bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3411: Proof of concept study of next generation drug screening platform for glioma patients
Authors: Her Nam-Gu , El-Heliebi Amin , Lee Gi Ju , Park San Ha , Prietl Barbara , Ahn Stephanie S. , Toh Hong Boon , Pieber Thomas R. , Nam Do-Hyun 
Published: April 2023

Abstract
Precision medicine endeavors to match patients to therapies mostly on the basis of the genomic alterations in their tumors. However, it has been shown that ‘genomics only’ approach is often insufficient for best drug selection. Functional precision medicine has been recently emerging as it provides directly translatable information on which drug to choose among available drugs. Traditionally, cancer drugs are tested in cancer cell line models, but cell lines cannot represent individual clinical patients and are too biologically pronounced to be useful for drug screening purposes. Our patient-derived cell (PDC) drug screening system overcomes these points and can generally also correlate with genome changes. AVATAMED and CBmed, together with AimedBio, are collaborating in a Precision Cancer Project, set out next generation drug screening platform to screen Austrian glioma patients for proof-of-concept study. Fresh native tissue from both low- and high-grade glioma are collected. Tumor tissue is used for PDC isolation using mechanical and enzymatic tissue dissociation. To preserve the original tumor similarity, tissue is short term cultured under two weeks, and PDCs are seeded and treated with a panel of clinical- and preclinical drugs followed by viability assessment. We have cultured 65 PDCs from both low- and high-grade glioma. Tissue culture success rate and drug screening success rate was &gt;85% suggesting that specimen logistics and tissue processing are well-established and conducted. PDCs were treated with 79 drugs that are commonly used in clinical setting. In order to evaluate the quality of the results, the screening was conducted at two different sites, AimedBio and CBmed, and the data were compared. Overall, high accuracy and reproducibility were confirmed by low Coefficient of Variation (CV) between replicates and high Z-factor between negative and positive controls. In addition, data generated from both sites showed high correlations. Collectively, our next-generation drug screening platform shows the potential to give the best therapeutic options to glioma patients. To this end, we are moving forward use this platform in clinical study.
Citation Format: Nam-Gu Her, Amin El-Heliebi, Gi Ju Lee, San Ha Park, Barbara Prietl, Stephanie S. Ahn, Hong Boon Toh, Thomas R. Pieber, Do-Hyun Nam. Proof of concept study of next generation drug screening platform for glioma patients [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 3411.
Abstract 3426: Catalytic degraders effectively address kinase site mutations in EML-ALK oncogenic fusions
Authors: Gao Yang , Jiang Baishan , Kim Hellen , Che Jianwei , Donovan Katherine , Hatcher John , Huerta Fidel , Kwiatkowski Nicholas , Liu Yingpeng , Liuni Peter , Metivier Rebecca J. , Murali Vineeth , Nowak Radosław , Zhang Tinghu , Fischer Eric , Gray Nathanael , Jones Lyn 
Published: April 2023

Abstract
Heterobifunctional degraders, known as proteolysis targeting chimeras (PROTACs), is an emerging modality for drug discovery, and theoretically possess catalytic mode-of-action, yet few studies have either confirmed or exploited this potential advantage of event-driven pharmacology. Degraders of oncogenic EML4-ALK fusions were developed by conjugating ALK inhibitors to cereblon ligands guided by computational models. To study the sub-stoichiometric capacity of the degrader molecules, simultaneous optimization of pharmacology and compound properties using ternary complex modeling and physicochemical considerations yielded multiple catalytic degraders that were more resilient to clinically relevant ATP-binding site mutations than parental kinase inhibitor drugs. Using HiBiT assay to assess the target degradation and NanoBRET for target occupancy, we illustrated the concept of catalytic degradation of EML4-ALK. Our strategy culminated in the design of the orally bioavailable derivative CPD-1224 that avoided hemolysis (a feature of detergent-like PROTACs), degraded the otherwise recalcitrant compounded mutant L1196M/G1202R in vivo, and commensurately slowed tumor growth, while the third generation ALK inhibitor drug lorlatinib had no effect. These results validate our original therapeutic hypothesis by exemplifying opportunities for catalytic degraders to proactively address binding site resistant mutations in cancer.
Citation Format: Yang Gao, Baishan Jiang, Hellen Kim, Jianwei Che, Katherine Donovan, John Hatcher, Fidel Huerta, Nicholas Kwiatkowski, Yingpeng Liu, Peter Liuni, Rebecca J. Metivier, Vineeth Murali, Radosław Nowak, Tinghu Zhang, Eric Fischer, Nathanael Gray, Lyn Jones. Catalytic degraders effectively address kinase site mutations in EML-ALK oncogenic fusions [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 3426.
Abstract 3452: TNG908, a brain-penetrant MTA-cooperative PRMT5 inhibitor, is efficacious in preclinical glioblastoma models
Authors: Zhang Minjie , Tsai Alice , Cottrell Kevin M. , Haines Brian B. , Wilker Erik , DiBenedetto Heather , Weitzman Ron , Huang Alan , Davis Charles B. , Maxwell John P. , Briggs Kimberly J. 
Published: April 2023

