bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6566: Defining the effects of inhibiting the beta-catenin-CBP signaling axis with the small molecule E7386 by integrative analysis of omics data
Authors: Federico Anthony , Owa Takashi , Nomoto Kenichi , Varelas Xaralabos , Kukuruzinksa Maria , Monti Stefano 
Published: September 2020

Abstract
Head and neck squamous cell carcinoma (HNSCC) is associated with high morbidity, poor survival rates, and limited treatment options. We previously reported that aberrant activation of nuclear β-catenin/cAMP-responsive element binding (CREB)-binding protein (CBP) signaling in primary HNSCC tumors was associated with progression to advanced disease and poor patient survival. Further, inhibition of β-catenin-CBP interaction with the first-generation inhibitor, ICG-001, greatly attenuated aggressive properties of HNSCC cells and tumor growth and metastases in murine and zebrafish models. Our recent findings show that a novel β-catenin/CBP modulator, E7386, displays an activity profile that closely overlaps with that of ICG-001, but exhibits ~50-100-fold lower EC50 values.
In this study, we used a novel method for gene regulatory network (GRN) reconstruction which analyzes publicly available high-throughput transcriptomics data from HNSCC to further elucidate the mechanisms of β-catenin-CBP inhibition by E7386. A Bayesian framework was used to reconstruct high-dimensional GRNs using constraint-based and shared structure learning from bulk RNA-seq data from TCGA. HNSCC patients were grouped into two subtypes, based on their “high” vs. “low” response to E7386 inhibition as predicted by the activation - or enrichment by Gene Set Variation Analysis (GSVA) - of the transcriptional signature we derived.
GRNs for the two subtypes were built, and their comparison highlighted new interactions in the “high” responders network between the β-catenin/CBP network and genes associated with histone modifications (ASH1L) and amino acid metabolism (MTR) concomitant with loss of interactions with regulators of cell cycle (ERCC6L) and protein secretion (SCAMP1) identified in the “low” responders network. Additionally, Kaplan-Meier survival plots showed that HNSCC patients with high activation of the E7386 signature had a significantly lower probability of survival. These results suggest that our GRN-based approach represents an important novel tool for assessing changes in regulatory network interactions in HNSCC and cancer.
Citation Format: Anthony Federico, Takashi Owa, Kenichi Nomoto, Xaralabos Varelas, Maria Kukuruzinksa, Stefano Monti. Defining the effects of inhibiting the beta-catenin-CBP signaling axis with the small molecule E7386 by integrative analysis of omics data [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6566.
Abstract 657: Inhibition of mTORC1 by dihydroartemisinin
Authors: Liu Wang , Luo Jun , Odaka Yoshinobu , Huang Shile 
Published: September 2020

