bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB169: Systemic Administration of an antibody/RNA complex results in tumor specific delivery of immunostimulatory RNAs and tumor growth suppression in a mouse model of melanoma
Authors: Quijano Elias , Liu Yanfeng , Squinto Stephen , Turner Bruce C. , Glazer Peter M. 
Published: July 2021

Abstract
There is intense interest in the development of nucleic acid ligands for immune stimulation of the tumor microenvironment via pattern recognition receptors, especially for the treatment of “cold” tumors. However, delivery of these ligands in a tumor-specific manner to avoid systemic toxicity has been a challenge. Many current efforts rely on direct intra-tumoral injection of RNAs or other stimulatory immune ligands, which is therapeutically sub-optimal, especially for metastatic disease. Here we report studies evaluating the utility of a lupus-derived, cell-penetrating antibody, to deliver nucleic acids including mRNA to tumors in vivo. This antibody, a modified version of 3E10-D31N, forms non-covalent complexes with RNAs and can mediate highly specific delivery broadly into tumors via intravenous injection by targeting the nucleoside transporter ENT2. Studies with labeled RNAs and with mRNAs expressing a GFP reporter gene show tumor specific delivery and functional expression by imaging, with minimal delivery to healthy tissues. Cell culture studies show antibody-mediated delivery of a series of RIG-I ligands, including hairpin RNAs and poly(I:C), resulting in robust RIG-I stimulation and induction of type-1 interferon signaling. Using mouse B16 melanoma tumors as a model, we observe substantial tumor growth suppression upon i.v. injection of a combination of 3E10 complexed with poly(I:C) (synthetic double-stranded RNA). These results highlight a novel approach for the systemic delivery of immunostimulatory RNAs in a targeted manner that may offer treatment advantages over current approaches.
Citation Format: Elias Quijano, Yanfeng Liu, Stephen Squinto, Bruce C. Turner, Peter M. Glazer. Systemic Administration of an antibody/RNA complex results in tumor specific delivery of immunostimulatory RNAs and tumor growth suppression in a mouse model of melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB169.
Abstract LB185: BBX and PLK1 feedback mechanisms regulate mitotic entry & exit
Authors: Li Gaiyun , Gillison Maura L. 
Published: July 2021

Abstract
Bobby Sox Homolog (BBX) is a highly conserved member of the high mobility group (HMG) box family of transcription factors, but its function remains largely unknown. We find human papillomavirus positive oropharyngeal squamous cell carcinomas (HPV-OPSCC) are enriched for BBX amplification and single nucleotide variants clustered within the BBX lysine rich domain. We therefore used the immortalized keratinocyte cell line HaCaT to elucidate BBX function. BBX is localized primarily in the nucleus. Cell synchronization at G1-S or G2-M shows BBX mRNA transcription and protein expression are highest at G1-S and rapidly decline at G2-M. Immunofluorescence (IF) shows high nuclear BBX expression during interphase and rapid reduction at mitosis (M). Induced overexpression of BBX decreases cellular proliferation, prolongs M phase, induces senescence, increases frequency of binucleated cells, and increases DNA damage as measured by γH2AX. Knockdown of BBX expression decreases cell proliferation, shortens M phase, and results in several mitotic defects, including lagging chromosomes, micronuclei, multi-polar spindles, and binucleated cells. Because effects of BBX dysregulation mirror those of Polo-like kinase-1 (PLK1), we investigated possible BBX-PLK1 interactions. BBX induction increases, whereas knockdown decreases, PLK1 mRNA and protein expression. BBX strongly activated transcription of the PLK1 promoter in a luciferase reporter assay. In contrast, PLK1 dramatically decreased BBX protein, but not mRNA, expression, and this effect was attenuated by a PLK1 T210 inactivating mutation and by a PLK1 small molecule inhibitor. We found a strong positive correlation between BBX and PLK1 mRNA expression in HNSCC tumors, but not in normal tissues. We conclude that BBX and PLK1 interact in a feedback mechanism to precisely regulate the G2-M transition. Future work will investigate interactions between BBX, HPV oncoproteins, and regulation of the cell cycle.
Citation Format: Gaiyun Li, Maura L. Gillison. BBX and PLK1 feedback mechanisms regulate mitotic entry & exit [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB185.
Abstract LB190: DNAscopeTM: A novel chromogenic in-situ hybridization technology for high-resolution detection of DNA copy number and structural variations
Authors: Wang Li-Chong , Tondnevis Farzaneh , Todorov Courtney , Gaspar Jayson , Sahajan Aparna , Murlidhar Vasudha , Zhang Bingqing , Ma Xiao-Jun 
Published: July 2021

