bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4730: A novel RAD51 inhibitor, CYT01B, shows anti-cancer activity in preclinical models of AID expressing solid tumors
Authors: Day Melinda , Maclay Tyler , Mills Kevin 
Published: August 2019

Abstract
AID, a DNA-directed cytidine deaminase, plays a critical role in somatic hypermutation and immunoglobulin class switching in maturing B-lymphocytes. Unlike site specific recombinases such as RAG1/2, AID is a promiscuous DNA damaging enzyme that deaminates cytidines at sites throughout the genome. AID expressing cells become critically dependent on the homologous recombination factor RAD51 to repair DNA double strand breaks that result from these off target deamination events. We have developed a novel small molecule, CYT01B, which inhibits RAD51 response to DSBs and is potent to a much greater extent in AID expressing cells. Previously, we have shown this molecule to have activity in mouse lymphoma xenograft models that constitutively express AID. Here we present new preclinical characterization data of CYT01B in solid cancer models. We first analyzed the frequency and levels of AID overexpression in solid tumor data in The Cancer Genome Atlas. Multiple solid tumor types displayed ectopic AID expression, including breast cancer, sarcoma, melanoma, pancreatic cancer, lung cancer, and head and neck cancers with about 30% of the patient samples 4-fold above the baseline expression level. We then tested CYT01B in several solid tumor derived human cell lines. We observed a correlation between AID expression and activity. Cell lines with low ectopic expression of AID had EC50 values in the low micromolar range (~2µM), while those without AID expression gave EC50 values of about 5µM and higher. Next, we examined the activity of our small molecule in 14 different PDX models with various levels of AID expression. These models included renal, head and neck, lung, pancreatic, ovarian, colorectal, and breast cancer samples. We observed a wide range of tumor growth inhibition across the different models (0% to 60%+), which tended to correspond with AID expression; the higher the AID expression the greater the observed tumor growth inhibition. Taken together, these data demonstrate that CYT01B shows anti-cancer activity in a range of solid tumor models. Overall, this provides the basis for continued development of CYT01B as an AID/RAD51 synthetic lethal therapeutic for solid cancers.
Citation Format: Melinda Day, Tyler Maclay, Kevin Mills. A novel RAD51 inhibitor, CYT01B, shows anti-cancer activity in preclinical models of AID expressing solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4730.
Abstract 4731: Therapeutic targeting of RNA splicing through inhibition of protein arginine methylation
Authors: Fong Jia Yi , Low Diana , Pignata Luca , Kawabata Kimihito Cojin , Lee Stanley CW , Koh Cheryl , Musiani Daniele , Massignani Enrico , Wun Cheng Mun , Goy Pierre-Alexis V. , Shen Yudao , Wollmann Heike , Gay Florence PH , Luciani Genna , Barsyte Dalia , Jin Jian , Melnick Ari M. , Bonaldi Tiziana , Abdel-Wahab Omar , Guccione Ernesto 
Published: August 2019

Abstract
Mutations in RNA splicing factors commonly occur in myeloid leukemia and solid tumors. These mutations occur in a heterozygous manner and confer dependency on the wild-type allele. Studies have shown that splicing factor mutant cancers are vulnerable to further perturbation of splicing, by pharmacological intervention that directly targets core splicing factors. Our project identifies the use of PRMT inhibitors, as plausible alternative therapeutic strategy to treat spliceosomal mutant leukemia. The data show that splicing factor mutant leukemia exhibit greater sensitivity to the use of inhibitors against Type I PRMTs and PRMT5, in comparison to their wild-type counterparts. As the need for new therapeutic strategies in cancer treatment increases, this study identifies PRMT inhibitors as a potential therapeutic intervention against cancers with splicing factor mutations.
