bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1817: EG-011 is a first-in-class Wiskott-Aldrich syndrome protein (WASp) activator with anti-tumor activity
Authors: Spriano Filippo , Barnabei Laura , Carrasco Del Amor Ana Maria , Tomasso Meagan R. , Tarantelli Chiara , Riveiro Eugenia , Pazzi Natalina , Padrick Shae B. , Cristobal Susana , Cavalli Franco , Gaudio Eugenio , Bertoni Francesco 
Published: June 2022

Abstract
Background. Novel therapeutic targets are needed to improve the outcome of individuals with cancer. EG-011 is a small molecule with in vitro and in vivo anti-tumor activity in lymphoma and acute leukemias, but, at least so far, no activity in solid tumor models (Gaudio et al AACR 2019). Since no information was available on its target, we have now performed experiments showing that EG-011 targets WASp.
Methods. Target identification: kinase screens with DiscoverX KINOMEscan, ProQinase Wildtype-Profiler; thermal proteomic profiling. Target validation: pyrene actin polymerization assay. In vitro drug treatment of cell lines followed for changes in actin filaments (F-actin) by confocal imaging with Alexa Fluor 488 Phalloidin.
Results. Extensive kinome screens excluded kinases as targets of EG-011. We then applied thermal proteomic profiling to identify new protein targets interacting with EG-011. Over 3,300 proteins from the soluble proteome from the EG-011 sensitive mantle cell lymphoma cell line REC1 were analyzed and 48 possible protein targets were initially identified. Among the proteins undergoing a thermal shift, WASp was among the most highly destabilized by EG-011. Due to the pattern of expression of WASp, compatible with the anti-tumor activity observed only in hematological cancers (Gaudio et al AACR 2019), we performed further experiments to confirm the possibility that EG-011 targets WASp. One of the main functions of WASp is the regulation of actin filaments formation. Pyrene actin polymerization assays demonstrated that EG-011 activated the auto-inhibited form of WASP with strong actin polymerization. Further confirmation was obtained using confocal imaging of cell lines exposed to DMSO or EG-011 (500 nM, 5 μM) and stained for F-actin. An increase in actine polymerization was seen in EG-011 sensitive (VL51) and not in resistant (Z138) cell lines at 4, 8 and 24h with both concentrations.
Conclusions. These data demonstrate that EG-011 is the “first-in-class” activator of the auto-inhibited form of WASp with selective anti-tumor activity in lymphomas.
Citation Format: Filippo Spriano, Laura Barnabei, Ana Maria Carrasco Del Amor, Meagan R. Tomasso, Chiara Tarantelli, Eugenia Riveiro, Natalina Pazzi, Shae B. Padrick, Susana Cristobal, Franco Cavalli, Eugenio Gaudio, Francesco Bertoni. EG-011 is a first-in-class Wiskott-Aldrich syndrome protein (WASp) activator with anti-tumor activity [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 1817.
Abstract 1819: CBP-1008 shows excellent efficacy and desirable drug safety profile in preclinical models
Authors: Tan Wei , Wang Wei , Bu Tingting , Liu Xuelian , Teng Yan , Huang Baohua 
Published: June 2022

