bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 937: Nr4a transcription factors limit CAR T-cell function in solid tumors
Authors: Chen Joyce , Lopez-Moyado Isaac F. , Seo Hyungseok , Lio Chan-Wang J. , Hempleman Laura J. , Sekiya Takashi , Yoshimura Akihiko , Scott-Browne James P. , Rao Anjana 
Published: August 2019

Abstract
In cancer immunotherapy, CD19-targeted CAR T cells have exhibited impressive clinical efficacy against B cell leukemias and lymphomas; however, they have been less effective against solid tumors. This is in part because CAR T cells enter a hyporesponsive (“exhausted” or “dysfunctional”) state that is triggered by chronic antigen stimulation and characterized by upregulation of several inhibitory surface receptors and loss of effector function. To identify transcriptional regulators and other candidates contributing to the diminished CAR T cell function in solid tumors, we developed a CAR T cell model in which recipient mice bearing murine melanoma tumors expressing human CD19 were adoptively transferred with CD19-targeted CAR T cells. We demonstrate that in both CD8+ CAR T tumor-infiltrating lymphocytes (TILs) and endogenous CD8+ TILs expressing high levels of PD-1 and TIM3, the Nr4a proteins Nr4a1 (Nur77), Nr4a2 (Nurr1), and Nr4a3 (Nor1) are prominent effectors of the transcriptional program downstream of NFAT: they promote the expression of inhibitory receptors and genes associated with early hyporesponsive state, and limit effector function. Most importantly, treatment of tumor-bearing mice with CD8+ CAR T cells lacking all three Nr4a factors (Nr4aTKO) resulted in tumor regression and prolonged survival. Nr4aTKO CD8+ CAR T TILs displayed a transcriptomic profile characteristic of effector function, including upregulation of granzymes and cytokines, and many of these gene expression changes were associated with altered regulatory element accessibility near effector genes. Our data identify Nr4a transcription factors as major players in the cell-intrinsic program of T cell hyporesponsiveness and point to Nr4a inhibition as a promising strategy for cancer immunotherapy.
Citation Format: Joyce Chen, Isaac F. Lopez-Moyado, Hyungseok Seo, Chan-Wang J. Lio, Laura J. Hempleman, Takashi Sekiya, Akihiko Yoshimura, James P. Scott-Browne, Anjana Rao. Nr4a transcription factors limit CAR T-cell function in 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 937.
Abstract 938: Disruption of TOX overcomes CAR T-cell dysfunction function in solid tumor
Authors: Seo Hyungseok , Chen Joyce , Das Arundhoti , Bhandoola Avinash , Rao Anjana 
Published: August 2019

Abstract
Adoptive cell therapy with chimeric antigen receptor expressing T (CAR T) cells has shown promising therapeutic efficacy against leukemia and lymphoma. However, CAR T cells in solid tumors fail to be as effective as in liquid tumors since they enter into a hyporesponsive (exhausted or dysfunctional) state that is induced by chronic antigen stimulation in cancer. Here, we show that CAR T cells in solid tumors exhibit low effector function and high expression of inhibitory receptors such as PD-1, Tim-3 and Lag 3. We also show that the nuclear factor, Thymocyte selection-associated HMG box protein, TOX - a target of the transcription factor NFAT - is highly expressed in CAR T cells in solid tumors with PD-1 expression. To determine how TOX transcription factors contribute to exhaustion/ dysfunction in CAR T cells, we developed CAR T cells targeting huCD19 and lacking TOX and TOX 2. Surprisingly, treatment of huCD19 expressing melanoma or colorectal tumor-bearing mice with CAR T cells doubly deficient in TOX and TOX2 resulted in the eradication of solid tumors and prolonged survival of the tumor-bearing mice, compared to mice treated with WT CAR T cells or CAR T cells lacking TOX or TOX2 alone. Tumor-infiltrating CAR T cells (CAR TILs) doubly deficient in TOX and TOX2 did not increase their expression of inhibitory receptors such as PD-1, Lag3 and CD160 and showed higher expression of TCF1 compared to WT CAR TILs. Our data identify TOX and TOX2 -high mobility group transcription factors belonging to the TOX family - as critical transcriptional factors for inducing hyporesponsiveness in CAR T cells in solid tumors. Our data suggest that disruption of TOX expression or activity could be a promising strategy for cancer immunotherapy.
Citation Format: Hyungseok Seo, Joyce Chen, Arundhoti Das, Avinash Bhandoola, Anjana Rao. Disruption of TOX overcomes CAR T-cell dysfunction function in solid tumor [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 938.
Abstract 968: Targeting intratumoral heterogeneity in TNBC with novel combinations of FDA-approved drugs
Authors: Truchan Nathan A. , Burnett Joseph P. , Sun Duxin 
Published: August 2019