Citation Format: Jia Yi Fong, Diana Low, Luca Pignata, Kimihito Cojin Kawabata, Stanley CW Lee, Cheryl Koh, Daniele Musiani, Enrico Massignani, Cheng Mun Wun, Pierre-Alexis V. Goy, Yudao Shen, Heike Wollmann, Florence PH Gay, Genna Luciani, Dalia Barsyte, Jian Jin, Ari M. Melnick, Tiziana Bonaldi, Omar Abdel-Wahab, Ernesto Guccione. Therapeutic targeting of RNA splicing through inhibition of protein arginine methylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4731.
Abstract 4737: Case report: Preclinical testing of NEDD8 and proteasome inhibitors for a treatment-refractory, metastatic high-grade mucinous colorectal cancer
Authors: Torchiaro Erica , Petti Consalvo , Isella Claudio , Medico Enzo 
Published: August 2019

Abstract
Colorectal cancer (CRC) is the third leading cause of death in the world. CRC shows variable phenotypic make-ups; among them, a particularly aggressive histological subtype is the “high grade mucinous” (HGM) adenocarcinoma, highly mucinous, prone to metastasis and typically refractory to treatments. In some cases, HGM is accompanied by a peculiar “signet ring” phenotype of cancer cells. Early stage diagnosis of signet ring HGM is rare, since clinical symptoms tend to occur late and most cases are usually detected at an advanced stage, with a poor overall survival. We previously demonstrated that a transcriptional signature of HGM displays negative prognosis and sensitivity to the NEDD-8 inhibitor pevonedistat, suggesting the involvement of neddylation- and ubiquitination-based mechanisms in these cases (Picco et al., JNCI 2017 djw209). To assess the clinical potential of colorectal cancer HGM identification and targeting by pevonedistat or other inhibitor of proteasome pathway, we recently propagated cells and PDXs from a case of early onset, metastatic CRC in a Lynch syndrome patient, refractory to standard care (FOLFOX6, FOLFIRI-Panitumumab) and, surprisingly, also to nivolumab. The tumor was highly mucinous, with signet ring undifferentiated cells. Mutational analysis on tumor tissue from the first surgery highlighted PIK3CA H1047R mutation and no mutations in KRAS, NRAS or BRAF. Surprisingly, exome analysis on two lesions from a subsequent surgery displayed a different scenario: KRAS G13D but not PIK3CA mutation. Probably these discording results suggest a strong tumor heterogeneity and evolution. Considering the failure of all previous therapies, the lack of actionable genetic alterations and the peculiarity of the phenotypic features, patient-derived models (organoids and 2D cell cultures) were derived from the two latter lesions and tested for sensitivity to the NEDD8 pathway inhibitor pevonedistat and the proteasome inhibitors bortezomib and carfilzomib. Interestingly, all models showed a strong sensitivity to both drugs, in particular to bortezomib. This is an example of a rare case of high-grade mucinous colorectal cancer where the integration of several approaches proves useful to identify possible therapeutic strategies for a patient without further standard treatment options.
Citation Format: Erica Torchiaro, Consalvo Petti, Claudio Isella, Enzo Medico. Case report: Preclinical testing of NEDD8 and proteasome inhibitors for a treatment-refractory, metastatic high-grade mucinous colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4737.
