bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-A15: An Ex-vivo Platform Predicts Anti-tumor Outcome of Metabolically-Targeted, Algorithm-Driven Combination Therapy in Triple-Negative Breast Cancer
Authors: Goldman Aaron J. 
Published: August 2018

Abstract
Abstract: Cancer cells undergo phenotypic cell state transitions in response to chemotherapy as a mechanism that can confer transient resistance. However, such cell state transitions can also unlock unique vulnerabilities that can be exploited using temporally-sequenced combination chemotherapy. Here, utilizing a primary breast cancer ex-vivo functional assay (CANScriptTM) that captures tumor heterogeneity, we report that in response to a chemotherapeutic agent, a subset of cancer cells can mount an acutely-induced phenotypic adaptive resistance to future cytotoxic pressure via the transient acquisition of a unique metabolic state defined by augmented glycolysis together with mitochondrial proficiency. These cells activate two complex, temporally-interdependent pathways that enable a glucose shunt towards the pentose phosphate pathway (PPP), which confers an adaptive cross-tolerance to different chemotherapeutic agents. Mathematically modeling these pathways, and simulating drug schedules, we define a rationally-designed 3-drug combination therapy of metabolic inhibitors and cytotoxic agents, which results in improved cancer survival. Our findings highlight a new bioenergetics-based adaptive resistance mechanism through which cancer cells can survive combinations of chemotherapy. Administration of metabolic inhibitors in rational, temporal sequence with existing chemotherapy can emerge as a new paradigm in the treatment of cancer.
Citation Format: Aaron J. Goldman. An Ex-vivo Platform Predicts Anti-tumor Outcome of Metabolically-Targeted, Algorithm-Driven Combination Therapy in Triple-Negative Breast Cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A15.
Abstract LB-A16: Targeting the WNT-pathway in 3D-cultured in vitro PDX models for pancreas cancer
Authors: Dijkmans Thomas 
Published: August 2018

Abstract
Creating patient-derived xenograft (PDX) models from human cancers allows bio-banking, propagation, characterization and drug testing on a large panel of tumor variants. To scale up the number of compound tests, identify relevant compound doses, increase the throughput, and study relevant cancer-driving pathways we developed 3D in vitro culture methods for PDX model-derived cell isolates. In this effort, each individual model is subjected to a wide panel of culture medium formulations, amongst which some media contain WNT-pathway stimulating components. In one of our campaigns we identified an absolute dependency of one of the tested Pancreatic in vitro PDX models to the WNT-signaling potentiating factor R-Spondin, while other Pancreas models showed little or no dependency. To further study the dependency of Pancreatic PDX models on the functionality and signaling of the WNT-pathway, we exposed these in vitro PDX models to increasing doses of bio-similars of 18R5 (anti-FZD7), 54F28 (FZD8-Fc decoy receptor) and to the Porcupine inhibitor LGK974, which blocks WNT palmitoylation and therefore secretion. Our findings are that the WNT-pathway is functional and contributing to Pancreas cancer outgrowth and morphological differentiation at different extents and levels in different patient-models. Our in vitro PDX culture system in combination with 3D phenotypic analysis allows in-detail study of the WNT-pathway, as well as by supplementation or omission of secreted factors, addition of small molecule inhibitors and by exposure to antibodies. These in vitro PDX models can be used to test novel compounds and antibodies targeting the WNT pathway.
Citation Format: Thomas Dijkmans. Targeting the WNT-pathway in 3D-cultured in vitro PDX models for pancreas cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A16.
Abstract LB-A23: Discovery of a potent catalytic p300/CBP inhibitor that targets lineage-specific tumors
Authors: Bromberg Kenneth D. , Lasko Loren M. , Jakob Clarissa G. , Qiu Wei , Montgomery Debra , Digiammarino Enrico L. , Hansen Todd M. , Risi Roberto M. , Frey Robin R. , Manaves Vlasios , Shaw Bailin , Algire Mikkel , Hessler Paul , Lam Lloyd T. , Uziel Tamar , Favire Emily , Ferguson Debra , Buchanan Fritz G. , Martin Ruth L. , Torrent Maricel , Rosenberg Saul H. , Michaelides Michael R. , Lai Albert 
Published: August 2018

