosing data within a clinically relevant timescale of 2-3 weeks. We conclude that our platform demonstrates the feasibility of 1) efficiently establishing MOS from breast cancer patient tumor samples from different subtypes and 2) performing drug dosing studies on these samples with improved turnaround times that enable clinical actionability for the patient. Together, these findings provide a foundation for evaluating this technology as a diagnostic tool in future clinical settings.
Citation Format: David M. Graham, Gabrielle Rupprecht, Eric D. Bankaitis, Jeremy M. Force, Wylie Watlington, Steven W. Metzger, Xiling Shen, David Hsu. A novel and rapid patient-derived organoid breast cancer platform for precision medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 192.
Abstract 1922: PhyloFrame: A machine learning framework for ancestry agnostic disease signatures
Authors: Smith Leslie A. , Cahill James A. , Graim Kiley 
Published: April 2023

Abstract
Rapid advancements in genomic sequencing technologies have catalyzed the molecular identification and treatment of previously elusive diseases. Despite these genomic advancements, disparities in precision medicine access and data have resulted in disparate impacts on different socioeconomic groups. Many of the gold standard datasets largely exclude minority populations, compounding their exclusion from medical research. This has resulted in a restricted understanding of cancer and other complex diseases. We demonstrate the effects of ancestral bias in gold standard genomics datasets through ancestral analysis of cancer-related genes in the Cancer Gene Census, spanning 17 ancestral populations. Additionally, we present a machine learning framework, PhyloFrame, that incorporates population genomics data to correct for ancestral bias by creating disease signatures representative of all ancestries. Our ancestral analysis results show that while a majority of the current cancer-related genes in the Cancer Gene Census have below average mutation frequency in non-European populations, there are peaks of ancestrally enriched mutations in ancestry-specific genes related to cancer, which can be targeted using PhyloFrame. PhyloFrame prioritizes gene expression from the cancer genes with high frequency mutations in a given human population in order to capture genes driving disease in each ancestry. It builds on existing disease gene signatures and big-data functional interaction networks to identify ancestry-relevant genes related to a disease, outputing an ancestry-agnostic disease signature. We test PhyloFrame on TCGA cancers with diverse patient populations, such as breast cancer, and compare PhyloFrame's disease signature output to the disease signature output of elastic net runs on cancer samples from a single ancestry. Our results demonstrate that the incorporation of ancestral information allows PhyloFrame to recapitulate disease signatures trained on only one ancestry in a dataset with individuals from many unquantified ancestries. With the incorporation of ancestral information, PhyloFrame is able to create disease signatures with genes pertinent to each ancestral population, even when individuals from those populations are not included in the training data. This work offers a quick and cheap alternative to the mass sequencing that would be required to capture disease-driving genes in minority populations in hopes to contribute to equitable representation in medical research.
Citation Format: Leslie A. Smith, James A. Cahill, Kiley Graim. PhyloFrame: A machine learning framework for ancestry agnostic disease signatures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1922.