bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5214: Targeting the estrogen receptor pathway in luminal breast cancer through inhibition of p300/CBP
Authors: Waddell Aaron , Mahmud Iqbal , Tian Guimei , Liao Daiqing 
Published: August 2019

Abstract
Luminal breast cancer represents approximately two thirds of all breast cancer cases and is characterized by the expression of hormone receptors, such as the estrogen receptor alpha (ER). ERα is a member of the steroid nuclear receptor family and is involved in a hormonal signaling pathway that drives tumor growth through upregulation of genes involved in cell cycle progression, such as MYC and CCND1. Antagonists of ER function are the standard of care treatment for ER+ luminal breast cancer. However, resistance to ER antagonists is common in advanced breast cancer cases. Therefore, there is an urgent need to investigate new therapeutics that can be utilized to treat tumors that are resistant to traditional therapies. p300/CBP are two paralogous acetyltransferases that catalyze histone 3, lysine 18 and 27 acetylation (H3K18ac and H3K27ac) at promoters and enhancers to promote gene expression. ER mediated transcription is critically reliant upon the recruitment of co-activators, including p300/CBP. However, the mechanistic role of p300/CBP catalytic activity in globally regulating ER mediated transcription remains poorly understood. Inhibition of p300/CBP, as a critical co-activator of ER, potentially represents an applicable strategy for inhibiting ER function in luminal breast tumors. Importantly, the catalytic histone acetyltransferase (HAT) domain of p300/CBP is under intense investigation as a target of small molecule therapeutics in cancer. We analyzed publicly available data and report that p300/CBP are upregulated at the mRNA level in breast cancer, including the luminal subtypes, and that their expression negatively correlates with patient survival. We also found that pharmacologic inhibition of p300/CBP HAT activity in ER+ cell lines potently suppresses ER mediated transcription, downregulates ER, c-Myc and Cyclin D1 protein levels and prevents estrogen induced growth in vitro. Studies are underway to understand how p300/CBP regulates ER signaling using genetic, pharmacologic, and biochemical methods to assess the therapeutic effects of pharmacologic p300/CBP inhibition on ER+ breast cancer. (Supported by Bankhead-Coley Research Program, and James and Esther King Biomedical Research Program, Florida Department of Health)
Citation Format: Aaron Waddell, Iqbal Mahmud, Guimei Tian, Daiqing Liao. Targeting the estrogen receptor pathway in luminal breast cancer through inhibition of p300/CBP [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 5214.
Abstract 5266: Kinetic measurements of intracellular ATP levels in co-culture models using live-cell analysis
Authors: Schramm Cicely L. , Bowe Michael L. , Skerlos Laura A. , Filonov Grigory S. , Chen Yong X. , Appledorn Daniel M. 
Published: August 2019