Abstract
The dynamic and reversible acetylation of proteins catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs) is a major epigenetic regulatory mechanism of gene transcription associated with multiple diseases. While HDAC inhibitors are approved to treat certain cancers, progress on the development of drug-like HAT inhibitors has lagged. The HAT paralogs p300 and CBP (p300/CBP) are key transcriptional co-activators essential for a multitude of cellular processes and also implicated in human pathological conditions, including cancer. Current p300/CBP HAT domain inhibitors including natural products, bi-substrate analogs (Lys-CoA) and the widely utilized C646 lack potency or selectivity. Here, we describe A-485, a potent, selective and drug-like p300/CBP catalytic inhibitor. We show the first high resolution (1.95Å) co-crystal structure of a small molecule bound to the catalytic active site of p300 and demonstrate that A-485 is acetyl-CoA competitive. A-485 selectively inhibited proliferation across lineage-specific tumor types, including several hematological malignancies and androgen receptor-positive prostate cancer. A-485 inhibited the androgen receptor transcriptional program in both androgen sensitive and castrate resistant prostate cancer and inhibited tumor growth in a castration resistant xenograft model. These results demonstrate the feasibility of selectively targeting the catalytic activity of histone acetyltransferases.
Citation Format: Kenneth D. Bromberg, Loren M. Lasko, Clarissa G. Jakob, Wei Qiu, Debra Montgomery, Enrico L. Digiammarino, Todd M. Hansen, Roberto M. Risi, Robin R. Frey, Vlasios Manaves, Bailin Shaw, Mikkel Algire, Paul Hessler, Lloyd T. Lam, Tamar Uziel, Emily Favire, Debra Ferguson, Fritz G. Buchanan, Ruth L. Martin, Maricel Torrent, Saul H. Rosenberg, Michael R. Michaelides, Albert Lai. Discovery of a potent catalytic p300/CBP inhibitor that targets lineage-specific tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A23.
Abstract LB-A26: Regulation of super-enhancers by GZ17-6.02 has therapeutic effect in pancreatic cancer (PDAC)
Authors: Ghosh Chandrayee , Gunewardena Sumedha , Paul Santanu , West Cameron , Dhar Animesh 
Published: August 2018

Abstract
Super enhancers (SE) are defined as unique areas of the genome that are densely bound by numerous transcription factors and play a pivotal role in the cell, including, tissue specification, identity and maintenance. Super enhancers are known to regulate the expression of associated genes and often drive high-level transcription. Studies have established many genes that play an important role in cancer biology as SE-driven oncogenes. It is likely that the peculiar pancreatic-specific tumor phenotype is a consequence of oncogenes hacking the resident tissue regenerative program, thus interfering with super enhancer-driven repair networks exerting a disproportionately disruptive effect on tumor versus normal pancreatic tissue. In this study, we have used ChIP-seq, RNA-seq and bioinformatics analysis to identify super-enhancers in the human metastatic pancreatic cancer cell line S2-007. H3K27ac marks were identified at enhancer region of numerous genes that act as SE in PDAC. The most prominent super-enhancers identified, based on a high level of H3K27ac marks were associated with c-MYC, MED1, OCT-4, NANOG and SOX2 genes. Previously we showed that “isovanillin”, one of the major compound of A. palaestinum, in combination with other anticancer agents termed as ‘GZ17-6.02’ inhibited tumor progression and metastasis in PDAC by suppressing cancer stem cells (CSCs) and sonic hedgehog (SHH) pathway in both in vitro and in vivo systems. In this study, we found that GZ17-6.02 affects acetylation of histones at some of the major SE related genes and at a high dose, a complete reduction in acetylation marks was seen in embryonic stem cell transcription factors. The mRNA sequencing data after GZ17-6.02 treatment also shows a reduction in transcription of, major transcription factors, SHH pathway genes, and stem cell markers. Cancer cells are more sensitive to lower doses of GZ17-6.02 than normal cells; hence normal cells are expected to have fewer side effects. There is no systematic study showing an association of super-enhancers with pancreatic cancer so far. Hence, in the present study, we have established that several super-enhancer targets can be targeted by GZ17-6.02 in PDAC. This study concludes that super-enhancers can be an important therapeutic target for PDAC.
Citation Format: Chandrayee Ghosh, Sumedha Gunewardena, Santanu Paul, Cameron West, Animesh Dhar. Regulation of super-enhancers by GZ17-6.02 has therapeutic effect in pancreatic cancer (PDAC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A26.
Abstract LB-B03: Exosome-based Detection of EGFR T790M in Plasma from Non-Small Cell Lung Cancer Patients
Authors: Castellanos Elena , Grimm Dominik G. , Tadigotla Vasisht , Bentink Stefan , Hurley James , Healy John , Neal Patricia L. , Sher Mia , Baughman Dan , Karlovich Chris , Raponi Mitch , Krug Anne , Noerholm Mikkel , Raez Luis E. , Skog Johan 
Published: August 2018