Abstract
Triple negative breast cancer, like so many other solid tumors, has intratumoral heterogeneity which makes it difficult to treat. It is paramount to understand the question, “where does the intratumoral heterogeneity come from?” To that end, we developed a dual color reporter cell line using CRISPR/Cas9 to precisely knock in fluorescent proteins, mCherry and EGFP, behind CSC marker ALDH1A3 and differentiation marker CD24 respectively, in the TNBC cell line SUM149. With fluorescent microscopy we are able to track individual cells over time, view symmetrical and asymmetrical self-renewal, differentiation, and lineage restriction. Through direct observation we determined that the intratumoral heterogeneity comes from CSCs. In short, CSCs give rise to all the different cell types found within TNBC. Once we established the reporter cell line we wanted to ensure that any response to therapeutics was the same as in the parental SUM149 cell line. In the past, we have treated parental SUM149 with docetaxel or sulforaphane. We therefore treated our reporter cells with either docetaxel or sulforaphane. The sulforaphane treatment resulted in a significant reduction of CSCs while the docetaxel resulted in significantly more CSCs, both results matched the results from parental SUM149. To our surprise the docetaxel treatment result was due to the significant de-differentiation of mCherrylow to mCherryhigh cells. The de-differentiation and incomplete elimination of the heterogeneous cell populations pose a significant problem for TNBC patients, one that must be addressed. In order to overcome this issue, we will use our reporter cells to test already approved FDA drugs to find and evaluate novel combinations for their ability to completely eliminate the heterogeneous cell populations found within TNBC.
Citation Format: Nathan A. Truchan, Joseph P. Burnett, Duxin Sun. Targeting intratumoral heterogeneity in TNBC with novel combinations of FDA-approved drugs [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 968.
Abstract 985: Development and validation of cell-based TFEB translocation assay in a high-content and high-throughput screening format
Authors: Zhang Li , Huang Ruili , Ding Wen Xing , Xia Menghang 
Published: August 2019

Abstract
Transcription factor EB (TFEB) is a master regulator of lysosomal gene expression and mitochondrial biogenesis. Autophagy is known to act as a double edged sword in cancer. Autophagy acts as a tumor suppressor during the tumorigenesis process but it also helps to sustain the survival of already transformed cancer cells. Lysosomes sit at the end of the autophagy pathway, which is critical to meet the needs of autophagy. Therefore, small molecules that inhibit TFEB-mediated lysosomal biogenesis and autophagic degradation may be helpful for inhibiting cancer cell growth and limiting cancer progression. On the other hand, small molecules that enhance TFEB-mediated lysosomal degradation may be used to prevent tumorigenesis. In order to identify compounds that modulate TFEB translocation, an image-based TFEB translocation assay was developed in a 1536-well plate format with a GFP-TFEB stable AML12 cell line, which is an immortalized mouse hepatocyte cell line. Torin 1, a known TFEB translocation inducer, was used as positive control in the study. Torin 1 increased TFEB nuclear translocation in a concentration dependent manner with an EC50 of 150nM. To optimize the assay condition, various cell densities per well and time courses were tested. To validate this assay, a group of 384 known anticancer compounds were screened at 11 concentrations ranging from 0.8 nM to 46 μM. From this screening, we identified 25 compounds that enhanced TFEB nuclear translocation with EC50s ranging from 2 nM to 12 μM. Several known and novel TFEB inducers were among these compounds. These results demonstrate that this high-content and high-throughput assay can be used to screen large numbers of chemicals and provide a robust in vitro system to identify TFEB agonists and antagonists, which may be used to either prevent (agonists) or treat (antagonist) cancer.
Citation Format: Li Zhang, Ruili Huang, Wen Xing Ding, Menghang Xia. Development and validation of cell-based TFEB translocation assay in a high-content and high-throughput screening format [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 985.
Abstract 989: The relationship between TP53 gene status and carboxylesterase 2 expression in human gastric cancer
Authors: Kohira Yoshinori , Lee Hyeon-Cheol , Ishimine Momoko , Orita Hajime , Kobayashi Toshiyuki , Sato Koichi , Yokomizo Takehiko , Fukunaga Tetsu 
Published: August 2019