Abstract
Glioblastoma multiforme (GBM) is one of the most aggressive primary malignant brain tumors in adults. The median overall survival (OS) of GBM patients is poor (1-2 years) on standard of care therapies, which include surgery, radiotherapy, and the alkylating agent temozolomide. Therefore, developing new treatments for GBM is an urgent unmet medical need. TNG908 is a clinical stage MTA-cooperative PRMT5 inhibitor that inhibits PRMT5 activity selectively in MTAP-null cells leveraging a synthetic lethal interaction. Approximately 40% of GBM tumors are homozygous null for MTAP [1, 2]. In preclinical in vitro studies, the antiproliferation activity of TNG908 was 15 times more potent in MTAP-null cancer cell lines than in MTAP WT cells. TNG908 has high passive permeability and is not a substrate for P-glycoprotein nor Breast Cancer Resistant Protein efflux transporters, attributes which are favorable for crossing the blood-brain barrier. TNG908 demonstrated in vivo brain penetration in multiple preclinical studies, including non-human primates and mice, suggesting that TNG908 may fulfill the significant unmet need in the treatment of GBM. Pharmacodynamic activity of TNG908 to inhibit PRMT5 was demonstrated by decreased SDMA-modified protein levels in a dose-dependent manner in a GBM xenograft model. TNG908 demonstrated dose-dependent antitumor activity in multiple hyper- and hypomethylated GBM subcutaneous models, including cell lines and patient-derived xenograft models. Despite reduced Kpuu in rodents compared to primates, oral administration of TNG908 drove near tumor stasis and increased median survival by 3-fold in a highly aggressive murine GBM orthotopic model. In summary, TNG908 is a potent, brain-penetrant small molecule PRMT5 inhibitor that is selective for MTAP-null tumor cells with good drug-like properties and strong antitumor activity in preclinical models of GBM. As such, TNG908 may provide a novel treatment strategy for MTAP-deleted GBM patients. *MZ and AT contributed equally to the work.
Reference: 1.Cerami et al., Cell, 2013. 2.Gao et al., Sci Signal, 2013
Citation Format: Minjie Zhang, Alice Tsai, Kevin M. Cottrell, Brian B. Haines, Erik Wilker, Heather DiBenedetto, Ron Weitzman, Alan Huang, Charles B. Davis, John P. Maxwell, Kimberly J. Briggs. TNG908, a brain-penetrant MTA-cooperative PRMT5 inhibitor, is efficacious in preclinical glioblastoma models [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 3452.
Abstract 3551: Single-cell characterization of pediatric T-cell acute lymphoblastic leukemia transcriptomes
Authors: Pushel Irina , Yoo Byunggil , Louiselle Daniel , Gibson Margaret , Farooqi Midhat S. , August Keith 
Published: April 2023

