bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4059: Design and in vitro antitumor analysis of a novel diphenyltin complex (diphenyltin dioxalate)
Authors: Witter Jade , Song Xuequing , Taraboletti Alexandra , Li William , Henry Tajera 
Published: June 2022

Abstract
Organotins are popular among chemists due to their potential biological properties against bacteria, fungus, and cancer cell lines. In particular, organotins have been utilized in chemotherapeutic applications. Compared to cisplatin, organotins give more favorable toxicological profiles and better cytotoxicity and antiproliferative activities. However, organotins have limited biological applications due to their poor water solubility. In this study we synthesized a diphenyltin complex (Diphenyltin Dioxalate) that possesses partial ionic characteristics, by reacting a diprotic carboxylic acid, with triphenyltin chloride in the presence of di-isopropylamine. A tin-carbon cleavage reaction was observed, as IR/NMR spectroscopy and X-ray Crystallography studies showed that diphenyltin dioxalate was successfully obtained in the reaction. Post synthesis solubility tests were performed to examine diphenyltin dioxalate’s water-soluble nature, compared to its precursor triphenyltin. Diphenyltin dioxalate was then tested to examine its cytotoxicity and antitumor activity on human glioblastoma cell model (T98G) and a normal human oligodendrocyte cell model (MO3.13). Further studies with the complex will consist of synthetic mechanistic studies on the Sn-C cleavage.
Citation Format: Jade Witter, Xuequing Song, Alexandra Taraboletti, William Li, Tajera Henry. Design and in vitro antitumor analysis of a novel diphenyltin complex (diphenyltin dioxalate) [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 4059.
Abstract 406: Mechanism of AXL regulation in chemotherapy resistance
Authors: Ahmed Mehreen , Kazi Julhash Uddin 
Published: June 2022

Abstract
Constitutive activation of receptor tyrosine kinase AXL is an important phenomenon in chemotherapy resistance and is highly expressed in several malignancies. Although studies over the past decade revealed that AXL is upregulated during treatment, the biological significance and the mechanism by which AXL is activated upon chemotherapy are yet to be determined. In this study, we aim to understand the biology of AXL mediated chemo-resistance, and the consequences of AXL activation. To investigate the biological significance of AXL, we generated iRFP-luciferase-expressing cell lines which facilitate live monitoring of cancer progression during treatment in an in vivo setting. In parallel, by knocking down AXL using shRNA, we observed inhibitory effect on cell migration and tumor forming efficiency in vitro. Moreover, using in vitro cell based models, we showed that while AXL expression was upregulated upon treatment with chemotherapeutic agents, pharmacological inhibition of AXL caused synergistic effect between selective AXL inhibitors and cisplatin. Additionally, our data suggest that upregulation of AXL and its tyrosine phosphorylation may mediate resistance to chemotherapy. Using phosphoproteomics, we identified a link between CDK9 activation and drug-induced AXL expression. We showed that while AXL expression was upregulated upon treatment with tyrosine kinase inhibitor, pharmacological inhibition of CDK9 completely blocked AXL expression. Collectively, our data suggest that activation of kinase signaling might be required for AXL repression, and thereby, for targeting AXL-axis in chemotherapy resistance.
Citation Format: Mehreen Ahmed, Julhash Uddin Kazi. Mechanism of AXL regulation in chemotherapy resistance [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 406.
Abstract 4096: Development of novel anticancer RNA therapeutics with dual-targeting siRNA that silences ubiquitin family members
Authors: Azorsa David O. , Lee David W. , O'Ketch Marvin , Azorsa Nathalie A. , Papacharalampous Ioanna , Castaño Lizette A. , Kiefer Jeffrey A. , Mousses Spyro 
Published: June 2022