Abstract
About 60% of non-small cell lung cancer (NSCLC) patients develop resistance to targeted epidermal growth factor receptor (EGFR) inhibitor therapy through the EGFR T790M mutation. Although these patients respond well to third generation tyrosine kinase inhibitors like osimertinib, obtaining tissue biopsies for mutation profiling poses risks and is often not feasible. Detecting the mutation in a liquid biopsy from plasma has emerged as a viable alternative to biopsy, however existing liquid biopsy tests using cell-free DNA (cfDNA) often suffer from low sensitivity due to the low copy number of mutant molecules in circulation. As an example, the Food and Drug Adminstration (FDA) approved companion diagnostic for T790M mutation status in plasma (cobas® EGFR mutation Test version 2) only has a 58% sensitivity at a specificity of 80%. In this study we aimed to achieve a higher performance by combining the mutated alleles on cfDNA as well as exosomal RNA and DNA (exoNA) .
ExoNA and cfDNA were extracted from the plasma of NSCLC patients with biopsy-confirmed T790M-positive (N = 102) or T790M-negative (N = 108) samples. The T790M mutation status in plasma exoNA and cfDNA was determined using an analytically validated allele-specific qPCR assay in a CLIA laboratory.
The training cohort consisted of 105 samples (51 positives, 54 negatives). The validation cohort consisted of 105 samples (51 positives, 54 negatives), where ~40% of the patients had intrathoracic disease(M0/M1a). Detection of the T790M mutation in exoNA and cfDNA achieved 92% sensitivity and 89% specificity when compared to tumor biopsy results in the validation cohort. We also observed a very high sensitivity (88%) in patients with intrathoracic disease (M0/M1a), patients for whom detection by liquid biopsy has been proven particularly challenging.
The combination of exoNA and cfDNA for EGFR T790M detection has a higher sensitivity and specificity compared to historical cohorts using ctDNA alone. This is especially important as it could aid giving the right treatment to patients where biopsy is not available or avoid unnecessary tumor biopsies for T790M mutation testing.
Citation Format: Elena Castellanos, Dominik G. Grimm, Vasisht Tadigotla, Stefan Bentink, James Hurley, John Healy, Patricia L. Neal, Mia Sher, Dan Baughman, Chris Karlovich, Mitch Raponi, Anne Krug, Mikkel Noerholm, Luis E. Raez, Johan Skog. Exosome-based Detection of EGFR T790M in Plasma from Non-Small Cell Lung Cancer Patients [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B03.
Abstract LB-B05: Targeting IDH1 inhibits survival and growth of pancreatic cancer cells
Authors: Vaziri-Gohar Ali , Dukleska Katerina , Brody Jonathan R. , Winter Jordan M. 
Published: August 2018