Abstract 4739: Induction of cell death by HDAC, Aromatase and MDM2 inhibitors in MCF-7 cells
Authors: Venkatesan Thiagarajan , Natarajan Umamaheswari , Radhakrishnan Vijayaraghavan , Samuel Shila , Rathinavelu Appu 
Published: August 2019

Abstract
The histone deacetylase (HDAC) enzymes are evolving as key enzymes in the regulation of many physiological processes, including chromatin remodeling, genome stability, DNA repair, regulation of transcription, protein secretion, cellular metabolism, cell cycle progression, differentiation, migration, and cell death. Among different regulators of HDACs, suberoylanilide hydroxamic acid (SAHA) is a potent inhibitor and it is known to cause strong growth arrest, differentiation and apoptosis of many tumor types in both in vitro and in vivo experimental models. Interestingly, treatment of MCF-7 breast cancer cells with SAHA was found to trigger necroptosis, which is a caspase independent form of cell death. Typically, stimulation of death domain receptors (DDR) by suitable ligands lead to the activation of RIP1, RIP3 and MLKL proteins which are the critical regulators of necroptosis. It appears that, during SAHA induced necroptosis elevation of p21 may be the main signal that triggers recruitment of RIP1, Phospho-RIP3 and MLKL intracellularly in MCF-7 cells. Also, our results confirmed that the apoptosis marker such as BAX and caspases are not elevated by SAHA in MCF-7 cells after 24 hrs of treatment. In addition, the fluorescence assay conducted with SYTOX Green after 10 and 50 µM necrostatin pre-treatments, confirmed that SAHA treatment activates RIP1 mediated necroptosis pathway in MCF-7 cells. The induction of p21 expression was also down-regulated significantly by 10 and 50 µM necrostatin pre-treatments, which further suggests that p21 is up-stream of the necroptosis executioners in MCF-7 cells. On the other hand, when the MCF-7 cells were treated with Letrazole and RG-7388, BAX appears to be involved in mediating cell death. Interestingly, both Letrazole and RG-7388 were not able to elevate p21 in MCF-7 cells. So far, our results suggest that SAHA can induce BAX independent necroptosis while Letrazole and RG-7388 induce cell death through elevation of BAX and BAK in MCF-7 cells. (The generous support from the Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida is gratefully acknowledged).
Citation Format: Thiagarajan Venkatesan, Umamaheswari Natarajan, Vijayaraghavan Radhakrishnan, Shila Samuel, Appu Rathinavelu. Induction of cell death by HDAC, Aromatase and MDM2 inhibitors in MCF-7 cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4739.
Abstract 4742: The influence of cellular developmental state on response to therapeutics in glioblastoma
Authors: Nuga Oluwademilade , deCarvalho Ana , Ruden Douglas , Brown Stephen , Datta Indrani , Malta Tathianne 
Published: August 2019

Abstract
Glioblastoma (GBM) is an aggressive tumor treated with ionizing radiation (IR) and temozolomide (TMZ). Here we investigate how developmental state of glioblastoma cells: cancer stem cells (CSC) or differentiated cells, influences cellular response to treatment. Tissue from untreated primary GBM tumors representing diverse genotype were dissociated and cultured in conditions selective for CSCs, which were subsequently differentiated into an astrocytic phenotype by culturing in media supplemented with 2% FBS. Stemness index was evaluated using a machine learning predictive algorithm. Sensitivity of both isogenic CSC and serum differentiated cell (SDC) populations to TMZ and IR was determined by non-linear fitting of dose-response curves, using CellTiterGlo to measure cell viability (n=5) . CSCs and SDCs were then subjected to sub-lethal TMZ, IR (4 Gy), or control treatments, in triplicate. Cells were harvested, and DNA was isolated and Illumina 450k DNA methylation array data was analyzed by using the Methylumi package in R software. RNA was isolated for sequencing, and differentially expressed genes were determined by NOISeq R package. Our results show that GBM CSCs are more vulnerable to both TMZ and IR treatment than the isogenic SDCs. Transcriptome profiling show that IR leads to increase in p53 mediated expression of pro-apoptotic genes such as MDM2, PUMA and BCL2 binding protein relative to control in CSCs. In differentiated cells, IR lead to an increase in WNT signaling, DNA-repair activity and histone modification /remodeling proteins. Enrichment analysis using Fisher’s exact test identified significant enrichment in lipid, fatty acid and metabolic processes as well as receptor tyrosine signaling. Globally, CSCs exhibited a decrease in protein coding genes and increase in regulatory RNA expression. DNA methylation show a global increase in CpG promoter methylation in differentiated cells relative to isogenic stem-like counterparts. We recovered significant differentially methylated probes between treatment groups (Wilcoxon signed rank test) as well as a global increase in CpG promoter methylation in IR treated cells relative to control. These findings underscore the challenge of treating a highly heterogeneous tumor and challenge a strategy of inducing differentiation to increase GBM sensitivity to treatment.