Abstract
Ubiquitination is a metabolic process in eukaryotic cells that modifies proteins with ubiquitin leading to protein degradation via the ubiquitin-proteosome pathway. Cellular levels of ubiquitin are driven by the expression of RPS27A, UBA52, UBB and UBC. In cancer, the dysregulation of ubiquitination can affect various aspects of tumor progression including cell cycle regulation and gene expression. Ubiquitin B (UBB) gene has been shown to be over-expressed in some tumor types, including NSCLC and cervical cancer, and under-expressed in other tumors, in particularly a subset of ovarian cancers. A role for ubiquitin C (UBC) in cancer has not been well established but UBC has been described as a biomarker in renal cancer and CLL. In recent studies, repression of UBB in ovarian cancer cells was associated with sensitivity to UBC knockdown and demonstrated a synthetic lethal relationship. Since both UBB and UBC show substantial sequence homology, we explored the possibility of developing dual targeting siRNA that would silence both UBB and UBC. We identified unique individual siRNA sequences that efficiently silenced both UBB and UBC and led to rapid cytotoxicity in several cancer cell lines including the colon cancer cell line HCT-116, the breast cancer cell line SK-BR3, and the prostate cancer cell line 22Rv1. Treatment with either UBB-specific or UBC-specific siRNA did not show the same lethal phenotype. Dose response assays using the dual targeting siRNA designated U21 indicated EC50 for cytotoxicity between 50–500 pM in several cancer lines. Treatment of cancer cell lines with U21 leads to rapid apoptosis and cell death. Chemical modifications to pharmacologically stabilize the U21 siRNA sequence did not change its activity. The efficient cytotoxic activity of the U21 siRNA sequence has been integrated into our SeekR™ platform to create aptamer-siRNA chimeras for targeted delivery of the lethal U21 payload to specific cancer cell types.
Citation Format: David O. Azorsa, David W. Lee, Marvin O'Ketch, Nathalie A. Azorsa, Ioanna Papacharalampous, Lizette A. Castaño, Jeffrey A. Kiefer, Spyro Mousses. Development of novel anticancer RNA therapeutics with dual-targeting siRNA that silences ubiquitin family members [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 4096.
Abstract 4145: Novel approach that combines an automated breast cancer grading platform with genomics to personalize risk assessment and management
Authors: Donovan Michael J. 
Published: June 2022

Abstract
Background: The role of histopathology including stage, tumor size and histologic grade in defining breast cancer (BCA) clinical risk assignment continues to be an important component of treatment choice and management. Recent publications have demonstrated the significance of combining these features with genomic signatures such as Oncotype and EndoPredict to provide precision risk assessment. Unfortunately, intra-inter pathologist BCA grading variability remains a significant limiting factor.
Methods: Using the Cancer Genome Atlas (TCGA) breast cancer (BCA) image dataset, clinical and genomic data (i.e., EndoPredict and Oncotype), we evaluated a series of H&E images from patients with infiltrating ductal BCA (one slide per patient). A machine-learning (ML) derived morphology feature array was used to normalize staining differences, identify regions of tumor vs. normal and characterize individual cellular attributes including tubule structure and organization, nuclear morphology, and mitotic figures. Individual features were correlated with overall survival using the concordance index (c-index), support vector models and Kaplan-Meier incidence curves to understand feature importance.
Results: ML curated image features representing BCA gland morphology were generated from 517 patients with 69 events (13%), 93% overall survival (OS), median 5-years. Three clinical variables including: age, 59 years (median), AJCC stage T2 and 49% grade 3 and 41% grade 2, along with results of the EndoPredict (EP) and an Onctoype (ONC) gene subset: PGR, ESR1, CCNB1, BIRC5, MYBL2, GRB7) and imaging features were evaluated. Only age, stage and 10 imaging features representing nuclear shape, size, mitotic activity, lymphoid aggregates and stromal content were selected. Two models consisting of clinical + gene expression + imaging produced a C-index of: 0.84 (EP) vs. 0.82 (ONC), respectively, vs. clinical (0.79) and clinical + genomics ( EP 0.81vs. ONC 0.79).
Conclusions: A machine-learning platform outperformed grade and produced accurate recurrence risk models with demonstrated added improvement over clinical and genomic analyses. Future studies include expanded cohort studies to confirm and expand these observations.
Citation Format: Michael J. Donovan. Novel approach that combines an automated breast cancer grading platform with genomics to personalize risk assessment and management [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 4145.
Abstract 4170: Integrative transcriptomic and proteomic analysis reveals immunogenic and spatially-conserved HLA-binding neoantigen targets derived from tumor-specific alternative splicing events
Authors: Kwok Darwin , Nejo Takahide , Du Aidan , Colton Maggie , Woo James , Costello Joseph , Okada Hideho 
Published: June 2022