Abstract
Folate Receptor Alpha (FRα) is the high affinity folate transporter which is highly expressed in ovarian, lung and breast cancer. Transient Receptor Potential Vanilloid 6(TRPV6), a calcium channel characterized by its high calcium selectivity. It plays an important role in calcium absorption in small intestine and calcium uptake in other epithelial tissues. TRPV6 is also upregulated in breast, ovarian and prostate cancer.
CBP-1008, A first-in-class drug conjugate which targets both FRα and TRPV6 with low molecular-weight ligands has been developed. CBP-1008 binds to FRα with high affinity and TRPV6 with low affinity. In presence of TRPV6, CBP-1008 shows faster FRα-mediated internalization and cytotoxicity than it does in absence of TRPV6. Systemic clearance CBP-1008 is observed within 6 hrs. However, the drug retained and accumulated in tumors with a half-life over 48 hrs. As a result, CBP-1008 shows excellent efficacy on tumors with target expression and the response is durable. MTD of CBP-1008 reaches 4 mg/kg in mice, 2 mg/kg in rat and 1 mg/kg in monkey.
During the development of molecularly-targeted therapeutics, biomarker assays which can stratify patients and enrich those who respond well to the therapy, play a very critical role. We generated an anti-TRPV6 antibody and developed a first-in-class IHC-based TRPV6 assay. This assay along with an FRα IHC assay have been validated per CAP/CLIA guidelines for patient selection in our clinical trials. Intended indications including ovarian cancer, endometrial cancer, breast, NSCLC and pancreatic cancer. We have evaluated a panel of ovarian PDX models for their biomarker expression and response to CBP-1008 to determine their correlation. It is found that FRα+/TRPV6+ tumor responds better than tumors which have at least one marker negative. Within the FRα+/TRPV6+ tumors, tumor growth inhibition well correlates with IHC score of FRα (R2=0.89).
It is indicated that clinical trials in selected indications using biomarkers assay to screening patients will expedite the clinical development of CBP-1008. Initial clinical response has been observed in our Phase I trial.
Citation Format: Wei Tan, Wei Wang, Tingting Bu, Xuelian Liu, Yan Teng, Baohua Huang. CBP-1008 shows excellent efficacy and desirable drug safety profile in preclinical 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 1819.
Abstract 1830: Phenylacetaldehyde induces apoptosis through endoplasmic reticulum and potentiates the effect of 5-FU treatment in colorectal cancer cells
Authors: Ferrandon Sylvain , Kong Cheng , Fedro Joseph , Aoun Rami-James , Chitchumroonchokchai Chureeporn , Clinton Steven , Kalady Matthew F. 
Published: June 2022

Abstract
Introduction: Phenylacetaldehyde (PAA), a product of phenylalanine metabolism, is generated by microbiota and has demonstrated anticancer properties in breast cancer. As the gut microbiome influences intestinal homeostasis, we investigated the effects of PAA on colorectal cancer (CRC).
Methods: Serum PAA levels and feces microbiota from 30 CRC patients and 30 healthy controls were analyzed by targeted GC-MS/MS and metagenomic sequencing. A validation cohort of 75 CRC patients and 53 healthy controls was analyzed for PAA level in serum. CRC cell lines and CRC-patient derived organoids were cultured and treated with PAA alone and in combination with 5-fluouracil (5-FU, standard chemotherapy used for CRC), then evaluated for viability, proliferation, cell cycle distribution, and cell death in vitro. We interrogated the mechanistic pathways induced by PAA treatment using RNA sequencing and western blot.
Results: PAA levels were significantly decreased in the circulation of CRC patients compared to healthy controls in our study population and the validation cohort. Metagenomic sequencing indicated the bacteria that positively correlated with PAA levels were significantly more abundant in healthy controls; while bacteria that negatively correlated with PAA were more abundant in CRC. In vitro, PAA inhibited the viability and colony formation of CRC cell lines as well as human-derived organoids in a concentration-dependent manner. Mechanistically, PAA treatment induced a P53-dependant G1 cell cycle arrest and cell death in HCT116 and RKO cell lines. Proteomic analysis also demonstrated a downregulation in PI3K/AKT/mTOR and ERK pathways. Investigation by RNA sequencing showed that PAA inhibits CRC by inducing endoplasmic reticulum stress-induced autophagy. When combined with 5-FU, PAA enhanced the potency of 5-FU on viability, cell death, and cell cycle arrest by inducing DNA damage.
Conclusions:The bacteria metabolite PAA increased CRC cell death by endoplasmic reticulum stress-induced autophagy and downregulation of the PI3K/AKT/mTOR and ERK pathways. PAA also potentiated chemotherapeutic efficacy of 5-FU through induction of DNA damages. These findings warrant further exploration of PAA as a potential CRC biomarker and novel therapeutic agent.
Citation Format: Sylvain Ferrandon, Cheng Kong, Joseph Fedro, Rami-James Aoun, Chureeporn Chitchumroonchokchai, Steven Clinton, Matthew F. Kalady. Phenylacetaldehyde induces apoptosis through endoplasmic reticulum and potentiates the effect of 5-FU treatment in colorectal cancer cells [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 1830.
Abstract 1833: Tumor treating fields induce DNA damage and apoptosis in medulloblastoma
Authors: Nitta Ryan T. , Li Gordon 
Published: June 2022

Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in children and accounts for approximately 20% of all pediatric central nervous system tumors. Current multimodal treatment has led to a 70-90% five-year overall survival rate, however, the prognosis for patients with tumor dissemination and recurrent MB remains poor. Additionally, the majority of survivors exhibit long-term neurocognitive and neuroendocrine complications because of the cytotoxic drugs and high dose radiation. Consequently, more effective and less toxic treatments are necessary in order to raise the quality of life for these young patients. Tumor Treating Fields (TTFields) are an exciting new therapeutic opportunity for MB. TTFields are low intensity, alternating electric fields that disrupt cell division through physical interactions with key molecules during mitosis. The side effects from TTFields treatments are incredibly low, making it an ideal candidate for MB therapy. Currently TTFields were found to increase the survival of adult brain tumor patients by dysregulating the cytoskeletal network leading to mitotic arrest as well as other varied multi-modal mechanisms of action. To determine if TTFields can be an effective treatment for MB, we conducted an in vitro study treating multiple MB cell lines with TTFields. We discovered that TTFields treatment reduced cell growth in three different MB molecular subgroups (SHH, Group 3, and Group 4) with an optimal frequency of 200-300 kHz. We also observed that TTFields treatment dysregulated actin polymerization that corresponded with a reduction in cell motility and invasion. TTFields treatment also increased DNA damage (γH2AX, 53BP1) that correlated with an increase in apoptotic cells. To expand on these initial findings, we conducted a combinatorial study with the small molecule inhibitor, CX-4945. CX-4945 is an inhibitor to casein kinase 2 and is currently being used in a phase I clinical trial to treat recurrent MB (NCT03904862). We discovered that CX-4945 enhanced the growth reduction of TTFields treatment. In addition, combining CX-4945 and TTFields increased the number of cells with dysregulated actin which correlated with a decrease in MB migration and invasion. Our findings demonstrate that TTFields may be a novel and less toxic method to treat MB patients.
Citation Format: Ryan T. Nitta, Gordon Li. Tumor treating fields induce DNA damage and apoptosis in medulloblastoma [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 1833.
Abstract 1849: Lipid metabolites as potential diagnostic biomarkers for stearoyl-CoA desaturase 1 targeting therapy in hepatocellular carcinoma (HCC)
Authors: Gleba Justyna Joanna 
Published: June 2022

Abstract
New effective therapies should be developed for the treatment of hepatocellular carcinoma (HCC). One of the very promising strategies is blocking the activity of stearoyl-CoA desaturase 1 (SCD1). SCD1 is the enzyme responsible for de novo fatty acid (FAs) synthesis by converting saturated fatty acids (SFAs) into monounsaturated fatty acids (MUFAs). In our laboratory, we developed a novel, highly specific SCD1inhibitor - SSI-4. We have tested the biological activity of SSI-4 against different HCC cell lines and patient-derived xenografts (PDX) mouse models. Of the twelve tested HCC cell lines, four were highly sensitive to SSI-4 (IC50 1-50 nM). Other cell lines showed moderate or no sensitivity to SSI-4. We conducted analysis of the enzymatic protein levels involved in de novo fatty acid synthesis. Protein expression levels for these enzymes don’t predict response to therapy. To determine whether lipid metabolites predict response to SSI-4 therapy, lipidomic analysis was investigated. Our studies showed thatSSI-4 sensitive cells when exposed to SSI-4 had a higher baseline level of key lipid metabolites such as phospholipids (PL), diglycerides (DAG), diglycerides (TAG), ceramides (CE), and free fatty acids (FFA),compared to insensitive cells. We are currently validating these results in our in vivo models at the tumor tissue and blood levels. Additionally, mechanistic studies are in progress to determine if SREBP1c, an AKT regulated transcription factor known to regulate each of the fatty acid synthetic enzymes plays a role in HCC fatty acid synthesis and sensitivity to SCD1 inhibition.
Citation Format: Justyna Joanna Gleba. Lipid metabolites as potential diagnostic biomarkers for stearoyl-CoA desaturase 1 targeting therapy in hepatocellular carcinoma (HCC) [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 1849.
Abstract 1874: Use of high throughput SPR to characterize antibodies to common cancer biomarkers
Authors: Bibikov Sergei , Rosenfeld John , Harvey Kevin J. 
Published: June 2022