Abstract
Genomic DNA anomalies such as copy number variations (gene duplication, amplification, deletion) and gene rearrangements are important biomarkers and drug targets in many cancer types. DNA in-situ hybridization (ISH) is the gold standard method to directly visualize these molecular alterations in formalin-fixed paraffin-embedded (FFPE) tumor tissues at single-cell resolution within a histological section. However, currently available fluorescent ISH (FISH) assays provide limited morphological detail due to the use of fluorescent nuclear staining compared to chromogenic staining. Furthermore, FISH techniques rely on expensive fluorescence microscopes, risk loss of fluorescent signal over time and involve tedious imaging at high magnifications (100X). There is thus an unmet need for a sensitive and robust chromogenic DNA-ISH assay that can enable high-resolution detection of genomic DNA targets with the ease of bright-field microscopy. We present here DNAscope - a novel chromogenic DNA-ISH assay - for detecting and visualizing genomic DNA targets under a standard light microscope. DNAscope is based on the widely used RNAscope® double-Z probe design and signal amplification technology and provides unparalleled sensitivity and specificity with large signal dots readily visualized at 40X magnification and with full morphological context. Furthermore, DNAscope ensures specific DNA detection without interference from RNA due to the use of a novel RNA removal method. Using a duplex chromogenic detection assay in red and blue, we demonstrate highly specific and efficient detection of gene rearrangements (ALK, ROS1, RET and NTRK1), gene amplification (ERBB2, EGFR, MET) and deletion (TP53 and CDKN2A). The DNAscope assay has been carefully optimized for probe signal size and color contrast to enable easy interpretation of signal patterns under conventional light microscopy or digital pathology. Compared to conventional FISH assays, DNAscope probes are standard oligos that are designed in silico to be free of any repetitive sequences and can be rapidly synthesized for any DNA target. In conclusion, the DNAscope assay provides a powerful and convenient alternative to commonly used FISH assays in many cancer research applications.
Citation Format: Li-Chong Wang, Farzaneh Tondnevis, Courtney Todorov, Jayson Gaspar, Aparna Sahajan, Vasudha Murlidhar, Bingqing Zhang, Xiao-Jun Ma. DNAscopeTM: A novel chromogenic in-situ hybridization technology for high-resolution detection of DNA copy number and structural variations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB190.
Abstract LB193: Lysine demethylase 5A is required for MYC driven transcription in multiple myeloma
Authors: Qi Jun , Ohguchi hiroto , Park Paul MC , wang tingjian , Anderson Kenneth C. , Hideshima Teru , Johansson Catrine , Oppermann Udo , Durbin Adam D. , Gryder Berkley , Khan Javed , zhang xiaofeng 
Published: July 2021

Abstract
Multiple myeloma (MM) is a malignant plasma cell disorder accounting for 10% of hematologic malignancies. Although high dose chemotherapy and targeted agents have improved patient outcomes, MM remains an incurable disorder. Thus, there is an urgent need to develop novel therapeutic strategies. We discovered that the distinct lysine demethylase 5A (KDM5A) plays a critical role in MM cell growth, through a unique link to MYC-driven transcriptional programs. KDM5A is a dominant regulator of histone H3K4 trimethylation, a histone mark associated with activated gene transcription. We identify that KDM5A interacts with P-TEFb complex and cooperates with MYC to control MYC targeted genes in MM cells. We develop a novel, cell-permeable and selective KDM5 inhibitor, JQKD82 that increases histone H3K4me3, and inhibits downstream MYC-driven transcriptional output in vitro and in vivo. Utilizing genetic ablation together with our inhibitor, we established a detail mechanism that KDM5A is required for transcriptional pause release by P-TEFb at MYC target genes. These data identify KDM5A as a unique vulnerability in MM through regulation of the driving MYC oncogene in MM, and defined JQKD82 as a tool compound to block KDM5A function as a potential therapeutic strategy for MM.
Citation Format: Jun Qi, hiroto Ohguchi, Paul MC Park, tingjian wang, Kenneth C. Anderson, Teru Hideshima, Catrine Johansson, Udo Oppermann, Adam D. Durbin, Berkley Gryder, Javed Khan, xiaofeng zhang. Lysine demethylase 5A is required for MYC driven transcription in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB193.
Abstract LB213: ACTL6A (Actin-like Protein 6A) enhances the cancer phenotype
Authors: Shrestha Suruchi , Adhikary Gautam , Xu Wen , Kandaysamy Sivaveera , Eckert Richard L. 
Published: July 2021