Abstract
Pancreatic ductal adenocarcinoma (PDA) cells have elevated levels of reactive oxygen species (ROS) compared to adjacent normal cells. Although ROS play a role in pancreatic carcinogenesis, the accumulation of excess ROS at later stages of cancer development threaten PDA cell viability. Therefore, adaptive mechanisms to neutralize excess ROS are critical for PDA cell survival. Recently, we discovered the regulatory RNA binding protein, HuR (ELAVL1), protects PDA cells under oxidative stressors, like chemotherapy and nutrient deprivation, by upregulating the NADPH-generating enzyme, isocitrate dehydrogenase 1 (IDH1) through post-transcriptional stabilization of the RNA transcript. This action enhances PDA reductive power under oxidative stress. We hypothesized that IDH1 would be an effective target to treat PDA under its native harsh microenvironment. We deleted IDH1 from isogenic PDA cells using CRISPR gene editing technology and studied the phenotypic impact under physiologic stress. Under both normal culture conditions and nutrient deprivation, IDH1-/- cells had increased ROS as measured by a DCFDA assay, and decreased cell viability as measured by the PicoGreen DNA quantitation assay. Furthermore, IDH1-/- cells were more susceptible to chemotherapy treatment in vitro (gemcitabine or 5-FU) compared with control cells. In vivo experiments revealed that IDH1-/- cells have reduced ability to engraft and grow as xenografts. Taken together, these results suggest that targeting wild type IDH1 is a compelling therapeutic strategy to treat PDA cells, particularly in the context of their extreme and austere microenvironment.
Citation Format: Ali Vaziri-Gohar, Katerina Dukleska, Jonathan R. Brody, Jordan M. Winter. Targeting IDH1 inhibits survival and growth of pancreatic cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B05.
Abstract LB-B06: p65BTK is a novel theranostic target in NSCLC
Authors: Grassilli Emanuela 
Published: August 2018

Abstract
Recently we identified new targets to overcome drug resistance in colon cancer; in particular, we discovered and characterized p65BTK, a novel isoform of the Bruton Tyrosine Kinase (BTK). p65BTK is a novel oncogene and a pivotal downstream effector of RAS; its inhibition affects growth and survival of colon cancer cells, (Grassilli et al, Oncogene 2016) and restore the response to chemotherapy in a p53-null background. Here, we investigated whether p65BTK might be a therapeutic target also in Non Small Cell Lung Cancer (NSCLC). Immunohistochemistry assays using anti-p65BTK specific polyclonal antibodies raised in the lab were performed to study p65BTK expression in NSCLC patient specimens. In order to determine the effect of p65BTK inhibition on cell biology, proliferation and viability of NSCLC cell lines with different genetic backgrounds, we carried out growth curves and colony formation assay in presence of increasing concentrations of different BTK inhibitors (Ibrutinib, AVL-292, RN-486). In order to determine whether p65BTK could be a novel theranostic target in NSCLC, representative cell lines were treated with chemotherapy (Cisplatin, Gemcitabine, Pemetrexed) or EGFR-targeted therapy (Gefitinib, Erlotinib) alone or in combination with non-toxic concentrations of BTK inhibitors and then their viability was assessed. First, we showed that p65BTK is expressed in 50% of NSCLC patients’ tissue and its expression correlates with histotype, smoke habit and wtEGFR. In fact, p65BTK is significantly more expressed in adenocarcinoma vs squamous carcinoma patients and in non-smoker vs smoker patients. Finally, its expression is significantly higher in non-smoker patients bearing wild type vs mutant EGFR. Then, we demonstrated that NSCLC cell lines scarcely sensitive to EGFR-targeted therapy overexpress active p65BTK and their viability of is affected in a dose-dependent manner by BTK inhibition. In fact, p65BTK inhibition strongly impairs proliferation and clonogenicity of the same NSCLC cell lines. Notably, p65BTK inhibition reverts resistance of NSCLC cell lines to Cisplatin and Gefitinib, independently of the EGFR and K-Ras status. In conclusion, our data indicate that the inhibition of p65BTK resensitizes NSCLC cells scarcely responsive to chemotherapy and targeted therapy, suggesting that the combined treatment of BTK inhibitors and classic chemotherapy or targeted therapy could represent a novel approach to overcome drug resistance.
Citation Format: Emanuela Grassilli. p65BTK is a novel theranostic target in NSCLC [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B06.
Abstract LB-B07: Photoreceptor phosphodiesterase 6H expression regulates HCT116 proliferation and cell cycle progression
Authors: Yalaz Ceren , Haider Syed , Chen Jianzhou , Prevo Remko , Woodcock Mick , Harris Adrian L. , Muschel Ruth J. 
Published: August 2018