Abstract
Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is a rare cancer with a diverse set of causative genomic abnormalities. The variety and limited characterization of genomic mechanisms underlying this disease presents a unique challenge for the development of improved treatments for these patients. Using the 10x Genomics Chromium system, we have generated single-cell gene expression (scRNA) and chromatin accessibility (scATAC) data for blood and/or bone marrow samples collected at diagnosis from eight pediatric T-ALL patients. We sequenced 21,669 high-confidence cells and performed normalization and downstream analysis using the Seurat v4.0.2 package in R 4.0.3. Our data show that patient cancer cells show highly individual transcriptomes and are often characterized by combinatorial expression patterns of genes including MEF2C, BCL11B, HOXA9, NKX2-1, and LMO2, which have been previously implicated for their roles in various T-ALL subtypes. Additionally, we observe that each patient has a unique ratio of cancer cells with a CD4+ T-cell, CD8+ T-cell, and hematopoietic stem cell-like identity, which may be linked to treatment response and patient outcome. This dataset represents one of the first forays into exploring the biology of pediatric T-ALL at the single-cell level. Our comparative analysis of patient cancer cells reveals novel insights into the transcriptional and chromatin-related for distinct subsets of pediatric T-ALL cases, paving the way for future treatment selection and drug development to improve outcomes for these patients.
Citation Format: Irina Pushel, Byunggil Yoo, Daniel Louiselle, Margaret Gibson, Midhat S. Farooqi, Keith August. Single-cell characterization of pediatric T-cell acute lymphoblastic leukemia transcriptomes. [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 3551.
Abstract 3569: An animal model of GLI2-amplified medulloblastoma
Authors: Pei Yanxin 
Published: April 2023

Abstract
Medulloblastoma (MB) is the most common malignant brain tumor affecting children. Among the known subtypes of MB, GLI2-amplified SHH-MB associated with P53 mutations has the worst prognosis, and a 5-year survival rate of less than 30%. Moreover, GLI2-amplified MBs are non-responsive to SMO inhibitors, the only targeted treatment option available for SHH-MB. To address this treatment gap, there is an urgent need to identify novel potential therapeutic targets, an effort that requires better understanding of key cellular and molecular mechanisms underlying GLI2-amplified MB. To that end, we generated a mouse model of GLI2-amplified MB and identified GL12 as the critical driver of tumorigenesis, and granule cell progenitors (GCPs) as the cells of tumor origin. We further found that GLI2 specifically drives embryonic, but not neonatal, Math1+ GCPs to form SHH-MB tumors. An scRNA-seq analysis revealed MAPK pathway activation specifically in embryonic Math1+ GCPs. The MAPK pathway was activated in mouse and human GLI2-driven MB tumors, and a MEK/ERK inhibitor significantly inhibited GLI2-driven MB in vivo. Based on these findings, we hypothesize that GLI2-driven MB originates from a specific population of Math1+ GCPs during a discrete temporal interval in cerebellar development, and that targeting MAPK/MEK/ERK pathway components represents a novel approach to treatment of GLI2-amplified MB.
Citation Format: Yanxin Pei. An animal model of GLI2-amplified medulloblastoma. [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 3569.
Abstract 3580: Noninvasive immuno-PET imaging of CD8+T cell behavior in tumor bearing mice models treated with SAR444245
Authors: d'Heilly Sebastion , Tirode Fabrice , Gaulin Maxime , Anne Dudzicki , Bluet Guillaume , Guerif Stéphane , Descamps Francis , Casteels Peter , Li Xiangming , Wang Rui , Meng Robin , Jouannot Erwan 
Published: April 2023

Abstract
SAR444245 (formerly THOR-707) is a site-specific pegylated recombinant human IL-2 molecule which blocks IL-2R alpha-binding while retains near-native affinity for beta/gamma IL-2 receptor subunits. SAR444245 reduces B16-F10 tumor proliferation in C57BL/6 mice and induces a short transient migration of CD8+ T and NK cells from peripheral blood to lymphoid organs before a strong proliferation (Ptacin et al, Nat Commun 2021). Here we report CD8+ T cells imaging post SAR444245 as monotherapy in naive and tumor bearing mice using nuclear imaging. An anti-murine CD8+ PET probe was injected in mice 24 hours post SAR444245 administration and nuclear imaging was performed at different times over 6 days. In C57BL/6 naive and in poorly immunogenic B16-F10 tumor bearing animals, images reveal a decreased Standardized Uptake Value (SUV) within blood in treated animals at 3mg/kg compared to control ones. In parallel, blood SUV Ratio (SUVR) increases within spleen, lymph nodes and thymus after SAR444245 injection compared to control mice. On tumor site, a stronger SUVR is measured at 144 hours post injection in SAR444245 treated group than in the control group. A dose escalation ranging from 1 to 6 mg/kg of SAR444245 was performed in highly immunogenic CT26 tumor bearing animal. Blood SUV decreases in the treated groups compared to the control group. In lymphoid organs, all SUVR increase at 144 hours post injection in the treated groups compared to the control one. In CT26 tumors, a slight increase of the SUVR is observed for groups treated at 3 and 6 mg/kg. In parallel, a pronounced reduction of tumor growth is observed in the treated group at 6mg/kg. These studies non-invasively confirm the mode of action of SAR444245 with a rapid relocation of CD8+ T cells from peripheral blood to lymphoid organs and tumor site.
Citation Format: Sebastion d'Heilly, Fabrice Tirode, Maxime Gaulin, Dudzicki Anne, Guillaume Bluet, Stéphane Guerif, Francis Descamps, Peter Casteels, Xiangming Li, Rui Wang, Robin Meng, Erwan Jouannot. Noninvasive immuno-PET imaging of CD8+T cell behavior in tumor bearing mice models treated with SAR444245. [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 3580.
Abstract 3583: Novel MRI contrast system using halloysite nanotubes embedded with iron-platinum nanoparticles for the regulation of the CHST11 expression for cancer treatment
Authors: Chan Ming-Hsien , Li Chien-Hsiu , Chang Yu-Chan , Hsiao Michael 
Published: April 2023