Citation Format: Oluwademilade Nuga, Ana deCarvalho, Douglas Ruden, Stephen Brown, Indrani Datta, Tathianne Malta. The influence of cellular developmental state on response to therapeutics in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4742.
Abstract 476: MEK inhibitors for treatment of oligodendroglioma
Authors: Majd Nazanin , Park Soon Young , Kraatz Marisela Martinez de , Balasubramaniyan Veerakumar , Sandeep Mittal , Hu Jian , Paik Jihye , Groot John de 
Published: August 2019

Abstract
Oligodendroglioma (OD) is defined by the 2016 WHO classification as IDH mutant gliomas with 1p19q co-deletion. Although ODs are sensitive to chemotherapy, they eventually recur leading to functional deficits and ultimately death. CIC gene mutations, located on chromosome 19q are seen in 60% of 1p19q co-deleted OD and have been linked to worse survival. Despite our growing knowledge of the molecular characteristics of OD, all recurrent OD patients are treated similarly mainly using radiation and/or poorly tolerated cytotoxic chemotherapy with modest benefit. There is therefore an urgent unmet medical need to understand the molecular consequence of recurrent mutations in OD in order to improve patient outcomes. CIC gene mutations result in truncated, degraded or non-functional CIC protein, disrupting CIC protein repressor functions. This leads to upregulation of ETS-Pea3 family of transcription factors which are known oncogenes in a variety of solid cancers. MAPK signaling pathway has been shown to directly activate ETS family of proteins in drosophila. However, the link between MAPK signaling, ETS proteins and CIC in OD is elusive. Here, we propose a model of aggressiveness in CIC mutant OD in which these cells are dependent on MAPK axis for activation of their augmented ETS proteins (i.e ETV1, ETV4) and therefore are sensitive to MAPK inhibition. To test our model, we evaluated mRNA and protein expression of ETS family of proteins in CIC mutant and CIC wild-type mouse OD cell lines and show that ETV1 and ETV4 have elevated protein and mRNA expression in CIC mutant OD cells, respectively. Consistent with our hypothesis, two different MEK inhibitors, trametinib and pimasertib, reduce cell viability of OD cell lines with greater reduction in CIC mutant than wild-type cells. As proof of concept, we demonstrate that CIC mutant cells have increased pERK expression when compared with CIC wild-type cells indicating that MAPK pathway is more active in CIC mutant cells. Overall, we were able to show that MEK inhibitors have anti-tumor effects in OD cell lines, with greater sensitivity seen in CIC mutant cells. This work lays the foundation for repurposing the widely clinically used MEK inhibitors for treatment oligodendroglioma patients with CIC mutation.
Citation Format: Nazanin Majd, Soon Young Park, Marisela Martinez de Kraatz, Veerakumar Balasubramaniyan, Mittal Sandeep, Jian Hu, Jihye Paik, John de Groot. MEK inhibitors for treatment of oligodendroglioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 476.
