bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 965: Deleterious effects of MAPK pathway hyperactivation in BRAF-mutant melanoma
Authors: Leung Grace P. , Feng Tianshu , Shirley Matthew D. , Sigoillot Frederic D. , Ruddy David A. , Freeman Alyson K. , Jaskelioff Mariela , Stuart Darrin D. 
Published: August 2018

Abstract
The most frequent genetic alterations in melanoma are gain-of-function mutations in BRAF, which result in addiction to RAF-MEK-ERK signaling. Given the centrality of this pathway in many cancers, inhibitors have been developed against various nodes in this signaling axis. Despite the success of these inhibitors in treating BRAFV600E mutant tumors, a major problem is the inevitable emergence of drug resistance. The mechanisms of acquired resistance often include reactivation of the MAPK pathway, thus efforts to combat resistance have used vertical combination strategies to inhibit multiple nodes of the pathway. Previous work from our group showed that vemurafenib-resistant melanoma tumors displayed increased levels of MAPK signaling as indicated by elevated phospho-ERK. Strikingly, cell lines derived from these resistant tumors were addicted to vemurafenib, and removal of drug caused loss in cell viability. Consistently, in vivo, the tumors regressed upon cessation of drug treatment, which was accompanied by elevated MAPK signaling. Recent studies have reported similar results for in vitro models of melanoma resistant to MAPK inhibitors, which are addicted to drug in an ERK2-dependent manner. Together these data suggest that extreme levels of MAPK signaling are not tolerated by tumor cells. To further characterize this phenomenon, we generated models of inducible MAPK hyperactivation in BRAFV600E melanoma cells. Using these model systems, we confirmed that increasing the levels of MAPK signaling can hinder tumor cell proliferation, and demonstrated that MAPK inhibitors can rescue this phenotype. Intriguingly, the effect of MAPK hyperactivation varied depending on the RAS/RAF mutation status of the tumor cells. Upon induction of MAPK hyperactivation in sensitive cells, there was no cell cycle arrest, but instead cell death occurred, which was accompanied by activation of caspases. On a global level, MAPK hyperactivation resulted in transcriptome changes that were opposite to those produced by treatment with an ERK inhibitor. This phenomenon of MAPK hyperactivation-induced cell death was also observed in vivo, where complete tumor regression was observed in a xenograft model. Ongoing studies seek to further define the mechanism of cell death, which could suggest potential avenues to leverage hyperactivation of MAPK signaling as a therapeutic approach.
Citation Format: Grace P. Leung, Tianshu Feng, Matthew D. Shirley, Frederic D. Sigoillot, David A. Ruddy, Alyson K. Freeman, Mariela Jaskelioff, Darrin D. Stuart. Deleterious effects of MAPK pathway hyperactivation in BRAF-mutant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 965.
Abstract 966: Oncogenic signaling pathways differentially regulate clathrin-mediated endocytosis in cancer cells
Authors: Xiao Guan-Yu , Schmid Sandra 
Published: August 2018

Abstract
Clathrin-mediated endocytosis (CME), the major endocytic pathway, regulates the rates of internalization of receptors as well as their downstream signaling activities. Recently, our lab has discovered that signaling can reciprocally regulate CME in cancer cells. The crosstalk between signaling and CME contributes to abnormal trafficking of signaling receptors and altered downstream signaling, leading to enhanced cancer metastasis. Accordingly, it is important to understand the nature and extent of interactions between CME and intracellular signaling in cancer cell biology. To address this issue, we targeted a set of prioritized kinases that are often implicated in cancer-relevant signaling pathways using validated pharmacologic inhibitors and compared their effects on CME function using different models for human noncancerous and cancer cells. We found that inhibition of several kinases selectively affected CME function in cancer cells. Notably, ERK inhibition had the most significant and consistent effects on CME activity across different types of cancer cells, while not affecting CME in several noncancerous cell lines tested. We established that a second ERK inhibitor, and importantly inhibition of the essential upstream kinase MEK, had the same cancer cell-specific effects on CME activity. Furthermore, we found that inhibition of ERK dramatically reduced the rate of clathrin-coated pit (CCP) initiation selectively in cancer cells. Characterization of one potential ERK substrate, FCHSD2, showed that knockdown of FCHSD2 had the similar cancer cell-specific effects on CME activity and on CCP initiation rate and that the cells depleted for FCHSD2 were insensitive to ERK inhibition. Surprisingly, the expression level of FCHSD2 is positively correlated with higher cancer patient survival rate, suggesting that FCHSD2 might be a tumor suppressor regulated by ERK. Our study provides new insight into the mechanisms and consequences of the reciprocal regulation of signaling and CME in cancer cells.
Citation Format: Guan-Yu Xiao, Sandra Schmid. Oncogenic signaling pathways differentially regulate clathrin-mediated endocytosis in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 966.
Abstract 967: Targeting notch one notch above
Authors: Ucar-Bilyeu Deniz A. , MATOSSIAN Margarite D. , Barnes VAN Hoang , Hossain Fokhrul M. , Gupta Mohit , BURKS HOPE E. , WRIGHT THOMAS D. , Cavanaugh Jane , Flaherty Patrick , Burow Matthew E. , Miele Lucio 
Published: August 2018