Abstract
mTOR functions as two complexes, mTORC1 and mTORC2, and is a central controller for cell growth and metabolism. Both mTORC1 and mTORC2 are activated in numerous cancers, and have become the focus of anticancer drug development. Rapalogs and mTOR kinase inhibitors (TORKIs) have been developed. However, the anticancer efficacy of rapalogs is clinically weak or mild to most cancers, and the adverse effects of rapalogs and TORKIs are greatly concerned. So, it is imperative to discover and develop new generation of mTOR inhibitors. Dihydroartemisinin (DHA) is an anti-malarial agent showing good safety in both children and adults. Recently, we have shown that DHA, at pharmacological concentrations, inhibits proliferation and induces apoptosis in cells derived from various cancer types but not in normal or immortalized cell lines, implying that DHA is potentially a selective anticancer agent and may be repurposed for cancer therapy. Of interest, DHA potently suppresses mTORC1-mediated phosphorylation of S6K1 and 4E-BP1, but does not obviously affect mTORC2-mediated phosphorylation of Akt, which is often activated by classic mTOR inhibitors (rapalogs) via a feedback mechanism. The results suggest that DHA is a novel mTORC1 inhibitor. This study was set to determine how DHA inhibits mTORC1. Here we found that DHA did not bind to any mTORC1 components (mTOR, mLST8 or raptor) directly, as determined by in vivo [3H]-DHA radiolabeling. Besides, our molecular docking revealed that DHA did not have the ability to bind FKBP12 or mTOR kinase domain, in contrast to the positive controls rapamycin (binding FKBP12) and INK128 (binding mTOR kinase domain). These data suggest that DHA inhibits mTORC1 via indirect mechanism(s). Further research revealed that DHA altered neither the phosphorylation of IGF-1R/PI3K/PTEN and ERK, nor the expression of REDD1, but induced phosphorylation of AMPKα (T172). Interestingly, DHA-induced mTORC1 inhibition was profoundly attenuated by inhibition with Compound C (AMPK inhibitor) or ectopic expression of dominant negative AMPKα2 (AMPKα2-DN), indicating that activation of AMPK links to inhibition of mTORC1. Collectively, the results support that DHA inhibits mTORC1 by activating AMPK. (Supported by the Feist-Weiller Cancer Center, LSU Health Sciences Center, Shreveport, LA, USA.)
Citation Format: Wang Liu, Jun Luo, Yoshinobu Odaka, Shile Huang. Inhibition of mTORC1 by dihydroartemisinin [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 657.
Abstract 6570: Predicting drug effects on breast cancer cell shapes by converging image and transcriptomic profiles
Authors: Yin Zheng , Bakal Chris , Wong Stephen T. 
Published: September 2020

Abstract
Cell shapes have long served as hallmarks for cancer diagnostics and therapeutics evaluations. This work converges public available image and transcriptome profiles to build a drug-gene-shape networks, thus facilitate the usage of cell shape features as drug targets during the development of novel cancer therapeutics. We took advantage of a previous work (Sailem et. al., 2017) of image-omits modeling where 504 shape-correlated genes were identified for 20 cell shape features across 18 breast cancer cell lines. Transcriptome profiles from Broad Institute Clue.io database were used to identify small molecular compounds that can significantly impact those shape-correlated genes. As a result, 22 compound families of at least two members were identified as candidates that can significantly impact the shape-correlating gene sets for 13 shape features. Our work re-opens the doors for using cell shape as drug target and considering the impact on cell shapes during drug repurposing and design of combination therapies for breast cancer.
Compound families with the most significant correlations with gene sets regulating average cell areaCompound famileAverage scoremTOR inhibitors94.975Tubulin inhibitors94.615Adrenergic receptor antagonist94.545PKC inhibitor-93.580MEK inhibitor-94.137HDAC inhibitor-94.153
Citation Format: Zheng Yin, Chris Bakal, Stephen T. Wong. Predicting drug effects on breast cancer cell shapes by converging image and transcriptomic profiles [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6570.
Abstract 6575: A novel AI-driven spatial genomics platform enables tumor enrichment and analysis of heterogeneity
Authors: Chaudhuri Bidhan , Konigsfeld Katie , Sanchez Marisa , Smith Jason , Laris Casey , Weston Claire , Butler John 
Published: September 2020