Abstract
Epidermal squamous cell carcinoma (SCC) is an extremely common, invasive and metastatic cancer. ACTL6A, an important protein subunit of the SWI/SNF epigenetic regulatory complex, is frequently overexpressed in cancer cells. In the present study, we show that ACTL6A drives SCC cell proliferation, invasion, migration and tumor formation, and that this aggressive phenotype is markedly reduced in ACTL6A knockdown cells. Expression of ACTL6A is associated with reduced p21Cip1 level and treatment with ACTL6A-siRNA results in a marked increase in p21Cip1 and attenuation of the cancer phenotype. Molecular studies reveal that ACTL6A suppresses p21Cip1 promoter activity to reduce mRNA and p21Cip1 protein and that loss of p21Cip1 expression appears to be biologically meaningful, as p21Cip1 knockdown enhances the aggressive phenotype. ACTL6A suppression of p21Cip1 expression requires the p53 and Sp1 transcription response elements in the p21Cip1 gene promoter. In addition, ACTL6A knockdown results in increased p53 tumor suppressor expression. These studies show that ACTL6A facilitates an aggressive cancer phenotype by reducing p53 and p21Cip1 mRNA and protein and suggests that ACTL6A contributes to an aggressive cancer phenotype in epidermal squamous cell carcinoma.
Citation Format: Suruchi Shrestha, Gautam Adhikary, Wen Xu, Sivaveera Kandaysamy, Richard L. Eckert. ACTL6A (Actin-like Protein 6A) enhances the cancer phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB213.
Abstract ND04: CLBR001+SWI019: A novel switchable CAR-T cell platform enabling functionally reversible on/off control of CAR-T cell activity for B cell malignancies
Authors: Young Travis 
Published: July 2021

Abstract
Chimeric antigen receptor (CAR) T cell therapy targeting CD19 has been transformative in the treatment of patients with relapsed, refractory B cell malignancies. However, despite remarkable response rates, CAR-T cell therapy is limited by the potential for uncontrolled cytokine production from the genetically engineered cells, resulting in cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Further, continuous activity of CD19-targeted CAR-T cells can result in persistent B cell aplasia due to on-target, off-tumor activity of CAR-T cells.
To address these challenges, we have developed a novel “switchable” CAR-T cell therapy which affords greater versatility and the potential for improved efficacy and safety compared with existing CAR-T cell approaches. The therapy has been designed in two parts - first, a “universal” genetically engineered autologous humanized, third generation CAR-T cell (CLBR001); and second, a humanized antibody-based “switch” molecule (SWI019) with conventional drug-like properties that controls the genetically engineered cells. As designed, SWI019 controls the turning “on” and “off” of the CLBR001 CAR-T cells. We have shown, the dose of SWI019 tightly correlates with the amount of cytokine produced from CLBR001 while retaining potent in vivo activity in mouse models of leukemia. Importantly, cessation of SWI019 dosing in preclinical models led to termination of CLBR001 cytotoxic and cytokine production within 5 days. This is expected to be important in mitigating adverse events such as CRS and ICANS in patients. We further found that the cyclical nature of on/off stimulation of the switchable CAR-T cells affords greater memory and persistence of the cells in surrogate mouse models, while also allowing B cell repopulation, thus avoiding potential long-term adverse events due to B cell aplasia. A Phase 1 trial was initiated in mid-2020 for patients with relapsed, refractory B cell malignancies. We believe this approach has the potential to be applied to solid tumors in the future leveraging these “universal” CLBR001 CAR-T cells.
Citation Format: Travis Young. CLBR001+SWI019: A novel switchable CAR-T cell platform enabling functionally reversible on/off control of CAR-T cell activity for B cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr ND04.
Abstract ND10: Discovery of RMC-5552: A selective bi-steric inhibitor of mTORC1 that suppresses 4EBP1 phosphorylation, for the treatment of mTORC1-activated tumors including RAS pathway escape
Authors: Burnett G. Leslie 
Published: July 2021