Abstract
Carboxylesterases are serine hydrolases that are involved in the metabolisms of various endogenous and exogenous compounds. They are also required for activation of many anti-cancer prodrugs. For example, irinotecan (CPT-11), an anti-cancer prodrug that has been approved for the treatment of many types of solid tumors including gastric cancer, is converted by the carboxylesterase CES2 to its active metabolite 7-ethyl-10-hydroxycamptothesin (SN-38), a very potent topoisomerase I inhibitor. Among carboxylesterase isozymes, CES2 is most highly expressed in the gastrointestinal tract. Thus, the expression of CES2 may play an important role in local (i.e., intratumoral) activation of anti-cancer prodrugs such as irinotecan in the gut. Recent studies with cultured cancer cell lines have shown that CES2 expression is regulated by the tumor suppressor protein p53. However, whether CES2 expression is affected by the presence of p53 mutation in clinical cancer samples still remains unclear. In this study, we focused on the regulatory mechanism of CES2 expression in gastric cancer. First, we examined the relationship between TP53 gene status and CES2 expression using gastric cancer cell lines. Several gastric cancer cell lines expressing wild-type p53 (AGS, NUGC4, MKN74, and HSC58) were treated with nutlin-3a, a drug that inhibits the interaction between p53 and the E3 ubiquitin ligase MDM2 and thereby directly activates p53 signaling without genotoxic side effects. The expression of p21, a downstream target of p53, was increased following nutlin-3a treatment in two p53 wild-type cell lines NUGC4 and HSC58. The expression of CES2 was also upregulated by nutlin-3a in three p53 wild-type cell lines AGS, NUGC4, and HSC58. As expected, the expression levels of p21 and CES2 were not largely affected by nutlin-3a in gastric cancer cell lines with TP53 mutations. These results indicate that CES2 expression is positively regulated by the p53 pathway in most gastric cancer cells. We also investigated the relationship between TP53 gene status and CES2 expression in human gastric cancer samples. Our results may provide useful information for predicting the efficacy of anti-cancer prodrugs that are activated by CES2 in gastric cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Yoshinori Kohira, Hyeon-Cheol Lee, Momoko Ishimine, Hajime Orita, Toshiyuki Kobayashi, Koichi Sato, Takehiko Yokomizo, Tetsu Fukunaga. The relationship between TP53 gene status and carboxylesterase 2 expression in human gastric 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 989.
Abstract 994: Combining ruthenium metallo-intercalators and targeted radionuclide therapy for EGFR-overexpressing oesophageal cancer
Authors: Gill Martin R. , Menon Jyothi U. , Carlisle Robert , Vallis Katherine A. 
Published: August 2019