Abstract
Spatial genomics and digital pathology continue to advance at a rapid pace, generating large amounts of data. There is a critical unmet need for advanced tools to expedite spatial data generation, visualization, and analysis, to facilitate an improved understanding of health and disease, especially with the advancement of personalized cancer treatments. In this study we present a novel method for the extraction and analysis of genomic information from specific regions of interest (ROI) within a series of formalin-fixed paraffin embedded (FFPE) breast cancer adenocarcinoma tissue sections. An artificial intelligence-based tumor profiling algorithm first identified tumor, stroma, inflammatory, and necrotic regions within the tissue, and segmentation results were confirmed by a Board Certified Pathologist. Automated lysate extraction was then performed in the selected ROIs using ink-jet technology and novel ink chemistry. The process was performed directly on the tissue slide and the crude lysates generated were transferred to a standard collection tube for subsequent sequencing. DNA was extracted from the selected areas before being purified and analyzed using a multi-cancer panel. Library QC showed optimal coverage at an average of &gt;95% uniformity. Sequencing results showed an average coverage of 95% at 250x across all amplicons of the panel. Variant calling was successfully performed. Sequencing data is presented to demonstrate the high coverage achieved using this workflow as well as the resulting tumor heterogeneity. This novel technology provides an efficient solution for the enrichment of tumor content with high sequencing coverage from FFPE tissue sections. Novel spatial data visualization and analysis techniques allowed a comprehensive assessment of tumor heterogeneity. Further studies on both DNA and RNA should be conducted to validate this approach for clinical molecular testing.
Citation Format: Bidhan Chaudhuri, Katie Konigsfeld, Marisa Sanchez, Jason Smith, Casey Laris, Claire Weston, John Butler. A novel AI-driven spatial genomics platform enables tumor enrichment and analysis of heterogeneity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6575.
Abstract 6585: Systems biology for investigating drug resistance mechanism of melanoma
Authors: Su Yapeng , Li Guideng , Ko Melissa , Cheng Hanjun , Zhu Ronghui , Xue Min , Robert Lidia , Levine Raphael , Ribas Antoni , Nolan Garry , Wei Wei , Plevritis Sylvia , Baltimore David , Heath James R. 
Published: September 2020

Abstract
Integrated proteomic and metabolic single-cell assays reveal multiple independent adaptive responses to drug tolerance in a BRAF-mutant melanoma cell line
Cancers commonly develop resistance against chemotherapeutics or targeted therapies through various types of genetic or non-genetic mechanisms. Non-genetic mechanisms have been shown to occur early on and can provide a latent reservoir of cells for the emergence of various different type of mechanisms, yet very limited understanding of process were resolve main from bulk analysis. Considering the heterogeneous nature of the tumor cells, a single-cell level characterization of the process worth detailed further investigation. Using MAPK inhibition of BRAF-mutant melanomas as a model system, we resolved that cells take different paths to go from drug-sensitive to drug-resistant state. Using a microfludic-based single-cell integrated proteomic and metabolic assay, we assayed for a panel of signaling, phenotypic, and metabolic regulators at four time points during the first five days of drug treatment. Dimensional reduction of the resultant data set, coupled with information theoretic analysis, uncovered a complex cell state landscape and identified two distinct paths connecting drug-naïve and drug-tolerant states. Cells are shown to exclusively traverse one of the two pathways depending on the level of the lineage restricted transcription factor MITF in the drug-naïve cells. The two trajectories are associated with distinct signaling and metabolic susceptibilities, and are independently druggable. Our results update the paradigm of adaptive resistance development in an isogenic cell population and offer insight into the design of more effective combination therapies.
Citation Format: Yapeng Su, Guideng Li, Melissa Ko, Hanjun Cheng, Ronghui Zhu, Min Xue, Lidia Robert, Raphael Levine, Antoni Ribas, Garry Nolan, Wei Wei, Sylvia Plevritis, David Baltimore, James R. Heath. Systems biology for investigating drug resistance mechanism of melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6585.
Abstract 6591: Antibody-based redirection of meditope-CAR T cells selectively kill antigen bearing tumor cells
Authors: Kuo Yi-Chiu , King Jeremy D. , Kuo Cheng-Fu , Kenyon Victor , Park Miso , Chang Wen-Chung , Stern Lawrence , Brown Christine E. , Williams John C. 
Published: September 2020