Abstract
BACKGROUND: While immunotherapy is profoundly efficacious in certain cancers, its success is limited in cancers with lower mutational burden, such as gliomas. Therefore, investigating neoantigens beyond those from somatic mutations can expand the repertoire of immunotherapy targets. Recent studies detected alternative-splicing (AS) events in various cancer types that could potentially translate into tumor-specific proteins. Our study investigates AS within glioma to identify novel MHC-I-presented neoantigen targets through an integrative transcriptomic and proteomic computational pipeline, complemented by an extensive spatiotemporal analysis of the AS candidates.
METHODS: Bulk RNA-seq of high tumor purity TCGA-GBM/LGG (n=429) were analyzed through a novel systematic pipeline, and tumor-specific splicing junctions (neojunctions) were identified in silico by cross-referencing with bulk RNA-seq of GTEx normal tissue (n=9,166). Two HLA-binding prediction algorithms were subsequently incorporated to predict peptide sequences with high likelihood for HLA-presentation. Investigation of the tumor-wide clonality and temporal stability of the candidates was performed on extensive RNA-seq data from our spatially mapped intratumoral samples and longitudinally collected tumor tissue RNA-seq. Proteomic validation was conducted through mass-spec analysis of the Clinical Proteomic Tumor Analysis Consortium (CPTAC)-GBM repository (n=99).
RESULTS: Our analysis of TCGA-GBM/LGG bulk RNA-seq identified 249 putative neojunctions that translate into 222 cancer-specific peptide sequences which confer 21,489 tumor-specific n-mers (8-11 amino acids in length). Both prediction algorithms concurrently identified 271 n-mers likely to bind and be presented by HLA*A0101, HLA*A0201, HLA*A0301, HLA*A1101, or HLA*A2402. We confirmed the expression of 15 out of 58 HLA*A0201-binding candidates in RNA-seq of two HLA*A0201+ patient-derived glioma cell lines with a subset of candidates found tumor-wide. Analysis of CPTAC-GBM mass-spec data detected 23 tumor-specific peptides with 5 containing detected n-mers highly predicted to be HLA-presented.
CONCLUSION: Tumor-specific neojunctions identified in our unique integrative pipeline present novel candidate immunotherapy targets for gliomas and offer a new avenue in neoantigen discovery across cancer types.
Citation Format: Darwin Kwok, Takahide Nejo, Aidan Du, Maggie Colton, James Woo, Joseph Costello, Hideho Okada. Integrative transcriptomic and proteomic analysis reveals immunogenic and spatially-conserved HLA-binding neoantigen targets derived from tumor-specific alternative splicing events [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 4170.
Abstract 4178: PAK4 inhibition improves PD1 blockade immunotherapy in prostate cancer
Authors: Su Shengchen , You Sungyong , Wang Yanping , Tamukong Patrick , Grasso Catherine S. , Kim Hyung L. 
Published: June 2022

Abstract
Prostate cancers have low immune infiltration and do not respond to PD1 blockade immunotherapy. The objective of this study was to examine the effect of PAK4 inhibition on anti-tumor immune response in preclinical prostate cancer models. C57BL/6J mice (male, 5-8 weeks old) were injected with wild type (WT) or PAK4 knockdown (KD) syngeneic Rm1 tumor cells (2X105 cell/mouse) and treated with or without αPD1 blockade (200μg, BioXCell). Tumor growth was monitored and analyzed using ANOVA of repeated measures (n=6). In a separate experiment, 1 cm RM1 tumors were collected for RNA sequencing (RNASeq) and immunohistochemistry (IHC). RNASeq data were normalized using the variance stabilizing transformation (VST) function as implemented within the DESeq2 package. IHC images were captured with Keyence BZ-X800 and positive staining was calculated using ImageJ. CD8+ lymphocytes depletion was achieved by CD8 antibody injection (200ug, BioXCell). PAK4 inhibitors PF-3758309 (PF) and KPT-9274 (KPT) were evaluated in murine models. PAK4 KD tumors treated with αPD1 antibody (αPD1) showed a significant reduction of tumor growth when compared to growth in WT (P&lt;.05), WT αPD1 (P&lt;.01), and KD (p&lt;.05). Analysis of bulk tumor RNAseq showed that the combination of PAK4 KD with αPD1 was associated with increased CD8a, IFNγ, and PD-L1 expression. IHC with αCD8 verified that PAK4 KD increased CD8+ cell infiltration in mouse tumors. Further, RNAseq showed that PAK4 KD increased the expression of cytokines, chemokines, and genes related to the IFNγ response. These results suggest that PAK4 KD primes the tumor for immune infiltration and improves αPD1 treatment response. The anti-tumor effect of PAK4 KD with αPD1 in mice was CD8-dependent and could be eliminated by CD8+ cell depletion (p&lt;.05). We tested two different PAK4 inhibitors in mice with WT Rm1 tumors. PF is a kinase inhibitor that blocks the function of PAK4. A combination of PF and αPD1 significantly reduced tumor growth when compared to WT (P&lt;.05), WT αPD1 (P&lt;.01), and PF (p&lt;.05). KPT is a dual inhibitor of PAK4 and NAMPT, which reduces the cytosolic protein concentration of PAK4. A combination of KPT and αPD1 significantly reduced tumor growth when compared to WT (P&lt;.01) and WT αPD1 (P&lt;.01). In conclusion, PAK4 inhibition increased immune infiltration and improved αPD1 treatment response in preclinical mouse prostate cancer models.
Citation Format: Shengchen Su, Sungyong You, Yanping Wang, Patrick Tamukong, Catherine S. Grasso, Hyung L. Kim. PAK4 inhibition improves PD1 blockade immunotherapy in prostate 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 4178.
Abstract 4216: Tipifarnib inhibits the secretion of tumor-derived small extracellular vesicles and enhances the immunotherapeutic efficacy of dinutuximab in neuroblastoma
Authors: Liu Xiaoming , Wills Carson A. , Chen Longgui , Zhang Jiawen , Zhao Yuanjun , Zhou Mi , Sundstrom Jeffrey M. , Schell Todd D. , Spiegelman Vladimir S. , Young Megan M. , Wang Hong-Gang 
Published: June 2022