Abstract
Differential metabolic requirements of tumor cells have gained recognition as attractive therapeutic targets. For example, clinical trials are currently underway to test the efficacy of the glutaminase-1 (GLS1) inhibitor CB-839 in a variety of indications, including triple-negative breast cancer (TNBC). Standard approaches to monitoring drug induced metabolic perturbations are limited to endpoint assays that lack cell-specific data in complex co-culture models and provide limited kinetic information. Here we describe a live-cell approach to image and analyze intracellular ATP levels of tumor cells in mono- or co-culture over time using the IncuCyte® CytoATP Sensor. A panel of breast cancer cell lines stably expressing a genetically encoded, fluorescent ATP sensor or a control (non-ATP binding) sensor were generated and cultured alone or with a monolayer of stromal cells. The effect of CB-839 treatment on tumor cell ATP levels was monitored over days and analyzed using the IncuCyte® S3 for Metabolism, which is equipped with a specialized optical module and image acquisition mode. In concordance with previous results, TNBC cell lines were more sensitive to GLS1 inhibition than their receptor-positive counterparts. Across all TNBC lines tested, CB-839 treatment resulted in a reduction in intracellular ATP that was sustained for the duration of the 3-day time course. In contrast, most receptor-positive cell lines displayed little to no effect of GLS1 inhibition. In some cases, a transient reduction followed by recovery within 48 hours was observed, highlighting the value of kinetic analysis. Co-culture with CCD-1086SK fibroblasts attenuated the effect of CB-839 in TNBC cell lines. This was not due to drug buffering, as the reduction in ATP induced by CB-839 treatment of MCF7 cells was unaffected by co-culture with stromal cells. Visualization tools included in the IncuCyte® ATP Analysis Software Module provide a quick, qualitative assessment of data across the assay plate and a view into the heterogeneity of responses to treatment. Measurements of proliferation, cell death, and mitochondrial membrane potential provided additional data supporting the observations generated via ATP readout. Overall, these data highlight the value of live-cell, kinetic analysis of metabolic and cell health measurements.
Citation Format: Cicely L. Schramm, Michael L. Bowe, Laura A. Skerlos, Grigory S. Filonov, Yong X. Chen, Daniel M. Appledorn. Kinetic measurements of intracellular ATP levels in co-culture models using live-cell analysis [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 5266.
Abstract 527: High-dimensional profiling of the systemic immune response informs on optimal sequencing of radiotherapy (RT) and immune checkpoint blockade (ICB)
Authors: Chua Kevin L. , Fehlings Michael , Chu Pek Lim , Lin Xiao-Tian , Yeo Eugenia , Low Kar Perng , Poon Dennis , Ong Enya , Woo Wai Yee , Wee Joseph , Nardin Alessandra , Iyer Gopalakrishna , Tan Daniel S. , Soo Kee Chee , Newell Evan , Chua Melvin 
Published: August 2019

Abstract
Background: Combinatorial RT-ICB potentiates anti-tumour reactivity by modulating the immune response. We therefore performed in-depth phenotypic profiling of the systemic T cell compartment following treatment with RT-ICB.
Methods: We recruited 20 patients with biopsy-proven metastatic renal cell and non-small cell lung carcinoma, who were treated with a sandwich regime of ICB-RT-ICB under a prospective observational study protocol, and compared against a RT alone-treated cohort (N=10). All patients received ablative RT (8-50Gy/1-5fr) for oligoprogression and/ or local palliation. Blood samples were longitudinally collected at pre-RT, 14 d post-RT and cycle 2 ICB post-RT. Deep T cell profiling was performed by mass cytometry using a customised 41 parameter panel, together with high dimensional analysis tools.
Results: Median follow-up of the overall cohort was 18mo; median duration of ICB received in the ICB-RT-ICB arm was 15mo. We observed significant diversity of the systemic T cell repertoire between patients at baseline, and this corresponded to significant interpatient heterogeneity in T cell responses specific to the central/ effector memory, EMRA and Treg subsets post-RT. Dramatic local response (complete response at 1 mo post-RT) was significantly higher in the ICB-RT-ICB cohort compared to the RT alone cohort (12/20 vs 1/10, P&lt;0.01). This clinical phenomenon corresponded to an increased %Ki67high CD8 and CD4 T cells post-RT exclusively in the combinatorial treated cohort, which was further enhanced upon resumption of ICB (mean = 10% vs 3% [CD8]; 13% vs 2% [CD4]; P&lt;0.01). Deeper immunophenotyping of the Ki67high subsets revealed associated high expression of GranzymeB and Eomes.
Conclusions: Here, we observed changes in the T cell phenotypes that varied remarkably across all patients following RT. We further highlight a RT-dependent T cell proliferation amongst all RT-ICB-treated patients that was further enhanced by ICB in prior responders. This immune phenomenon may account for the dramatic responses to combinatorial treatment, and informs on optimal sequencing strategies for combining RT and ICB.
Citation Format: Kevin L. Chua, Michael Fehlings, Pek Lim Chu, Xiao-Tian Lin, Eugenia Yeo, Kar Perng Low, Dennis Poon, Enya Ong, Wai Yee Woo, Joseph Wee, Alessandra Nardin, Gopalakrishna Iyer, Daniel S. Tan, Kee Chee Soo, Evan Newell, Melvin Chua. High-dimensional profiling of the systemic immune response informs on optimal sequencing of radiotherapy (RT) and immune checkpoint blockade (ICB) [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 527.
Abstract 5283: Prognostic value of resectable hepatocellular carcinoma: Clinico-pathologic findings
Authors: Kim Jin Young , Heo Mi Hwa , Shin So Jin 
Published: August 2019