Abstract
Adoptive T cell transfer of engineered T cells with a chimeric antigen receptor (CAR) can harness the patients' immune system to recognize a specific antigen and redirect T cells to target disease. Conventional CAR T cells, however, are specific to a single antigen. While remarkably effective, antigen escape, due in part to the heterogeneous nature of a tumor, renders these CAR T cells ineffective. In order to address the disadvantage of conventional CAR T cells, we developed a switchable CAR T cell system. Specifically, we replaced the antigen-binding domain of a conventional CAR with a meditope and used meditope-enabled monoclonal antibodies (memAbs) to alter antigen specificity. As the T cell decoration is similar to how a bike rack is used to transport bicycles on cars, we have coined the technology a Fabrack. To fully examine our switchable CAR T cell system, Fabrack CAR Jurkat-NFAT-Luc cells were established to quantitate T cell activation through NFAT-regulated luciferase expression. Multiple memAbs with unique antigen specificity were combined with the Fabrack CAR Jurkat cells and target tumor cells and demonstrated the feasibility, specificity and robustness of the in vitro system. Next, native human T cells transduced with Fabrack showed dramatic tumor-killing effect when coupled with an antigen specific memAb. The engaged Fabrack T cells proliferated with remarkably increased CD107a and IFNγ, indicating functional activation of T cells. Live cell imaging demonstrated selective killing of target cells in the presence of corresponding memAbs. Furthermore, tumor burden in immunocompromised mice with OVCAR3 xenografts was largely reduced when mice were treated with Fabrack T cells and memAbs. Collectively, these studies suggest the feasibility of switchable CAR T cell and support further development for future clinical use in cancer immunotherapy.
Citation Format: Yi-Chiu Kuo, Jeremy D. King, Cheng-Fu Kuo, Victor Kenyon, Miso Park, Wen-Chung Chang, Lawrence Stern, Christine E. Brown, John C. Williams. Antibody-based redirection of meditope-CAR T cells selectively kill antigen bearing tumor cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6591.
Abstract 6595: Targeting T cell lymphomas with CRISPR/Cas9-generated anti-CD70 allogeneic CAR-T cells
Authors: Karnik Sushant , Pham Minh Thu , Keerthipati Pooja , Padalia Zinkal , Carson Julie , Ho Tony , Morawa Ewelina , Will Matthias , Terrett Jonathan , Dequeant Mary-Lee 
Published: September 2020

Abstract
T cell lymphomas account for 10% to 15% of non-Hodgkin lymphomas and are diverse biologically and clinically. Unlike B-cell lymphomas, T cell lymphomas are rather resistant to conventional therapies, such as chemotherapy and antibody-based therapeutics. This resistance coupled with the diversity of the T cell diseases means that there is a significant unmet need across the T cell lymphoma subtypes. CD70 (CD27 ligand) is a candidate target antigen for T cell lymphomas and has been is the subject of clinical trials using an enhanced ADCC antibody (ARGX-110). Using flow cytometry and immunohistochemistry (IHC) methods, we analyzed the expression of CD70 in cell lines and clinical samples representing T cell lymphomas and found significant expression of CD70 in multiple types of T cell lymphoma, but at highly variable antigen density. CAR-T cells targeting CD70 may thus be a potent new therapy to tackle these diseases. However, the use of autologous CAR-T therapy against T cell lymphomas is complicated by the likelihood of creating lymphoma cells carrying the CAR construct. Thus, we sought to examine the potency of our allogeneic anti-CD70 CAR-T cells (CTX130) against T cell lymphoma cells. CTX130 has previously been shown to be active across a range of CD70 expression levels in other cell types representing other malignancies. Consistent with these prior observations, CTX130 exhibited high potency in vitro and in vivo against T cell lymphoma cells across a range of CD70 antigen density and representing different types of T cell lymphomas such as Sezary syndrome and cutaneous T cell lymphoma (CTCL). CTX130 may thus be a valid therapeutic to evaluate in T cell lymphoma patients.
Citation Format: Sushant Karnik, Minh Thu Pham, Pooja Keerthipati, Zinkal Padalia, Julie Carson, Tony Ho, Ewelina Morawa, Matthias Will, Jonathan Terrett, Mary-Lee Dequeant. Targeting T cell lymphomas with CRISPR/Cas9-generated anti-CD70 allogeneic CAR-T cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6595.
Abstract 660: Combination of mTOR kinase inhibitors with Src inhibitors in PTEN-mt prostate cancer cells
Authors: Dai Yao , Siemann Dietmar 
Published: September 2020