Abstract 4762: Activation of AXL as a preclinical acquired resistance mechanism against osimertinib treatment in EGFR-mutant non-small cell lung cancer cells
Authors: Namba Kei , Shien Kazuhiko , Takahashi Yuta , Sato Hiroki , Yoshioka Takahiro , Suzawa Ken , Yamamoto Hiromasa , Soh Junichi , Tomida Shuta , Toyooka Shinichi 
Published: August 2019

Abstract
Osimertinib (AZD9291) has an efficacy superior to that of standard EGFR-tyrosine kinase inhibitors for the first-line treatment of EGFR-mutant advanced non-small cell lung cancer (NSCLC) patients. However, patients treated with osimertinib eventually acquire drug resistance, and novel therapeutic strategies to overcome acquired resistance are needed. In clinical or preclinical models, several mechanisms of acquired resistance to osimertinib have been elucidated. However, the acquired resistance mechanisms when osimertinib is initially used for EGFR-mutant NSCLC remain unclear. In this study, we experimentally established acquired osimertinib-resistance cell lines from EGFR-mutant NSCLC cell lines and investigated the molecular profiles of resistant cells to uncover the mechanisms of acquired resistance. Various resistance mechanisms were identified, including the acquisition of MET amplification, EMT induction, and the upregulation of AXL. Using targeted next-generation sequencing with a multi-gene panel, no secondary mutations were detected in our resistant cell lines. Among three MET-amplified cell lines, one cell line was sensitive to a combination of osimertinib and crizotinib. Acquired resistance cell lines derived from H1975 harboring the T790M mutation showed AXL upregulation, and the cell growth of these cell lines was suppressed by a combination of osimertinib and cabozantinib, an inhibitor of multiple tyrosine kinases including AXL, both in vitro and in vivo. Our results suggest that AXL might be a therapeutic target for overcoming acquired resistance to osimertinib.
Citation Format: Kei Namba, Kazuhiko Shien, Yuta Takahashi, Hiroki Sato, Takahiro Yoshioka, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Shuta Tomida, Shinichi Toyooka. Activation of AXL as a preclinical acquired resistance mechanism against osimertinib treatment in EGFR-mutant non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4762.
Abstract 4774: Engineering an oncolytic adenovirus to target CEA in colorectal cancer
Authors: Schaumburg Jessica C. 
Published: August 2019

Abstract
Colorectal cancer is the second leading cause of cancer-related deaths in the United States and the third most commonly diagnosed cancer overall. Screening methods can identify precancerous polyps before they progress, leading to five-year survival rates of 92%. However, if diagnosed in later stages the survival rates decrease to 12%. While treatment options are available for advanced stages, they remain inadequate to affect overall survival. Thus, new therapies are needed to improve treatment outcomes. Oncolytic virotherapy is a unique therapeutic approach in which a virus is genetically modified to target cancer cells while sparing normal tissue. Oncolytic virotherapy takes advantage of the lytic properties of the viral life cycle. These viruses are used replicate inside cancer cells, lyse them and spread to adjacent cells throughout the tumor. The adenovirus is a well-characterized vector that is easily manipulated and produced and is capable of infecting a wide range of cells. However, the endogenous receptor for adenovirus, the Coxsackie and adenovirus receptor (CXADR), is often downregulated in cancers, thus decreasing the ability to selectively infect cancer cells. In this study, an adenovirus was genetically engineered to present the single variable domain (VHH) derived from a camelid heavy chain antibody B2. The B2 antibody recognizes the human carcinoembryonic antigen (CEA), which is often overexpressed in a variety of cancers, including colorectal cancer. Here, the wild-type fiber and knob domain of the adenovirus fiber gene was replaced with a modified T4 fibritin fiber linked to the B2 VHH. To provide for visual tracking of adenovirus infection and biodistribution, a red fluorescent protein (RFP) marker gene was also fused to the capsid protein IX (pIX). This virus was rescued and amplified in the HEK293 F28 packaging cell line with a final round of amplification in HEK293 cells. The virus was purified by CsCl ultracentrifugation and dialysis. The resulting viral stock was titered and characterized for the presence of the modified fiber and knob. Subsequently, the vector was modified to express the human sodium-iodide symporter (NIS) transgene, to allow for noninvasive imaging of the adenovirus uptake and replication as well as radiotherapy using 131I. Further experiments will be completed to confirm viral selectivity for CEA and subsequent lysis of colorectal cancer cells. The results of this study will advance targeting oncolytic adenoviruses to metastatic colorectal cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Jessica C. Schaumburg. Engineering an oncolytic adenovirus to target CEA in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4774.