Abstract
We investigated the prognostic factors of resectable hepatocellular carcinoma (HCC). Preoperative peripheral blood factors, fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and pathologic parameters were investigated for progression free survival (PFS). From February 2008 to December 2012, a retrospective analysis was conducted on 65 patients who had received liver resection. Peripheral blood parameters were collected within 7 days based on operation date. The 18F-FDG uptake was calculated based on the maximum standardized uptake value of the tumor (SUVmax), the liver mean SUV and the tumor-to-normal SUV ratio (TNR). Immuno-histochemical (IHC) stain results were reviewed by a pathologist through specimen. A total of 65 patients were included (46 males, 19 females; average age, 57.5 ± 8.9 years). The median PFS of HCC was 52.9 months. SUVmax was correlated with PFS and the optimal cut off value of SUVmax was 3.25 (p = 0.005). Median PFS of low SUVmax was 76.4 months and high SUVmax was 8.5 months. The optimal cut-off value of TNR was 1.77 for PFS. The median PFS of HCC in patients with low TNR (&lt; 1.77) and high TNR (≥ 1.77) was 82.3 and 7.0 months, respectively (p = 0.002). AST to platelet ratio index (APRI) could be a predictable marker for recurrence of HCC (p = 0.034). The median PFS of high PNI and low PNI were 64.9 and 10.9 months, respectively (p = 0.004). The IHC expression of glucose uptake transporter 2 was correlated with SUVmax. Preoperative SUVmax, TNR, APRI and PNI could predict recurrence after curative resection of HCC.
Citation Format: Jin Young Kim, Mi Hwa Heo, So Jin Shin. Prognostic value of resectable hepatocellular carcinoma: Clinico-pathologic findings [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 5283.
Abstract 5285: The role of HIV-1 TAT interactive protein 2 in modulating tumor response to hypoxia
Authors: Zhou Qingyu Stephanie , Guo Xiaofang , Li Minghua , Pan Hua 
Published: August 2019

Abstract
While there is ample evidence that HIV-1 TAT interactive protein 2 (HTATIP2) is a tumor suppressor exerting its pro-apoptotic and anti-metastatic activities by regulating the expression of a subset of pro-apoptotic and anti-apoptotic genes and metastasis suppressor genes, it remains unclear if HTATIP2 has a role in tumor response to hypoxia. The objective of this study was to define the role of HTATIP2 in mediating certain molecular and cellular changes in response to hypoxia in tumors. We employed a series of isogenic A549 human lung adenocarcinoma sublines that were genetically deficient for HTATIP2 and/or HIF-1α to examine the potential modulatory effect of HTATIP2 on oncogenic signaling pathways mediated by HIF-1α and HIF-2α, and established the HTATIP2-deficient A549 xenograft model to explore the impact of deletion of HTATIP2 on tumor response to hypoxia. Results from the human HIF-regulated cDNA plate array study revealed that under hypoxic condition (0.5% O2), several genes promoting tumor metastasis and resistance to apoptosis and anticancer treatment, including HIF1α, CYSD, MMP1, MXI1, NDRG2, PAI1 and NDRG1, were upregulated to a greater extent in HTATIP2 knockdown A549 cells than in the control A549 cells. In contrast, genes involved in angiogenesis, glucose metabolism and protection of apoptosis under hypoxia, such as PDGF, PDK1, CA9, and SAG, were upregulated to a greater extent in control A549 cells than in HTATIP2-knockdown A549 cells. Results from the in vivo study demonstrated that the mean growth rate of HTATIP2-deficient A549 xenograft tumors was significantly increased as compared with that of parental A549 xenograft tumors irrespective of the presence or absence of sorafenib treatment. Moreover, the data of photoacoustic imaging (PAI) of tumor hypoxia revealed that the parental A549 tumors were better oxygenated than the counterpart HTATIP2-deficient A549 tumors. After the 10-day sorafenib treatment, the oxygenated regions in sorafenib-treated parental A549 tumors were significantly reduced as compared with the vehicle-treated parental A549 tumors, whereas no significant change in the oxygenated regions was found between vehicle- and sorafenib-treated HTATIP2-deficient A549 tumors. The overall finding of our study suggests that downregulation of HTATIP2 affords growth advantage to tumor cells by fine-tuning tumor adaptation to hypoxia, leading to tumor progression and aggression.
Citation Format: Qingyu Stephanie Zhou, Xiaofang Guo, Minghua Li, Hua Pan. The role of HIV-1 TAT interactive protein 2 in modulating tumor response to hypoxia [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 5285.
Abstract 5288: Evaluating the potential to repurpose statins for ovarian cancer therapy
Authors: Kroeger Paul T. , Drapkin Ronny 
Published: August 2019