Abstract
Targeted radionuclide therapy (TRT) combines the specificity of molecular targeting with the potent cytotoxicity of ionising radiation. An emerging question is how to most effectively integrate TRT with radiosensitizing small molecules [1]. Auger electron-emitting radionuclides such as 111In are well-suited as the therapeutic radionuclide as their short-range reduces “cross fire” damage to neighbouring cells. As a novel chemical class of radiosensitizing agent, we have found ruthenium polypyridyl complexes (RPCs) that intercalate between DNA base pairs such as Ru(phen)2(tpphz)2+ (phen = 1,10 phenanthroline, tpphz = tetrapyridophenazine) act to stall replication forks and impede mitotic progression in human oesophageal cancer cells [2,3]. This dual mechanism of action results in preferential growth inhibition of rapidly-proliferating oesophageal cancer cells with elevated mitotic indices. In contrast to cisplatin and other DNA-damaging agents, relatively low DSB levels are generated in response to RPC metallo-intercalation and reduced cytotoxicity towards non-cancer cells is observed. In addition to this, treatment is able to enhance cancer cell sensitivity to IR by increasing IR-induced DNA double-strand break (DSB) damage, decreasing cell survival in a synergistic manner. Based on these discoveries, we explore how nanoparticle-mediated delivery of Ru(phen)2(tpphz)2+ and the Auger electron emitting radionuclide 111In can achieve localised cytotoxicity enhancement specifically in EGFR-overexpressing oesophageal cancer cells, thereby demonstrating both a combinational effect alongside molecular targeting for this novel combination [4].
References:[1] M. R. Gill, N. Falzone, Y. Du and K. A. Vallis, Lancet Oncol, 18, e414 (2017).[2] M. R. Gill, S. N. Harun, S. Halder, R. A. Boghozian, K. Ramadan, H. Ahmad and K. A. Vallis, Sci. Rep., 6, 31973 (2016).[3] M. R. Gill, P. J. Jarman, S. Halder, M. G. Walker, H. K. Saeed, J. A. Thomas, C. Smythe, K. Ramadan and K. A. Vallis, Chem. Sci., 9, 841 (2018).[4] M. R. Gill, J. U. Menon, P. J. Jarman, J. Owen, I. Skaripa-Koukelli, S. Able, J. A. Thomas, R. Carlisle, K. A. Vallis, Nanoscale, 10, 10596 (2018).
Citation Format: Martin R. Gill, Jyothi U. Menon, Robert Carlisle, Katherine A. Vallis. Combining ruthenium metallo-intercalators and targeted radionuclide therapy for EGFR-overexpressing oesophageal 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 994.
Abstract 997: Three-dimensional high-throughput drug screening for bladder cancer
Authors: Lee Sang-Cheol , Kim Young Saing , Hwang In Gyu , Lee Su Jin , Park Se Hoon 
Published: August 2019

Abstract
Recent progress in understanding the molecular mechanisms that underlie bladder cancer carcinogenesis offers the prospect of specifically targeting signaling pathways to achieve more effective and rational treatment. In a novel, 3-dimensional high-throughput drug screening (3D HTS) platform to identify novel agents affecting bladder cancer cells, 24 molecularly-targeted agents were screened in seven human bladder cancer cell lines (UCUM3, T24, SW780, RT4, J82, 5637 and 253J-BV). The efficacy of 24 targeted agents on the bladder cell lines varied dramatically on their genomic alterations. BEZ235 (mTOR and PI3K inhibitor) showed antitumor effect in most of cell lines except UMUC3. Another mTOR inhibitor, AZD2014 (inhibitors of mTORC1 and mTORC2) also had IC50 &lt;2 μM in 3 cell lines (5637, J82 and RT4). However, FGFR targeted agents (AZD4547 and BGJ398) did not show the efficacy in cell lines with FGFR3 alterations (J82, SW780 and RT4). In HER2 mutated/amplified cell line (5637), dacomitinib, lapatinib and neratinib showed anti-tumor effect. Immunoblot assay showed that lapatinib and neratinib suppressed phosphorylated HER2 and downstream molecules such as p-AKT or p-ERK. In conclusion, 3D HTS drug screening platform could be a useful preclinical tool to evaluate various kinds of drugs rapidly, and eventually provide a valuable insight into precision medicine along with comprehensive genomic analysis.
Note: This abstract was not presented at the meeting.
Citation Format: Sang-Cheol Lee, Young Saing Kim, In Gyu Hwang, Su Jin Lee, Se Hoon Park. Three-dimensional high-throughput drug screening for bladder 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 997.
Abstract 998: HEx: A computational and synthetic biology platform applied to oncology drug discovery
Authors: Schlecht Ulrich , Cordero Pablo , Hillenmeyer Maureen , Jeon Ju Eun , Kvitek Dan , Naughton Brian , Wiemann Philipp , Harvey Colin 
Published: August 2019