Abstract
Anti-GD2 monoclonal antibody (Dinutuximab) immunotherapy has significantly improved the overall survival rate for high-risk neuroblastoma patients. However, 40% of patients fail to respond or develop resistance to the treatment, and the molecular mechanisms by which this occurs remain poorly understood. Here we utilize the syngeneic 9464D-GD2 mouse model to investigate the role of neuroblastoma tumor-derived small extracellular vesicles (sEVs) in developing resistance to the anti-GD2 monoclonal antibody Dinutuximab. Neuroblastoma-derived sEVs significantly attenuated the efficacy of Dinutuximab treatment in vivo. Mechanistically, both RNA-sequencing and flow cytometry analysis of whole tumors demonstrated that neuroblastoma-derived sEVs modulate immune cells tumor infiltration upon Dinutuximab treatment to create an immunosuppressive tumor microenvironment, which contains more tumor-associated macrophages (TAMs) and fewer tumor-infiltrating NK cells, in addition to suppression of splenic NK cell maturation in vivo. Moreover, neuroblastoma-derived sEVs suppressed Dinutuximab-mediated NK cell antibody-dependent cellular cytotoxicity in vitro. Importantly, Tipifarnib, a farnesyltransferase inhibitor that inhibits sEV secretion, drastically enhanced the efficacy of Dinutuximab in vivo and reversed the immunosuppressive effects of neuroblastoma-derived sEVs. Notably, Tipifarnib modulated immature myeloid cells in the bone marrow to disfavor the formation of CD11b+Ly6ChighLy6Glow subpopulations, which are the precursors for TAMs. Taken together, these preclinical findings uncover a novel mechanism by which neuroblastoma-derived sEVs modulate the immune system to promote resistance to Dinutuximab and suggest that Tipifarnib-mediated inhibition of sEV secretion may serve as a viable treatment strategy to improve immunotherapy in high-risk patients.
Citation Format: Xiaoming Liu, Carson A. Wills, Longgui Chen, Jiawen Zhang, Yuanjun Zhao, Mi Zhou, Jeffrey M. Sundstrom, Todd D. Schell, Vladimir S. Spiegelman, Megan M. Young, Hong-Gang Wang. Tipifarnib inhibits the secretion of tumor-derived small extracellular vesicles and enhances the immunotherapeutic efficacy of dinutuximab in neuroblastoma [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 4216.
Abstract 4235: PPRX-1701, a deliverable nanoparticle formulation of 6-bromo-acetoxime, blocks tumoral IDO1 expression and shows efficacy in immunocompetent murine glioblastoma models
Authors: Zdioruk Mykola , Nowicki Michal , Wu Bin , Boucher Paul , Takeda Yuji , Li Weiyi , Chiocca E Antonio , Lawler Sean E. 
Published: June 2022

