bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2682: Small molecule targeting the lipoic acid post-translational modification impacts proliferation of colorectal and PIK3CA-mutant cell lines
Authors: Doherty Laura , Sangpo Tenzin , Tsvetkov Peter , Davis John , Dianati Navid , Schwede Wolfgang , Zimmermann Katja , Evans Laura , Amatucci Aldo , Seidel Henrik , Kamburov Atanas , Akcay Gizem , Golub Todd , Eheim Ashley , Burkhardt Nils , Eis Knut , Christian Sven , Rees Matt , Roth Jennifer 
Published: June 2022

Abstract
To identify novel therapeutic targets, we utilize the PRISM platform, a multiplexed cell line viability technology of 500 solid tumor cell lines and correlate responses to functional genomic and baseline genetic data. We describe ESD0140656, a small molecule with selective anti-proliferative effect on colorectal and PIK3CA-mutant cell lines. Response to ESD0140656 is correlated to sensitivity to CRISPR/Cas9 KO of components of the protein lipoylation pathway and OGDH complex members, which catalyze a step of the TCA cycle. Lipoylation is a rare post-translational modification attached to just four enzymes in humans, including the OGDH complex. Knockout of the protein that transfers lipoic acid to these four enzymes (LIPT1) sensitizes cells to ESD0140656, and ESD0140656 treatment leads to reduction of lipoic acid in cells. These results suggest ESD0140656 targets the lipoylation pathway and may represent a novel therapeutic angle for colorectal and PIK3CA-mutant tumors.
Citation Format: Laura Doherty, Tenzin Sangpo, Peter Tsvetkov, John Davis, Navid Dianati, Wolfgang Schwede, Katja Zimmermann, Laura Evans, Aldo Amatucci, Henrik Seidel, Atanas Kamburov, Gizem Akcay, Todd Golub, Ashley Eheim, Nils Burkhardt, Knut Eis, Sven Christian, Matt Rees, Jennifer Roth. Small molecule targeting the lipoic acid post-translational modification impacts proliferation of colorectal and PIK3CA-mutant cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2682.
Abstract 2692: Identification of functional single nucleotide polymorphisms in cryptic exon 3 of the androgen receptor gene
Authors: Van Goubergen Jasper , Handle Florian , Cronauer Marcus V. , Santer Frédéric R. 
Published: June 2022

Abstract
Castration resistant prostate cancer (CRPC) involves the upregulation of androgen receptor variants (AR-Vs), of which AR-V7 is clinically the most relevant. By lacking the ligand-binding domain, AR-V7 is constitutively active and may therefore bypass AR signaling inhibitors. Treating CRPC involves improved AR signaling inhibitors or taxane-based chemotherapy. However, the optimal treating sequence may differ from patient to patient. The presence of AR-V7 in the nucleus of circulating PCa cells, which is associated with AR targeted therapy resistance, is used as a therapy-guiding biomarker. This stratification has a high predictive power and specificity, but its sensitivity is unsatisfying and can only be done by highly specialized laboratories. A PCR/sequencing based test would improve the sensitivity of this biomarker, but it requires a better understanding of AR-V7’s functional regulation. Therefore, we aim here to analyze single nucleotide polymorphisms (SNPs) in the 3’ untranslated region (UTR) of AR-V7 that might have an impact on AR-V7’s expression and/or functional activity.
The LD trait tool of NIH was used to search for trait association with AR cryptic exon (CE3) SNPs. Four RNA binding motif databases (oRNAment, ATtRACT, RBP map, and RBPDB) and SpliceAid v2 were used for evaluating SNPs in their capacity to alter motifs. By CRISPR/CAS9 mediated non-homologous end joining (NHEJ) these predictions were assessed experimentally using qPCR and Westen Blot.
SNP rs5918762 was selected as it is in linkage disequilibrium with several PCa tagSNPs (rs5919393, rs5919432). rs5918762T/C is characterized by an unequal minor allele frequency (MAF) distribution among different populations. Using an in silico approach, this SNP is predicted to destroy/create a binding site for the splicing machinery involved protein SRSF9. Disrupting this SNP region via NHEJ resulted respectively in an increased and decreased expression of AR-FL and AR-V7 mRNA in 22RV1 cells (C allele). Additionally, analysis of the SU2C dataset (CRPC patients) correlated SRSF9 expression with AR-V7 expression. Subsequently, SRSF9 knock out (KO) resulted in reduced AR-V7 mRNA expression.
Our data suggests that SNP rs5918762T/C is located in a region important for CE3 inclusion during AR splicing, which might involve SRSF9. Further validation of these results is in need and encompasses splicing assays by an AR-V7 mini-gene assay, protein-RNA interaction assays and an analysis of a lack of effect in cell lines expressing the T allele.
Citation Format: Jasper Van Goubergen, Florian Handle, Marcus V. Cronauer, Frédéric R. Santer. Identification of functional single nucleotide polymorphisms in cryptic exon 3 of the androgen receptor gene [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2692.
Abstract 2711: Repurposing CAR targets in solid tumors from pan-cancer single-cell RNA-seq data
Authors: Madan Sanna , Schäffer Alejandro , Ruppin Eytan 
Published: June 2022