Abstract
Topic: TB Tumor Biology (TB03) In Vivo Imaging.
Multifunctional nanocomposites have been a popular research target in recent years. This research aims to produce magnetic nanocomposites with high saturation magnetization (Ms) and good biocompatibility to improve the disadvantage of iron-oxide was easy decomposition in the biological environment and overcome the unclear contrast problem of T2-weighted magnetic resonance imaging (MRI) of lung adenocarcinoma. In order to fit the suitable size of iron-based nanoparticles embedded into the halloysite nanotubes (HNT), the iron-platinum (FePt) nanoparticles were chosen as the MRI’s core materials. The FePt@HNT nanocomposites have low toxicity, and superparamagnetism is expected to be used in biomedical therapy and magnetic separation for disease treatment and environmental protection. Lung adenocarcinoma cancer cells grow in situ, usually invade, and are frequently recurrent after treatment. Since CHST11-mediated gene regulation may serve as a possible means of reducing tyrosine kinase inhibitor (TKI)-induced mitotic cell death, CHST11 modulation of integrin signaling may help lung cancer cells enhance their resistance to gefitinib. To enable the FePt@HNT nanocomposite to be effective in treating lung tumors, we designed miRNAs that inhibit CHST11 expression in an attempt to diagnose lung adenocarcinoma concurrently for treatment.
Keywords: Magnetic resonance imaging, halloysite nanotubes, FePt nanoparticles, CHST11, Lung adenocarcinoma
References
1. Zhou T, Jia L, Luo YF, Xu J, Chen RH, Ge ZJ, et al. Multifunctional nanocomposite based on halloysite nanotubes for efficient luminescent bioimaging and magnetic resonance imaging. Int. J. Nanomed. 2016;11:4765-76.
2. Abdullayev E, Joshi A, Wei WB, Zhao YF, Lvov Y. Enlargement of Halloysite Clay Nanotube Lumen by Selective Etching of Aluminum Oxide. ACS Nano 2012;6:7216-26.
Citation Format: Ming-Hsien Chan, Chien-Hsiu Li, Yu-Chan Chang, Michael Hsiao. Novel MRI contrast system using halloysite nanotubes embedded with iron-platinum nanoparticles for the regulation of the CHST11 expression for cancer treatment. [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 3583.
Abstract 3595: Epigenetic driven IL32 expression contributes to a JNK related cell stress response in breast cancer stem cells to promote cellular invasion
Authors: Wilson Megan A. , Benson Elayne M. , Gray Emma , Cairns Paige , Ouzounova Maria , Korkaya Hasan , Shull Austin Y. 
Published: April 2023