Abstract
Triple negative breast cancer (TNBC) is a molecularly heterogeneous, clinically aggressive disease group that is highly prevalent among African-Americans and younger patients. Standard chemo/radio therapy often produces clinical responses, but recurrence and metastasis are unfortunately common. Metastatic disease is generally incurable. Chemo/radiotherapy has been shown to induce EMT and enrich a chemo-resistant cancer stem cell-like (CSC) population in TNBC. CSCs are thought to drive disease recurrence. Notch signaling, particularly Notch1, is critical for maintenance of TNBC CSC. Expression of Notch1 and its ligand Jagged1 are correlated with poor prognosis. Efforts to pharmacologically target Notch directly have been impaired by the systemic toxicity of the Gamma Secretase Inhibitors (GSI) used, and by the fact that Notch1 also plays a key role in anti-tumor adaptive immunity. Therapeutic agents that target Notch signaling in breast cancer cells indirectly and selectively are a potentially attractive strategy. However, no such target has been identified to date. We have found that the MAPK5-ERK5 kinase pathway, which contains at least two druggable targets, functions as a master regulator of Notch signaling in TNBC cells. ERK5 knockout TNBC cells have dramatically decreased expression of Notch receptors, ligands and targets. In vivo, these cells form barely detectable tumors that do not metastasize and express lower levels of Notch1 and its ligand Jagged1. Using in silico screening method, we have identified a small molecule compound that targets MAP2K5 (MEK5) and decreases phosphorylation of MAPK7 (ERK5). Expression of ERK5 is associated with poor prognosis in TNBC. Consistent with ERK5KO cells, suppression of ERK5 phosphorylation decreased the amount of Notch1 and Jagged1 protein and mRNAs. More importantly, a selective MEK5 inhibitor, SC-181, reversed EMT and reduced the CD44hi/CD24lo CSC population in TNBC cells without suppressing T-cell proliferation. Treatment with nanomolar concentration of this compound decreased the number and size of mammospheres in a dose- dependent manner. Our preliminary results suggest that targeting the MEK5-ERK5 pathway is a promising strategy to selectively target Notch signaling in TNBC CSC without systemic Notch inhibition.
Citation Format: Deniz A. Ucar-Bilyeu, Margarite D. MATOSSIAN, VAN Hoang Barnes, Fokhrul M. Hossain, Mohit Gupta, HOPE E. BURKS, THOMAS D. WRIGHT, Jane Cavanaugh, Patrick Flaherty, Matthew E. Burow, Lucio Miele. Targeting notch one notch above [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 967.
Abstract 97: UBE3A regulates SIRT6 levels to promote tumorigenesis in an ANXA2 dependent manner
Authors: Kohli Saishruti , Das Sanjeev 
Published: August 2018