Abstract
Although Src inhibitors are able to suppress malignant functions, their clinical outcomes are modest for the treatment of advanced prostate cancer, many of which harbor mutated PTEN. mTOR pathway is commonly hyperactivated in prostate cancer due to frequent PTEN mutation, and it is known that two mTOR complexes are both critical in prostate cancer progression. However, the functional role of mTOR kinase in Src inhibitor-mediated response remains unknown. In the current study, we combined mTOR kinase inhibitor AZD8055 and Src inhibitor dasatinib to evaluate functional behaviors in PTEN-deleted prostate cancer cells. Gene silencing was achieved by siRNA or shRNA transfection. Cell proliferation and clonogenic survival were performed by MTT and colony formation assay, respectively. “Wound-healing” scratch assay was conducted to monitor cell migration, and Matrigel-based transwell assay was applied to assess cell invasion. Protein expression was detected by Western blotting. We found that in PTEN-mt cells, C4-2B showed greater expression of p-Akt, p-S6, p-4EBP1 and p-eIF4E, all of which are mTOR complexes downstream components. Such molecular profile is consistent with functional observation that C4-2B cells are more resistant to dasatinib. Interestingly, single knockdown of either 4EBP1, S6RP or AKT showed little effects of inhibiting cell survival, while double knockdown of both 4EBP1 and AKT, cell survival was significantly inhibited. Consistently, two agents together showed significantly greater inhibition on proliferation and clonogenic survival than either single agent. Such combination effects were either additive or synergistic depending on the cell types, as reflected by combination index calculation. In addition, cell migration and invasion were inhibited in a greater extent by AZD8055 plus dasatinib, compared to either treatment alone. At the molecular level, co-targeting mTOR and Src kinases leads to strong inhibition of mTOR and Src pathways, such as FAK, Akt, S6RP and 4E-BP1. These data indicate that adding AZD8055 to dasatinib may achieve better treatment outcomes in PTEN-mt prostate cancer models. Such combination modality hold potential for future development as a novel strategy for PTEN-mutated prostate cancer patients who are less responsive to Src inhibitors.
Citation Format: Yao Dai, Dietmar Siemann. Combination of mTOR kinase inhibitors with Src inhibitors in PTEN-mt prostate cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 660.
Abstract 6621: A combined VHH and small molecule approach to modulate the antitumor immunity function of ERAP1
Authors: Basse Nicolas 
Published: September 2020

Abstract
ERAP1 is a multifunctional enzyme trimming N-terminal amino acids of peptides. Its most characterised function is its role in generating peptide ligands in the endoplasmic reticulum for loading onto MHC class I (MHCI) molecules for presentation at the cell surface. Here it acts as an antigenic peptide editor influencing the peptide repertoire displayed at the cell surface to circulating CD8+ T cells and NK cells. ERAP1 modulates the immunopeptidome and could play a key role in tumor antigenicity.
ERAP1 is a highly dynamic enzyme and its conformation is crucial for intracellular immuno-signals and also various extracellular functions. The precise molecular mechanisms behind the secretion and conformational status of ERAP1 remain unclear. To study ERAP1, we combined a VHH and a small molecule approach. After Lama immunization, the selected ERAP1 binders were filtered for functional activity. To measure ERAP1 activity with relevant substrates, we developed a mass spectrometry assay and a fluorogenic substrate mimicking ERAP1 peptidic substrates. Nanobodies modulators of ERAP1 activity are currently used for structural studies.
In addition to the mechanistic studies, the team also developed ERAP1 small molecule modulators to induce or restore tumor immunogenicity. Herein, we report a chemical family of potent ERAP1 inhibitors that demonstrate structure activity relationship.
The nanobodies and small molecule modulators we developed provide useful tools to better understand the biology of ERAP1 in immune responses.
Citation Format: Nicolas Basse. A combined VHH and small molecule approach to modulate the antitumor immunity function of ERAP1 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6621.