Abstract
Metastatic potential in basal-like breast cancers typically correspond with increased enrichment of EpCAM-/CD49f- cancer stem cells (CSC). With this premise in mind, it is important to better understand the mechanistic driver of these cell populations and their distinctive potential to interact with the tumor microenvironment (TME) for cancer promotion. Previous work from our lab has compared the 450K DNA methylation profile of EpCAM-/CD49f- poor breast cancer cell lines to that of EpCAM-/CD49f- enriched breast cancer cell lines and found the IL32 promoter to be hypomethylated in EpCAM-/CD49f- enriched cell lines, a result which corresponded basal-like patient samples in TCGA. By identifying IL32 being differentially regulated in CSC-enriched cell lines, we further sought to characterize IL32’s role in breast cancer aggressiveness. We first were able to identify several overarching mechanisms altered in siIL32 treated SUM15PT cells by RNAseq differential expression analysis (FDR p-value &lt;0.01). Most notable from our RNAseq results was the significant enrichment of upregulated pathways involved in extracellular matrix (ECM) organization as well as significant enrichment of downregulated pathways involved in cellular and replicative stress responses. Particular examples of transcripts differentially expressed between control and siIL32-treated SUM159PT cells included COL6A1, ITGB3, and CD24 that were upregulated as well as NQO1, HMOX1, and CXCL2/CXCL3 that were downregulated. Furthermore, IL32 suppression decreased SUM159PT invasion in both an ECM-matrix cell invasion assay and a chick CAM xenograft/angiogenesis model. From our RNAseq results, we then performed a multi-pathway protein phosphorylation array to determine whether any key signaling events were affected by siIL32 knockdown in SUM159PT cells. Based on this approach, we were able observe a significant decrease in phosphorylated JNK and phosphorylated NFKB in siL32-treated cells when compared to control, both of which are well-established events that can coordinate both cell stress responses and cellular invasion. Collectively, our results reflect the notion that differential IL32 expression by promoter hypomethylation in breast CSCs plays a role to mitigating intracellular stress and subsequently allowing for breast cancer cell invasion and metastasis.
Citation Format: Megan A. Wilson, Elayne M. Benson, Emma Gray, Paige Cairns, Maria Ouzounova, Hasan Korkaya, Austin Y. Shull. Epigenetic driven IL32 expression contributes to a JNK related cell stress response in breast cancer stem cells to promote cellular invasion. [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 3595.
Abstract 3598: Cooperative NF-KappaB and Notch1 signaling promotes a macrophage-mediated metastatic phenotype in breast cancer
Authors: Duran Camille L. , Karagiannis George S. , Chen Xiaoming , Sharma Ved P. , Entenberg David , Condeelis John S. , Oktay Maja H. 
Published: April 2023

Abstract
Metastasis is a multistep process that leads to the formation of clinically detectable tumor foci at distant organs and, frequently, to patient demise. Only a subpopulation of breast cancer cells within the primary tumor can disseminate systemically and cause metastasis. To disseminate, cancer cells must express MenaINV, an isoform of the actin-regulatory protein, Mena, encoded by the ENAH gene that endows tumor cells with transendothelial migration activity allowing them to enter and exit the blood circulation. We have previously demonstrated that MenaINV mRNA and protein expression is induced in cancer cells by macrophage contact. Here, we report on the discovery of the precise mechanism by which macrophages induce MenaINV expression in tumor cells. We examined the promoter of the human and mouse ENAH gene and discovered a conserved NF-κB transcription factor binding site. Using live imaging of an NF-κB activity reporter and staining of fixed tissues from mouse and human breast cancer we further determined that, for maximal induction of MenaINV in cancer cells, NF-κB needs to cooperate with the Notch1 signaling pathway. Mechanistically, Notch1 signaling does not directly increase MenaINV expression, but instead enhances and sustains NF-κB signaling through retention of p65, an NF-κB transcription factor, in the nucleus of tumor cells, leading to increased MenaINV expression. In mice, these signals are augmented following chemotherapy treatment and abrogated upon macrophage depletion. Targeting Notch1 signaling in vivo decreased NF-κB signaling and MenaINV expression in the primary tumor and decreased metastasis. Altogether, these data uncover mechanistic targets for blocking MenaINV induction that should be explored clinically to decrease cancer cell dissemination and improve survival of patients with metastatic disease.
Citation Format: Camille L. Duran, George S. Karagiannis, Xiaoming Chen, Ved P. Sharma, David Entenberg, John S. Condeelis, Maja H. Oktay. Cooperative NF-KappaB and Notch1 signaling promotes a macrophage-mediated metastatic phenotype in breast cancer. [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 3598.