Abstract
Background: UBE3A is the founding member of the HECT family of E3 ubiquitin ligases, implicated in cervical, prostate and breast cancer. A recent study has reported that UBE3A promotes proliferation and invasiveness of cancer cells by inducing Annexin A2 (ANXA2) levels. We have delineated a cascade in which UBE3A brings about the proteasomal degradation of SIRT6. Furthermore, we have also established that SIRT6 transcriptionally regulates ANXA2 expression. Here, we have confirmed that UBE3A-mediated SIRT6 downregulation and consequent derepression of ANXA2 promotes tumor metastasis.
Methods: HepG2, a Hepatocellular carcinoma cell line, was used to study the effects of the UBE3A-SIRT6-AXA2 axis. HepG2 UBE3A knockdown, SIRT6 knockdown, UBE3A/SIRT6 double knockdown and SIRT6/ANXA2 double knockdown cells were used to examine in-vitro cell proliferation, invasion, plasmin generation and MMP activation. These cell lines were also used for obtaining subcutaneous and orthotopic xenografts in immunodeficient mice and multiple parameters were analyzed to determine tumor growth and metastases.
Results: We observed that upon UBE3A abrogation, cells exhibited reduced tumor-forming potential and resulted in smaller tumors with low metastasis. On the other hand, increased tumorigenesis, and much larger tumors with increased metastasis were observed upon SIRT6 knockdown, which was significantly reversed upon simultaneous knockdown of UBE3A. Furthermore, smaller tumors were observed in case of SIRT6/ANXA2 double knockdown cells as compared to UBE3A/SIRT6 double knockdown cells. These results suggest that UBE3A-mediated ANXA2 upregulation, via SIRT6 degradation, is critical for its oncogenic functions
Conclusion: UBE3A mediated SIRT6 degradation leads to ANXA2 upregulation and hence enhances tumorigenesis. It would be beneficial to identify drugs targeting UBE3A as a therapeutic approach in hepatocellular carcinoma. Alternatively, mechanisms which inhibit ANXA2 activity must be deciphered to identify druggable targets.
Citation Format: Saishruti Kohli, Sanjeev Das. UBE3A regulates SIRT6 levels to promote tumorigenesis in an ANXA2 dependent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 97.
Abstract 974: Alternative polyadenylation of androgen receptor variants in castration-resistant prostate cancer
Authors: Etten Jamie L. Van , Nyquist Michael , Li Yingming , LaRue Rebecca , Ho Yeung , Yang Rendong , Voytas Daniel F. , Henzler Christine , Dehm Scott M. 
Published: August 2018

Abstract
The androgen receptor (AR), which is activated by androgens, functions in the normal prostate as a master transcriptional regulator. Accordingly, prostate cancer (PCa) presents as an androgen- and AR-dependent disease. Inhibition of AR transcriptional activity with androgen-deprivation therapy (ADT) is effective for patients with locally advanced and metastatic disease. All ADT suppresses AR via interference with its ligand binding domain (LBD)-dependent transcriptional activity. However, development of therapy resistance and transition to castration-resistant prostate cancer (CRPC) represents a major clinical challenge. CRPC circumvents ADT by expressing constitutively active AR variants (AR-Vs) that lack the LBD. Therapies targeting constitutively active AR variants are not currently available. To address this problem, we investigated the mechanisms underlying AR-V expression in CRPC. One particular AR-V, called AR-V7, consists of contiguously spliced exons 1, 2, 3, and a cryptic exon, CE3, and has been shown to be associated with clinical resistance to second-generation AR inhibitors abiraterone and enzalutamide. We noted that CE3 contains a consensus hexameric AAUAAA polyadenylation signal (PAS). We hypothesized that intronic polyadenylation promotes AR-V7 expression in CRPC. To test this, we developed a morpholino that sterically blocked the CE3 PAS to prevent splicing of AR-V7. We have demonstrated that the PAS in CE3 controls expression of AR-V7, as well as a broad array of AR variants arising by splicing of adjacent cryptic exons that use the shared CE3 PAS. Furthermore, our data demonstrate that the cleavage and polyadenylation complex (CPSF complex) is enriched in primary PCa tumors relative to normal tissues. We have also demonstrated that CPSF1, a member of the CPSF complex, controls expression of AR-Vs relative to full length AR and plays a global role in the determination of mRNA isoform length in prostate cancer cells. Collectively, these findings reveal alterations in the cellular machinery governing mRNA cleavage and polyadenylation in prostate cancer, and identify specific opportunities for therapeutic intervention.
Citation Format: Jamie L. Van Etten, Michael Nyquist, Yingming Li, Rebecca LaRue, Yeung Ho, Rendong Yang, Daniel F. Voytas, Christine Henzler, Scott M. Dehm. Alternative polyadenylation of androgen receptor variants in castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 974.
Abstract 996: Host-derived MCP-1 dictates prostate cancer skeletal metastasis in vivo
Authors: Meng Jie , Liang Weiping , Tong Haibo , Keller Evan T. , Zhang Jian , Lu Yi 
Published: August 2018