Abstract
The PI3K/mTOR and RAS signaling pathways are hyperactivated in a wide range of human cancers. Several points of cross-talk and intersecting feedback mechanisms have been described and activation of mTOR signaling frequently mediates escape from RAS pathway inhibition. Revolution Medicines has developed a novel class of selective mTORC1 inhibitors, termed ‘bi-steric inhibitors', that interact with both the ATP- and FKBP12/FRB-binding sites of mTORC1. These compounds potently and selectively inhibit mTORC1 over mTORC2 and other lipid kinases. Unlike rapalogs, such as everolimus, these bi-steric inhibitors suppress 4EBP1 phosphorylation in vivo and induce growth suppression and apoptosis in various genetically-defined preclinical models of human cancer. We will describe our SAR investigations and findings for our preclinical tool compound, RMC-6272 (also known as RM-006) and for RMC-5552, our clinical candidate. We will demonstrate that mTORC1-selective bi-steric inhibitors show combinatorial activity with both KRASG12C(OFF) and KRASG12C(ON) inhibitors, in KRASG12C STK11deficient NSCLC models and can forestall resistance to KRASG12C inhibitor monotherapy. In addition, we will show single agent activity of bi-steric mTORC1 inhibitors in preclinical models of tumors bearing PI3K/mTOR pathway alterations as primary drivers, including PTEN-deficient glioblastoma multiforme, TSC1/2-deficient renal cystadenoma cancer, and hepatocellular cancers harboring mTOR-activating β-catenin mutations. RMC-5552, through reactivation of 4EBP1 and inhibition of cap-dependent translation, has the potential to benefit cancer patients with genetically-defined tumors with activating mutations in the RAS and PI3K/mTOR pathways both as a single agent or in combination with RAS inhibitors.
Citation Format: G. Leslie Burnett. Discovery of RMC-5552: A selective bi-steric inhibitor of mTORC1 that suppresses 4EBP1 phosphorylation, for the treatment of mTORC1-activated tumors including RAS pathway escape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr ND10.
Abstract PL03-03: Inherited susceptibility to cancer: From family reunions to the front line of precision healthcare
Authors: Olopade Olufunmilayo I. 
Published: July 2021

Abstract
Cancer genomics has shed much light on tumorigenesis, leading to improved diagnoses and treatments. The marriage of Big Data and genetics research has produced groundbreaking, epidemiologic studies of large swaths of the world's population showing the links between cancer(s) and inherited risk. This work has led to breakthroughs in our understanding of pathogenic mutations, such as in BRCA1 and BRCA2 genes—strong predictors of breast and ovarian cancer risk and possibly the strongest known predictors of aggressive prostate cancer risk. Inherited and sporadic forms of cancer often share common mutational events, with implications for diagnosis, prognosis, treatment and prevention. Our work and that of others demonstrate the significant burden of early onset ER negative breast cancer as well as high rates of pathogenic BRCA1, BRCA2 and PALB2 mutations among young women diagnosed with breast cancer. Our more recent work on the BRCA1 pseudogene identifies a novel mechanism of innate immunity driven by a host pseudogene RNA that inhibits innate immune defense mechanisms and anti-tumor responses through regulation of antiviral gene expression. Genome-Wide Association Studies (GWAS) have also identified single nucleotide polymorphisms (SNPS) associated with increased breast cancer risk, including SNP rs13074711 identified from GWAS in women of African Ancestry with breast cancer, which regulates TNFSF10/TRAIL expression in ER negative breastcancer cells. Germline genetics influence somatic mutations and the evolutionary trajectory and life history of individual cancer genomes in diverse populations. Deeper understanding of the nature of this influence will allow us to explore innovative interventions to accelerate progress in precision health care and promote health equity.
Citation Format: Olufunmilayo I. Olopade. Inherited susceptibility to cancer: From family reunions to the front line of precision healthcare [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr PL03-03.
Abstract SY16-02: Using patient-derived models for functional precision oncology in advanced breast cancer
Authors: Welm Alana L. 
Published: July 2021