Abstract
The recent exciting results using primary PARP inhibitor maintenance after upfront treatment for advanced ovarian cancer in BRCA1/2 mutation carriers highlight the importance of identifying druggable vulnerabilities in this disease. The fact that not all ovarian cancer patients will benefit from PARP inhibitors or experience durable responses, places great emphasis on the need to identify additional therapies. Re-purposing existing FDA-approved drugs offers an opportunity to accelerate progress in this area. Statins are drugs primarily prescribed for hypercholesterolemia and have been intensely researched for decades. Some of this work has demonstrated, through epidemiologic approaches and limited experimental studies, that statins have anticancer properties. We hypothesized that statins can be repositioned as part of a therapeutic regimen for HGSOC. Here, we demonstrate that certain ovarian cancer cell lines are exquisitely sensitive to treatment with statins. Our ongoing studies reveal that HGSOC cells that are sensitive to stain treatment manifest an amplification of chromosome 1q21. Within this genomic region are the S100 proteins, previously identified as potential biomarkers in several cancer types, as well as the anti-apoptotic protein MCL1. We performed a Reverse Phase Protein Array (RPPA) analysis on higher dose/short exposure, and low dose/longer exposure statin-treated cells. In both conditions, MCL1 levels were altered in statin-sensitive cell lines, while there was no such change in non-sensitive lines. After identifying MCL1 as a potential marker of response, Western blot analysis demonstrated a dose-dependent decrease in protein level of MCL1 with increasing statin concentration. Additionally, a short pro-apoptotic splice variant of MCL1 was produced upon statin treatment, but only in the sensitive lines. Mechanistically, we find that phospho-YAP (inactive) is upregulated after statin treatment. This data corroborated previous research that suggested that multiple different statins decrease nuclear YAP. Given its role as an oncogene, the apparent ability of statins to deactivate YAP and downregulate MCL1 steers statins in a promising direction for their repositioning for future therapeutic use.
Citation Format: Paul T. Kroeger, Ronny Drapkin. Evaluating the potential to repurpose statins for ovarian cancer therapy [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 5288.
Abstract 5299: Role of short chain free fatty acid receptors in colorectal cancer
Authors: AlGhamdi Amal , AlMahri Saeed , AlAkiel Maaged , Mohammad Sameer , Aziz Mohammad 
Published: August 2019

Abstract
One of the well established risk factors for colorectal cancer is dietary profile. A well recognized negative association of dietary fiber with colorectal cancer warrants further understanding of the underlying mechanism. Bacterial fermentation of dietary fibre results in formation of short chain free fatty acids in the gut. There are two receptors for these fatty acids one of which has been implicated in colorectal cancer. Free fatty acid receptor 2 has been associated with development of colorectal adenoma in a mouse model. We analyzed the differential expression of FFAR2 gene in colorectal cancer patients. Further, we generated genetically engineered colorectal cancer cell line with reduced level of expression of these receptors. These engineered cells were found to have enhanced rate of cell proliferation. In order to understand the mechanism of increased proliferation, we explored the involevement of glucose uptake and cAMP pathways. While there was an increased level of glucose uptake in engineered cells, there was no evidence of involvement of Protein kinase A mediated cAMP pathway. Further studies are needed to fully establish the connection between dietary fibre, gut microbiota and colorectal cancer.
Citation Format: Amal AlGhamdi, Saeed AlMahri, Maaged AlAkiel, Sameer Mohammad, Mohammad Aziz. Role of short chain free fatty acid receptors 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 5299.
Abstract 5310: Novel, single-tube, multiplex rhPCR technology for detection of low-frequency variants in BRCA1 and BRCA2
Authors: Sponer Nicole , Wang Yu , Wang Junzhou , Chen Shengyao , Lai Kevin , Rose Scott , Lau Patrick 
Published: August 2019