Abstract
Chimeric antigen receptor (CAR) T cell therapy is a powerful and promising tool for unleashing lasting antitumor immunity, which is currently studied in numerous blood and solid cancers. Here, mining single cell transcriptomics datasets of solid tumors, we survey many existing CAR targets, aiming to identify new solid tumor types in which these targets are differentially expressed in tumor cells and not on non-tumor cells within the tumor microenvironment, thus providing new repurposing opportunities. Quite surprisingly, we find that many existing solid cancer CAR targets have a better discriminatory power in uncharted cancer types than in the ones they have been developed or being tested for. Furthermore, we show that several existing liquid cancer CAR targets may also hold promise in specific solid tumors. Taken together, this analysis uncovers a large potential of repurposing current CARs that is currently yet untapped.
Citation Format: Sanna Madan, Alejandro Schäffer, Eytan Ruppin. Repurposing CAR targets in solid tumors from pan-cancer single-cell RNA-seq data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2711.
Abstract 2743: Tumor growth modeling and its applications in preclinical pharmacology studies to improve translatability of animal models
Authors: Zhou Huajun , Mao Binchen , Guo Sheng 
Published: June 2022

Abstract
Successful oncology drug development hinges on proper use of preclinical xenograft and allograft mouse models that faithfully reflect histopathology and genomic features of patient tumors and exhibit clinically similar drug response. For in vivo pharmacology studies, tumor-bearing mice are treated by drugs and efficacy is monitored by continuingly measuring tumor volumes over weeks or even months, resulting in mouse-specific tumor growth data. In our previous study, we used linear mixed model (LMM) to fit tumor growth data and demonstrated its superiority to simple readouts, such as tumor growth inhibition (TGI), in discovering biomarkers and exploring mechanism of action for drugs. Here we extended the study to more parametric statistical models on an expanded dataset with over 100 thousand tumor growth curves. Six parametric models (exponential, exponential square, Gompertz, Logistic, Monomolecular, and von Bertalanffy) were fit to tumor growth curves within a single-treatment group, by the least square method after variance stabilization transformation. Best models were selected by Akaike information criterion (AIC)-based confidence set. In the Irinotecan case study, logarithmic transformation of tumor volume converts exponential or exponential square models to mixed-effects linear models that integrate random effect of mouse difference within a treatment group, and are used to identify predictive biomarkers for drug efficacy. We compared three variance stabilization transformations and found that log transformation of tumor volume is appropriate for majority of tumor growth curves. In log transformed data, exponential or exponential square model can satisfactorily fit nearly all tumor growth curves, as 96.1% of best model confidence sets contain exponential or exponential square model, followed by von Bertalanffy (92.5%), Gompertz (92.1%), Logistic (90.5%), and Monomolecular (58.9%). The percentage of studies, in which all treatment groups can be best fit by exponential or exponential square model, is 91.3% (82.4% for von Bertalanffy, 81.4% for Gompertz, 79.1% for Logistic, 37.3% for Monomolecular). Thus, exponential or exponential square model can be applied to most in vivo mouse studies, and should be preferred for their mathematical simplicity and interpretability. We further demonstrated the utility of the modeling method on a 16-PDX-model study for Irinotecan to identify biological processes and pathways related to its mechanism of action.
Citation Format: Huajun Zhou, Binchen Mao, Sheng Guo. Tumor growth modeling and its applications in preclinical pharmacology studies to improve translatability of animal models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2743.
Abstract 2855: Antitumor activity of BAFF-R targeting CAR T-cells on chronic lymphocytic leukemia
Authors: Luo Yan , Lui Kaihin , To Tommy T. , liu Andrew , Yassine Farah , Dabaja Mohamed A. Kharfan , Gadd Martha E. , Qin Hong 
Published: June 2022