Abstract
Patient derived xenografts (PDX) are valuable, clinically-relevant models of cancer. Their close genomic, phenotypic, and temporal association with patient tumors makes them well-suited for pre-clinical and co-clinical studies that assess the potential of new therapeutics. However, PDX models are not amenable to large-scale drug sensitivity studies or real-time precision oncology due to their relatively slow growth, high cost, and low throughput. To address this, we established and characterized organoid lines from breast cancer patient tumors and PDXs and evaluated their fidelity to the original tumors and their utility in high-throughput therapeutic studies. Results of comparisons between in vitro and in vivo patient-derived models of breast cancer will be presented, along with extension of this technology to inform patient care in an IRB-approved study of precision oncology. Our work demonstrates that breast cancer organoid models are a powerful parallel resource to PDX models, especially useful for efficient determination of drug responses, and are amenable to informing real-time patient care in a functional precision oncology setting.
Citation Format: Alana L. Welm. Using patient-derived models for functional precision oncology in advanced breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr SY16-02.
Abstract SY37-01: Genomic instability and hypoxia as co-drivers of prostate cancer aggression
Authors: Bristow Robert G. 
Published: July 2021

Abstract
Understanding the mechanistic basis for transition to late stage aggressive disease is vital for both assigning patient risk status in the localised setting and also identifying novel treatment strategies to prevent progression. Sub-regions of intratumoral hypoxia are found in all solid tumours and are associated with many biologic drivers of tumour progression. Crucially, more recent findings show the co-presence of hypoxia and genomic instability can confer a uniquely adverse prognosis in prostate cancer. In-depth informatic and functional studies suggests a role for hypoxia in co-operating with oncogenic drivers (e.g. loss of PTEN) and suppressing DNA repair capacity. To delineate a direct relationship between hypoxia and PTEN loss, we interrogated the impact of chronic hypoxia (1% O2, 0.2% O2; 72 h) on PTEN oncogenic signalling and chromosome instability. Quantitative immunofluorescence of centrosome aberrations, using antibodies to phospho-Histone H3 and Centrin-1, show significant increases in centriole numbers (p &lt; 0.05) in mitotic cells under chronic hypoxic conditions and an increase in the incidence of micronuclei (p &lt; 0.005) specifically in chronic hypoxic cells with PTEN loss. Hypoxic suppression of homologous recombination represents a "contextual lethal" vulnerability in hypoxic prostate tumours which could extend the application of existing DNA repair targeting agents such as poly-ADP ribose polymerase inhibitors. Additional mechanistic studies using hTERT-immortalized, primary prostate epithelial cells isogenic for c-MYC, BRCA2, or TP53/RB (SV40-transduced) were studied as to the relationship between hypoxia, inherent versus acquired genetic instability and DNA repair capacity in-vitro and in-situ. Chronic hypoxia (20 generation doublings at 0.2% O2) was sufficient to drive increased copy number alterations (CNAs) in selected clones by up to 30% in TP53/RB null cells. This finding is now being quantitated with a clonal evolution model and genotype-phenotype associations are being validated using functional transformation and invasion assays. Further investigation is now required to assess this relationship on the background of existing genomic alterations relevant to prostate and other cancers and also characterise the role of hypoxia in driving early metastatic spread. Supported by core funding from Cancer Research UK Manchester Institute and grants within the Cancer Research UK Manchester RadNet Unit, NIHR Manchester Biomedical Research Centre and a Prostate Cancer UK-Movember Centre of Excellence award.
Citation Format: Robert G. Bristow. Genomic instability and hypoxia as co-drivers of prostate cancer aggression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr SY37-01.