Abstract
As a disease of mis-regulation, cancer is characterized both genetically and proteomically, requiring high quality tools to dissect the change difference between cell states. Among the reagents used to characterize biological systems at the protein level, antibodies are routinely applied, and engineered versions have proven useful for treating multiple therapeutic indications. We have generated a human proteome wide toolbox of polyclonal antibodies, identifying three antigenic 14mer sequences within each of the 20,000+ open reading frames at N-terminal, middle and C-terminal regions. Using a high throughput SPR system, Carterra LSA, we are able to define average on-rates, off-rates, and KD’s for pAb’s generated to important cancer regulators and biomarkers, including KRAS, STAT3, and Gli1. Due to the small size of the peptide targets, the kinetics of the observed interactions with polyclonal antibodies exhibit remarkable 1:1 fit typically observed when measuring monoclonal antibody affinities. The platform is a sensitive system capable of both identifying multiple antibody-antigen interactions with KD in the nanomolar to picomolar range, but also as a mass screening tool for developing de novo antibody pairs. We define the kinetic characteristics of these antibody reagents relative to performance in western blotting specifically. Improving the characterization of such widely used tools is critical for advancing translational opportunities into use in the clinic.
Citation Format: Sergei Bibikov, John Rosenfeld, Kevin J. Harvey. Use of high throughput SPR to characterize antibodies to common cancer biomarkers [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 1874.
Abstract 1882: Passenger gene co-amplification leads to collateral vulnerabilities in cancer
Authors: Bei Yi , Kirchner Marieluise , Brame Luca , Fritsche-Guenther Raphaela , Koeppke Julia , Heeren-Hagemann Anja , Mertins Philipp , Dörr Jan , Henssen Anton George 
Published: June 2022

Abstract
The activation of oncogenes via genomic amplification is a hallmark of the cancer genomes, yet such amplifications frequently also encompass neighboring genes. Such passenger genes are involved in essential cellular activities. We hypothesized that co-amplification of passenger genes create cancer-specific collateral therapeutic vulnerabilities. To test this, we analyzed one of the most commonly amplified gene locus near MYCN, which is amplified in nearly 25% of neuroblastoma and around 5% of all cancers. We observed that DDX1, a DEAD-Box helicase, is the most frequently co-amplified passenger gene in MYCN-amplified cancers. Using CRISPR/Cas9 loss-of-function screen results from the Cancer Dependency Map across 739 human cancer cell lines, we reveal that cells with DDX1 co-amplification are highly dependent on the mTOR complex 1(mTORC1). Mechanistically, western blot and immunoprecipitation analyses shows that DDX1 expression leads to higher mTORC1 pathway activity through the interaction between DDX1 and alpha-ketoglutarate dehydrogenase(alpha-KGDH) in mitochondria. DDX1 hijacks alpha-KGDH complex, thereby impairing the function of the Krebs cycle by interfering with the conversion of alpha-ketoglutarate to succinyl-coA. Live cell metabolomics shows accumulated alpha-ketoglutarate in turn activates mTORC1 pathway to promote the ATP production via oxidative phosphorylation(OXPHOS) to maintain cell survival. Consequently, interference with mTORC1 function reduced ATP production and led to accumulated alpha-KG leading to cell death, specifically in DDX1 expressing cells. This suggests that co-amplification of a passenger gene can result in collateral vulnerabilities in cancers, which has the potential to transform future therapeutic target discovery in oncology.
Citation Format: Yi Bei, Marieluise Kirchner, Luca Brame, Raphaela Fritsche-Guenther, Julia Koeppke, Anja Heeren-Hagemann, Philipp Mertins, Jan Dörr, Anton George Henssen. Passenger gene co-amplification leads to collateral vulnerabilities in cancer [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 1882.
Abstract 1891: Identifying new therapeutic antibodies using the RenMice™ HiTS Platform
Authors: Zhang Xiaoqian , Zhang Shujin , Jin Tianquan , Ji Xin , Zhang Jing 
Published: June 2022