Abstract
B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in adults with CD19-targeting CAR T-cell therapy showing an excellent initial curative response. However, 10-20% of patients who receive anti-C19 CAR T-cell treatment experience relapse due to CD19 antigen loss. B-cell activating factor receptor (BAFF-R) that is expressed on the surface of normal and neoplastic B cells mediates the survival of mature peripheral B cells along with the B-cell receptor. Since B-CLL is characterized by apoptotic disruption and subsequent accumulation of mature B cells, BAFF-R is a logical, novel target for CAR T-cell therapy directed against B-CLL, especially if CD19 antigen loss occurs. In this study, we first manufactured BAFF-R CAR T-cells by infecting healthy donor Tnaïve/memory (Tn/mem) cells with BAFF-R CAR lentivirus before evaluating the antitumor activity of BAFF-R CAR T-cells on wild type MEC-1 (a B-CLL cell line), modified MEC-1, and primary cell lines. Antigen-specific cytotoxicity and activation of the BAFF-R CAR T-cells or control CD19 CAR T-cells were determined upon incubation with B-CLL cell lines and patient-derived primary B-CLL by measuring degranulation and IFN-γ release, respectively. BAFF-R CAR T-cells demonstrated substantial cytotoxicity against MEC-1, CD19-deficient MEC-1, and primary B-CLL cell lines; CD19 CAR T-cells showed no effect on CD19-deficient MEC-1 cells but did show effects with primary B-CLL and MEC-1 cells. Similarly, the release of IFN-γ was greater when BAFF-R CAR T-cells were co-cultured with CD19-deficient MEC-1 or primary B-CLL compared to CD19 CAR T-cells co-cultured with CD19-deficient MEC-1. In summary, BAFF-R CAR T-cells exert significant antitumor properties not only on patient-derived primary B-CLL cells but also on a CD19-deficient B-CLL cell line. We, therefore, assert BAFF-R-targeting CAR T-cells to be a novel therapeutic avenue for patients newly diagnosed with B-CLL and patients experiencing relapsed B-CLL after anti-CD19 therapy.
Citation Format: Yan Luo, Kaihin Lui, Tommy T. To, Andrew liu, Farah Yassine, Mohamed A. Kharfan Dabaja, Martha E. Gadd, Hong Qin. Antitumor activity of BAFF-R targeting CAR T-cells on chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2855.
Abstract 2886: Antigen internalization and its prevention during treatment with bispecific antibodies
Authors: Klimovich Maria , Zekri Latifa , Jung Gundram , Salih Helmut R. 
Published: June 2022