Abstract
We present a computational and synthetic biology platform for producing novel compounds targeting proteins relevant to oncology. As eukaryotes, fungi share approximately one third of human genes, including many relevant to core metabolism, cell cycle, DNA repair, and protein degradation. We have developed a computational method for mining fungal genomes to identify genes likely to produce compounds that inhibit specific human target proteins, including undruggable targets such as protein-protein interactions. We engineer these genes using our synthetic biology pipeline to produce the novel compounds in a heterologous host. We present in vitro data for an Aurora Kinase (AURKA) inhibitor developed using this platform as proof of concept for Hexagon Bio's pipeline. These data demonstrate the potential of this system to target the more than 6000 genes shared between fungi and humans.
Citation Format: Ulrich Schlecht, Pablo Cordero, Maureen Hillenmeyer, Ju Eun Jeon, Dan Kvitek, Brian Naughton, Philipp Wiemann, Colin Harvey. HEx: A computational and synthetic biology platform applied to oncology drug discovery [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 998.
Abstract CT008: Tumor Treating Fields combined with radiotherapy and temzolomide for newly diagnosed glioblastoma: Final results from a pilot study
Authors: Grossman Rachel , Limon Dror , Bokstein Felix , Ram Zvi 
Published: August 2019

Abstract
Background: Tumor Treating Fields (TTFields) are a non-invasive, loco-regional, anti-mitotic treatment comprising low intensity alternating electric fields. In the Phase III EF-14 study in newly diagnosed glioblastoma (ndGBM), TTFields significantly improved survival compared to temozolomide (TMZ). Preclinical data have demonstrated that TTFields increased glioma cell death following radiation therapy (RT), suggesting a radio-sensitizing effect of TTFields. We therefore initiated a pilot study to evaluate the safety and feasibility of administering TTFields concomitant to RT and TMZ in ndGBM patients.
Methods: Patients with histologically confirmed ndGBM were treated with TTFields/RT/TMZ followed by maintenance TTFields and TMZ for up to 24 months. TTFields (200kHz) were delivered for &gt;18 hours/day with removal of the transducer arrays during delivery of RT. TMZ was administered at a dose of 75 mg/m2/daily for 6 weeks and RT at a total dose of 60 Gy. The primary endpoint was safety of the combined TTFields/RT/TMZ; secondary endpoints included progression-free survival (PFS), overall survival (OS) and toxicity. Adverse events (AEs) were graded according to CTCAE V4.0.
Results: Ten patients were enrolled at a single center in Israel between April and December 2017. All patients had recovered from maximal debulking surgery or biopsy. Five patients (50%) had undergone gross total resection while the rest had biopsy only. Median age was 59 and median KPS was 80. Median dose of RT was 60 Gy. Six patients (60%) reported at least one AE. The most common AE was TTFields-related skin toxicity, reported in 4 patients (40%), all of which were Grade 1-2 in severity. Two patients reported serious AEs (seizures and general deterioration) that were considered unrelated to TTFields. Median PFS with RT/TMZ/TTFields was 10.5 months. Median OS has not yet been reached.
Conclusions: The proportion of patients with TTFields-related skin toxicity was similar to that reported in ndGBM patients in the randomized Phase III study (52%). No other TTFields-related toxicities were reported, nor was there an increase in RT- or TMZ-related toxicities as a result of combining TTFields with RT in addition to TMZ. Based on the safety and preliminary efficacy results of this pilot study, a Phase II randomized study has been initiated to investigate the efficacy of concomitant RT/TMZ/TTFields in 60 ndGBM patients.
Citation Format: Rachel Grossman, Dror Limon, Felix Bokstein, Zvi Ram. Tumor Treating Fields combined with radiotherapy and temzolomide for newly diagnosed glioblastoma: Final results from a pilot study [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 CT008.