Abstract
Over the past decade, an increasing number of therapeutic antibodies have been approved to target cancer. However, the process of identifying new therapeutic antibodies is routinely hampered by limitations in the traditional discovery process, including immune tolerance of highly homologous genes, and challenges with antibody sequence humanization, clone selection and drug efficacy and safety evaluation. RenMice™ HiTS (Hyperimmune Target Specific) is a collection of chromosome engineered mice with fully human immunoglobulin variable domains replacing mouse counterparts, each with a specific drug target gene knocked out. The goal of the RenMice™ HiTS platform is to overcome the challenges of traditional antibody drug discovery and increase the diversity of antibody paratopes and sequences which recognize functional epitopes. Immunization of target-specific RenMice™ generates a greater diversity of antibodies, including those that recognize the conserved regions between the antigen and the endogenous proteins of the immunized host. The platform is ideal for challenging targets, such as proteins with high homology between human and mouse, or multi-pass transmembrane proteins (eg. GPCRs/ion channels). The platform can be used to generate antibodies that cross-react with human, monkey, dog, and mouse targets, using a hybrid immunization strategy with both human and mouse/dog antigen. Generation of these species cross-reactive antibodies allows for high-throughput in vivo efficacy screening using wild-type mice. It is also possible to predict the preliminary response and toxicity in dogs with these cross-reactive antibodies. Thus, selection of the best antibody candidate based on in vivo efficacy and safety allows for a streamlined and successful preclinical phase. In conclusion, the RenMice™ HiTS platform facilitates the generation of antibodies with better developability properties that recognize challenging targets and novel epitopes.
Citation Format: Xiaoqian Zhang, Shujin Zhang, Tianquan Jin, Xin Ji, Jing Zhang. Identifying new therapeutic antibodies using the RenMice™ HiTS Platform [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 1891.
Abstract 1912: A versatile computational pipeline for the preprocessing of cell-free DNA fragmentation data
Authors: Ivankovic Ivna , Balázs Zsolt , Gitchev Todor , Banos Daniel Trejo , Moldovan Norbert , Balermpas Panagiotis , Willmann Jonas , Andratschke Nicolaus , Moulière Florent , Krauthammer Michael 
Published: June 2022

Abstract
Cell-free DNA (cfDNA) emerges as a promising liquid biopsy biomarker for cancer diagnosis and patient monitoring. Complementing mutation-based assays, cfDNA carries information about epigenetic modifications from decaying cells. This information is encoded in the shape of the cfDNA fragments. Specifically, fragments from cancer tend to be shorter than those originating from other adult cells, enabling a distinction between cancer patients and healthy individuals. Additional cfDNA features such as fragment end motifs and information on nucleosome positioning provide further insight into cancer biology. These cfDNA measures are typically inferred from low-pass whole genome sequencing and subsequent bioinformatics processing. A key bioinformatics step is the alignment of DNA sequencing reads to the reference genome, which critically depends on preprocessing steps such as read trimming and alignment filters. A good understanding of preprocessing settings is thus crucial to derive accurate information from cfDNA. We therefore investigated to what extent preprocessing choices affect cfDNA analysis. To this end, we have built a robust bioinformatics pipeline that evaluates a range of possible preprocessing settings. The pipeline is implemented in a bioinformatics workflow engine, enabling a scalable and reproducible workflow. We are currently evaluating the effect of preprocessing on global and regional fragmentation patterns, detection of nucleosome positioning and identification of fragment end motifs. The different preprocessing settings are also evaluated for their ability to distinguish cancer from control samples using cfDNA fragmentation information. We are benchmarking the pipeline using cfDNA datasets from multiple centres to ensure our findings are generalizable over different platforms and experimental procedures. Our investigations will allow us to build a versatile bioinformatics preprocessing pipeline for the analysis of cell-free DNA fragmentation data.
Citation Format: Ivna Ivankovic, Zsolt Balázs, Todor Gitchev, Daniel Trejo Banos, Norbert Moldovan, Panagiotis Balermpas, Jonas Willmann, Nicolaus Andratschke, Florent Moulière, Michael Krauthammer. A versatile computational pipeline for the preprocessing of cell-free DNA fragmentation 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 1912.