Abstract
Antigen-mediated antibody internalization is an important factor influencing kinetics and efficacy of antibody-based therapeutics. Antibodies directed against HER2, CD20, FLT3, EGFR, CD10 and CD22 have been shown to undergo internalization upon binding to their target antigens. Although antibody-induced internalization may be desirable under some circumstances, for example in case of antibody-drug conjugates, it can subvert the therapeutic efficacy of ADCC-inducing antibodies and bispecific antibodies (bsAbs) aiming to mobilize T cells against cancer. Here we examined the turnover of PSMA, a target antigen widely used for diagnostic and therapeutic interventions in prostate cancer. As a model system, we used prostate cancer cell lines expressing varying levels of PSMA in functional analyses with our PSMAxCD3 bsAb CC-1 which is currently being evaluated in two clinical trials (NCT04104607 and NCT04496674). Antigen internalization kinetics was analyzed by flow cytometric-internalization assays and live-cell imaging of antibody internalization. These analyses revealed that surface PSMA expression is rapidly downregulated after binding of PSMAxCD3 bsAb. Internalization occured in a dose-dependent manner, with complete negativity observed at concentrations ≥0.1 µg/ml. After withdrawal of the bsAb, antigen surface levels were fully restored within 24 hours. PSMA internalization was found to be partially prevented by inhibiting clathrin-dependent endocytosis. Currently, we are screening various clinically approved clathrin-dependent endocytosis inhibitors (e.g. statins and chloroquine) to identify compounds for combinatorial approaches to prevent undesired PSMA internalization in patients receiving PSMAxCD3 bsAbs. Altogether, our results document the involvement of clathrin-dependent endocytosis in bsAbs-driven PSMA internalization and provide a basis for combinatorial approaches to increase the efficacy of PSMA-directed therapeutics.
Citation Format: Maria Klimovich, Latifa Zekri, Gundram Jung, Helmut R. Salih. Antigen internalization and its prevention during treatment with bispecific antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2886.
Abstract 2887: Three dimensional colon cancer organoids model the response to CEA CD3 T cell engagers
Authors: Teijeira Alvaro , Migueliz Itziar , Garasa Saray , Bacac Marina , Klein Christian , Melero Ignacio 
Published: June 2022

Abstract
Rationale: The CEA-CD3 T cell bispecific antibody cibisatamab (CEA-TCB) is currently undergoing clinical trials. Here we study its performance against three-dimensional tumor organoids in cocultures with T cells as compared to a higher affinity CEACAM5-CD3 (CEACAM5-TCB) bispecific antibody using time-lapse confocal microscopy.
Methods: Pre-labelled spheroids derived from colon cancer cell lines and primary organoids derived from four colorectal cancer surgical specimens, which expressed different graded levels of CEA, were exposed in cocultures to T lymphocytes. Cocultures were treated with CEA-CD3 T-cell engagers and were followed by live confocal microscopy. Caspase 3 activation detected in real-time was used as an indicator of tumor cell death. Co-cultures were also set up with autologous tumor-associated fibroblasts to test the co-stimulatory effect of a fibroblast activated protein (FAP)- targeted 4-1BBL bispecific antibody fusion protein currently undergoing clinical trials.
Results: Tumor-cell killing of 3D colon carcinoma cultures was dependent on the levels of surface CEA expression, in such a way that the lower affinity agent (CEA-TCB) did not mediate killing by human preactivated T cells below a certain CEA expression threshold, while the high affinity construct (CEACAM5-TCB) remained active on the low CEA expressing organoids. Modelling heterogeneity in the levels of CEA expression by coculturing CEA high and low organoids showed measurable but weak bystander killing. Cocultures of tumor organoids, autologous fibroblasts and T cells allowed to observe a costimulatory effect of anti-FAP-4-1BBL both to release IFNγ and to attain more efficacious tumor cell killing.
Conclusion: Three-dimensional tumor cocultures with T cells using live confocal microscopy provide suitable models to test the requirements for colon-cancer redirected killing as elicited by CEA-targeted T-cell engagers undergoing clinical trials and treatment allow combinations to be tested in a relevant preclinical system.
Citation Format: Alvaro Teijeira, Itziar Migueliz, Saray Garasa, Marina Bacac, Christian Klein, Ignacio Melero. Three dimensional colon cancer organoids model the response to CEA CD3 T cell engagers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2887.
Abstract 2929: High-Definition Digital PCR (HDPCR™) enables sensitive measurement of DNA and RNA variants in non-small cell lung cancer samples
Authors: Leatham Bryan , McNall Katie , Subramanian Hari K. , Alvarado John , Jacky Lucien , Wang Mimi , Rajagopal Aditya , Schwartz Jerrod 
Published: June 2022