Abstract
Targeted next-generation sequencing (NGS) technologies serve as critical tools for cancer diagnostics. For example, individuals with pathological BRCA1 and BRCA2 (BRCA1/2) mutations have a dramatically increased risk for certain cancers, including breast and ovarian cancer. Those mutations are either germline or somatically acquired, and play an important role in cancer risk assessment, prevention of malignancy, and management of disease. A variety of methodologies are currently available to screen for BRCA1/2 mutations. Amplicon-based sequencing technologies are prevalent due to their easy workflow but have specific challenges due to inherent limitations of PCR, such as difficulties with amplification of overlapping amplicons for contiguous coverage in a single-tube or with detection of somatic low-frequency variants due to high polymerase error rates. We developed a robust, highly multiplex rhPCR workflow to screen for BRCA1/2 mutations across their entire coding regions in a single-tube. This method allows for detection of low-frequency variants through use of unique molecular identifiers (UMIs), which correct for PCR and sequencing errors and dramatically increase specificity. This method supports a wide DNA input range (1 to 50 ng) from cell-free, formalin-fixed paraffin-embedded (FFPE), or small biopsy samples. Our rhAmpSeq™ chemistry uses a two-enzyme system coupled with uniquely designed RNA-DNA hybrid primers, which enable the amplification of overlapping, multiplexed amplicons. Thus, we eliminate the need to split precious DNA samples into multiple tubes and prevent UMI hopping. Here, we demonstrate the performance of our novel, highly specific amplicon-based technology for detection of low-frequency variants of BRCA1/2 and compare our technology to current industry standards.
Citation Format: Nicole Sponer, Yu Wang, Junzhou Wang, Shengyao Chen, Kevin Lai, Scott Rose, Patrick Lau. Novel, single-tube, multiplex rhPCR technology for detection of low-frequency variants in BRCA1 and BRCA2 [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 5310.
Abstract 532: Irradiation alters the tumor microenvironment of orthotropic pancreatic tumor in favoring the infiltration of PD1+CD8 and G-MDSC and the delivery of immune checkpoint blockade therapy agents
Authors: Lee Yu Hung 
Published: August 2019

Abstract
Immunotherapy (IT) is trending on cancer research, but its efficacy heavily depends on the tumor microenvironment (TME). IT is also frequently combined with radiation therapy (RT). Here, we explored the effect of radiation therapy (RT) on the TME and its consequence on the combination of IT using a syngeneic orthotropic UN-KC6141 PDAC tumor model. The result of immunohistochemical staining (IHC) demonstrates that 25Gy of IR could effectively decrease the number of CD31+ vessels, but significantly increase distribution area of Dextran, an indication of vessel normalization. The normalized tumor vessels are more effectively on delivering ICBT (immune checkpoint blockade therapy) drug delivery as shown by the increase of anti-PD-L1 antibody in irradiated tumor. In addition, we also found that the number of PD1+CD8+ Tc cells and Ly6G+G-MDSC is also increased in irradiated tumor. This indicates that RT could alter TME of pancreatic tumor in favoring the combination with IT, not only alters an immune desert tumor to become an immune infiltrating tumor, but also enhances the delivery of ICBT agents. For this tumor model, the combination of RT with anti-PD-L1 or anti-Ly6G therapy could be effective. To test this hypothesis, the combination of RT with ICBT agents was performed. The preliminary results show that anti-PD-L1 ICBT could enhance the efficacy of RT on decreasing tumor burden. The combination of anit-Ly6G therapy with RT is currently under investigation.
Citation Format: Yu Hung Lee. Irradiation alters the tumor microenvironment of orthotropic pancreatic tumor in favoring the infiltration of PD1+CD8 and G-MDSC and the delivery of immune checkpoint blockade therapy agents [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 532.