Abstract
Phosphodiesterase 6 (PDE6) protein complex, which is responsible for the turnover of the second messenger cyclic guanosine monophosphate (cGMP) and is involved in visual signal transduction of light stimuli, is highly expressed in certain cancer cell lines. Despite having been discovered in the outer segment of rods and cones of the retina, PDE6 protein is also detected in brain, adrenal glands, lungs, and gonads. Genes encoding the catalytic subunits of the enzyme are known to be upregulated in certain breast, non-small cell lung cancer and medulloblastoma cells. PDE6H, which encodes the cone-specific inhibitory gamma subunit of PDE6 protein, is part of the gene signature of achromatopsia and congenital stationary night blindness while its relation to cancer remains unclear. We recently identified PDE6H as a cell cycle controller in HCT116 colorectal cancer cell line, as part of an siRNA screen in which DNA content measurement via flow cytometry was undertaken to monitor cell cycle distribution. The screen was conducted with a custom library of metabolic genes commonly amplified in primary tumours, as well as those known to be involved in the key regulatory points of metabolic pathways.
We have shown that PDE6H knockdown and pharmacological inhibition of PDE6 protein hindered the activity of the protein complex, causing an accumulation of cGMP in various colorectal and breast cancer cell lines. This inhibition resulted in a G1 cell cycle arrest and disruption of G1/S checkpoint mechanism. PDE6H knockdown inhibited cell proliferation and cellular oxidative phosphorylation. It also altered mitochondrial morphology and induced apoptosis. Our results suggest that the gamma subunit is important for the function of photoreceptor phosphodiesterase PDE6 complex and PDE6H inhibition can be explored as an anti-proliferative strategy.
Citation Format: Ceren Yalaz, Syed Haider, Jianzhou Chen, Remko Prevo, Mick Woodcock, Adrian L. Harris, Ruth J. Muschel. Photoreceptor phosphodiesterase 6H expression regulates HCT116 proliferation and cell cycle progression [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B07.
Abstract LB-B09: Application of Fluorescence Correlation Spectroscopy as a novel tool to quantify target occupancy in cells and tumor tissue
Authors: Becker Frank , Hansen Kerrin , Crochiere Marsha , Landesmann Yosef , Hannus Stefan 
Published: August 2018

Abstract
The quantification of Target Occupancy (TO) in cells after application of an inhibitor is an important parameter to correlate the biochemical features of a drug with its in vivo efficacy. Experimental evidence of TO is a robust support of the target hypothesis and helps to identify optimal dosing of the drug. The sensitive correlation spectroscopy methods (FCS and FCCS) have been used successfully in the past to analyze drug- target interactions. The technology is fast, specific and allows detection of drug target interactions in smallest sample volumes. Here we adopted the FCCS method to quantify the occupancy of the XPO1 target in cells and tumors treated with the Selective Inhibitor of Nuclear Export (SINE) compound Selinexor (KPT-330), currently in advanced clinical trials in patients with hematological and solid cancers. We used a fluorescently labeled tracer (Leptomycin B -Cy5; LMB-Cy5) to quantify the loading of XPO1 with Selinexor and confirmed target specificity of the signal using a fluorescent labeled antibody detecting native XPO1 protein. The amount of Antibody-XPO1-tracer complex was determined by FCCS. Occupancy of XPO1 target with Selinexor decreases the amount of tracer-target complexes in a dose and time dependent manner. Target occupancy studies of XPO1 were carried out in different cancer relevant cell lines and xenograft tumors retrieved from treated animals. As such the approach can be applied to study target occupancy in vitro and in vivo.
Citation Format: Frank Becker, Kerrin Hansen, Marsha Crochiere, Yosef Landesmann, Stefan Hannus. Application of Fluorescence Correlation Spectroscopy as a novel tool to quantify target occupancy in cells and tumor tissue [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B09.