Abstract
Digital PCR (dPCR) is an emerging platform for detecting genomic variants in cancer genomes due to its high sensitivity and fast time to result compared to massively parallel sequencing. However, translational oncology applications often require the measurement of more biomarkers than there are color channels available on dPCR platforms. One approach to address this is to split a sample across many wells and profile a subset of variants in each well. For input-limited samples, however, this results in fewer molecules being profiled in each well, resulting in a reduction in sensitivity and fewer samples processed per instrument run.
ChromaCode has developed a research use only (RUO) high-definition digital PCR assay, for multiplexed detection of 14 DNA variants and 15 RNA fusion variants relevant in non-small cell lung cancer (NSCLC) samples. The assay is constructed using both amplitude modulation and multi-channel resilient signal encoding methods. Amplitude modulation enables different variants to generate a signal at different intensity levels in single color channel, allowing for greater than n targets in n color channels. In contrast, resilient encoding generates a signal in more than one color channel to create a form of error detecting code.
DNA and RNA samples were obtained using a combination of synthetic templates, cell line nucleic acids, and commercially available reference materials. Samples were run with the HDPCR NSCLC RUO assay on the Thermo Fisher Absolute Q digital PCR system, and data analysis was performed with custom analysis algorithms. The HDPCR NSCLC RUO assay demonstrated a limit of detection as low as 10 variant copies in a 10,000 haploid human genome copy DNA background. By employing HDPCR technology on digital PCR systems, it is possible to build a comprehensive and sensitive research assay that quickly detects many genomic alterations relevant to NSCLC samples.
Citation Format: Bryan Leatham, Katie McNall, Hari K. Subramanian, John Alvarado, Lucien Jacky, Mimi Wang, Aditya Rajagopal, Jerrod Schwartz. High-Definition Digital PCR (HDPCR™) enables sensitive measurement of DNA and RNA variants in non-small cell lung cancer samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2929.
Abstract 297: Prophylaxis and treatment of metastatic breast cancer and melanoma using S100A9-targeted cowpea mosaic virus nanoparticles
Authors: Chung Young Hun , Park Jooneon , Cai Hui , Steinmetz Nicole F. 
Published: June 2022

Abstract
The current study investigates the use of an immunostimulatory plant virus nanoparticle called the cowpea mosaic virus (CPMV) in both the prophylaxis and treatment of metastatic breast cancer and melanoma. Metastatic cancer remains to this day one of the most difficult areas in oncology to treat and diagnose. Current standardized treatments consist of systemically administered chemotherapeutics, which are not targeted to the diseased areas and oftentimes cause significant side effects. Therefore, novel treatments such as targeted immunotherapies are under development. The S100A9 protein is upregulated in the tumor microenvironment and it plays an important role in tumor metastasis, aggressiveness, and tumor immunosuppression. It is present not only in the pre-metastatic tumor environment, but is also heavily secreted and expressed after metastatic tumor establishment has occurred. This makes S100A9 a prime target in both prophylactic and therapeutic settings; yet, targeted immunotherapies against S100A9 have never previously been explored. CPMV has been shown in the past to be immunostimulatory when injected directly into the tumor with the ability to recruit immune cells for tumor cell killing. However, metastatic tumors cannot be treated through intratumoral injections; therefore, the current work utilizes systemically-administered S100A9-targeted CPMV nanoparticles. Biodistribution studies indicate that S100A9-targeted CPMV homes to the lung while confocal imaging of S100A9 and S100A9-targeted CPMV within the lungs of tumor-inoculated mice demonstrates co-localization. We further demonstrate using flow cytometry that after CPMV homes to the lungs, immune cells such as neutrophils and dendritic cells are recruited to the lungs, and macrophages are polarized towards their antitumor M1 phenotype. Prophylaxis efficacy studies where CPMV is injected before the tumors show that the S100A9-targeted CPMV causes tumor rejection in both metastatic breast cancer and melanoma but that native CPMV does not produce a significant effect. When used as a treatment, the targeted CPMV, similarly shows efficacy against these two cancer models with native CPMV again showing ineffectiveness. The S100A9-targeted CPMV holds great potential as a targeted immunotherapy both prophylactically (e.g. after primary tumor debulking to reduce the onset of metastases) and therapeutically after tumor establishment has occurred.
Citation Format: Young Hun Chung, Jooneon Park, Hui Cai, Nicole F. Steinmetz. Prophylaxis and treatment of metastatic breast cancer and melanoma using S100A9-targeted cowpea mosaic virus nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 297.