Abstract
Introduction: We previously showed that derivatives of the Chinese traditional medicine indirubin promote survival in murine models of the brain tumor glioblastoma. However, poor drug solubility hampered further development of this approach. Here we introduce PPRX-1701, a 6’-bromoindirubin acetoxime (BiA) containing drug/polymer nanoparticle formulation which can be injected intravenously at relatively high concentrations. Here we examine the efficacy and mechanism of PPRX-1701 in murine glioblastoma models.
Methods: In vitro glioblastoma cell proliferation and migration assays were performed using standard approaches. Effects of PPRX-1701 on interferon-γ (IFN γ) signaling were determined by Western blotting. Delivery to murine GBM was assessed using a luminescent reporter assay, and survival studies were performed in immunocompetent murine glioblastoma models.
Results: PPRX-1701 effects on glioblastoma cell proliferation and migration were indistinguishable from BiA alone. Our data show that intravenous administration of PPRX-1701 is well-tolerated and can reach intracranial murine glioblastoma as assessed by luminescent reporter assays. PPRX-1701 administration leads to improved survival in the GL261 glioblastoma mouse model (median survival 30 days (control), 47 days (treated), p &lt; 0.0001). Treatment with PPRX-1701 was associated with alterations in the tumor immune microenvironment, with reduced Tregs and pro-tumor macrophages, and increased CD8+ T cells. Further mechanistic studies have shown that PPRX-1701/BiA blocks the expression of multiple immunosuppressive molecules in GBM downstream of interferon-γ (IFNγ) including PD-L1 and indoleamine 2,3-dioxygenase 1 (IDO1) - a key enzyme in the tryptophan-kynurenine-aryl hydrocarbon receptor (Trp-Kyn-AhR) immunosuppressive pathway. BiA promoted more effective T-cell mediated tumor cell killing using patient derived glioblastoma ex vivo co-culture models.
Conclusion: This data supports further development of PPRX-1701 as a candidate immunotherapeutic agent for glioblastoma treatment. Ongoing pre-clinical studies are investigating combination with other relevant therapies.
Citation Format: Mykola Zdioruk, Michal Nowicki, Bin Wu, Paul Boucher, Yuji Takeda, Weiyi Li, E Antonio Chiocca, Sean E. Lawler. PPRX-1701, a deliverable nanoparticle formulation of 6-bromo-acetoxime, blocks tumoral IDO1 expression and shows efficacy in immunocompetent murine glioblastoma 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 4235.
Abstract 4236: Temporal inhibition of BCAT1 alters metal homeostasis leading to reversal of terminal exhaustion of CD8 T cells, increased cytotoxicity, and increased efficacy of checkpoint inhibition in cancer
Authors: Papathanassiu Adonia E. , Li Weixing , Vu Hong A. 
Published: June 2022

Abstract
We have previously demonstrated that BCAT1, the enzyme responsible for the reversible transamination of leucine in the cytosol, is a druggable target in immune-oncology: the small molecule inhibitor ERG245 dramatically increases the efficacy of anti-PD-1 treatment in the moderately immunogenic CT26 colon cancer model. We have also shown that Bcat1 gene expression is enriched in exhausted CD4+ and CD8+ intratumoral cells in cancer patients from diverse cancers. Here, we illustrate that the adoptive cell transfer (ACT) of murine CD8+ T cells treated with ERG245 increased the median survival of CT26 tumor-bearing mice from 25 days, observed with the ACT of untreated CD8+ T cells, to 32 days. This suggested that inhibition of BCAT1 prevented the known exhaustion of adoptively transferred CD8+ T cells, induced by the tumor microenvironment of CT26 tumors. To confirm this hypothesis, we developed an in vitro model of generating terminally exhausted (PD-1+TIM-3+GZMB+CXCL13+) CD8+ T cells by subjecting the cells to consecutive cycles of αCD3/αCD28 activation in the presence of TGF-β. Addition of ERG245 in the last activation cycle decreased terminal exhaustion of the cells. Mechanistically, bulk RNAseq experiments indicated and ICP analysis confirmed that inhibition of BCAT1 interfered with metal homeostasis leading to increased concentrations of Fe in the mitochondria and decreased concentrations of Zn in the nucleus of newly activated CD8+ T cells. The immediate impact of ERG245 treatment on the cells included a general decrease in the genes of processes depending on proper metal equilibrium such as cholesterol biosynthesis and ribosome biogenesis. Withdrawal of BCAT1 restored or reversed the cell phenotype leading to epigenetically altered CD8+ T cells with decreased histone acetyltransferase and histone demethylase presence, increased cytotoxicity, and increased ribosome biogenesis. Collectively, the data suggest that temporal inhibition of BCAT1 inhibition induces profound effects on CD8+ T cells including increased cytotoxicity and suppression of terminal exhaustion, thus rendering the cells rescuable by anti-PD-1 therapy.
Citation Format: Adonia E. Papathanassiu, Weixing Li, Hong A. Vu. Temporal inhibition of BCAT1 alters metal homeostasis leading to reversal of terminal exhaustion of CD8 T cells, increased cytotoxicity, and increased efficacy of checkpoint inhibition 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 4236.