Abstract
Overexpression of the tumor-derived monocyte chemotactic protein-1 (MCP-1) has been suggested to partially promote prostate cancer bone metastasis, but the function for host-derived MCP-1 in these processes is not well established. To understand the function of host-derived MCP-1 on bone metastasis, we developed a mouse model using intracardiac injection and in vivo selection to obtain tumor cell subpopulations with a higher propensity for bone metastasis. Here, we found that a loss of host MCP-1 (MCP-1 knockout) retarded tumor growth in bone and prolonged survival of mice by intracardiac injection of tumor cells in vivo. Moreover, a decrease in osteolytic bone lesion was observed in MCP-1 knockout mice by bone density analysis, as compared to wild-type control. Systemically, MCP-1 deficiency inhibited the proportion of PMN-and M-MDSC populations with immunosuppressive function. Together, this study indicates that the dysregulated immunity resulting from a loss of host MCP-1 signaling is sufficient to drive PCa bone metastasis, and provides a new perspective for targeting the endogenous MCP-1 pathway as an antimetastatic strategy.
Supported by NSFC Key Project 81130046; NSFC projects 81773146, 81272415; JCYJ20170412152943794, JCYJ20170412154619484, JCYJ20170307105128101, JCYJ2017030711041760; Guangxi Key Projects 2013GXNSFEA053004.
Citation Format: Jie Meng, Weiping Liang, Haibo Tong, Evan T. Keller, Jian Zhang, Yi Lu. Host-derived MCP-1 dictates prostate cancer skeletal metastasis in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 996.
Abstract 999: Unravelling myeloid and T cell compartment interactions through a novel approach to tumor multimodal analysis combining whole slide multiplexed immunofluorescence and gene expression profiling
Authors: Zwing Natalie 
Published: August 2018

Abstract
Understanding the role of myeloid cells in tumor biology requires a systems approach combining phenotypic and functional biomarkers. As a model system, colorectal cancer (CRC) tumors represent well-described clinically relevant immune subtypes. Distinct immune patterns have been reported involving the myeloid cells acting as immune suppressors for CD8 cytotoxic T cells. We hypothesized that myeloid derived suppressor cells (MDSCs) and CD8 T cells co-localize due to their direct interactions.
A cohort of 85 CRC primary tumors were analyzed by multiplexed immunohistochemistry/ immunofluorescence and subsequent quantitative and qualitative whole slide image analysis. To define the functional status of the identified immune cell populations, their corresponding signatures were analyzed by gene expression profiling.
Combining density and distribution of both myeloid cells and T cells as well as their distance to epithelial cancer cells, specific patterns were observed. In both microsatellite stable (MSS) and instable (MSI) tumors, MDSCs showed a comparable stromal distribution. By contrast, in MSI cases only, effector T cells tended to accumulate in the tumor epithelium suggesting they overcome the immunosuppressive environment. Additionally, the assessment of CD8 T cell morphology revealed changes potentially reflecting their cancer cell eliminating properties.
This multimodal analysis represents a novel approach to characterize and understand the role of the myeloid compartment through a combination of morphological and spatial characteristics of the T cell compartment.
Citation Format: Natalie Zwing. Unravelling myeloid and T cell compartment interactions through a novel approach to tumor multimodal analysis combining whole slide multiplexed immunofluorescence and gene expression profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 999.
Abstract CT097: Quantitative MR measurements in glioblastoma patients: Mean diffusivity with tumor treating fields plus standard therapy versus standard treatment alone
Authors: Vymazal Josef , Zacek Radovan , Sroubek Jan , Klener Jan , Rulseh Aaron M. 
Published: August 2018

Abstract
Introduction: Quantitative MR parameters, including those derived from diffusion imaging, may advance knowledge on the biological characteristics of gliomas in both diagnostic and treatment settings. We evaluated quantitative diffusion differences that could be detected in glioblastoma patients treated with standard therapy plus TTFields (Optune) versus standard therapy alone.
Methods: Twelve patients with glioblastoma were subjected to surgical resection, radiotherapy and temozolomide. Six subjects were additionally treated with TTFields. All patients were followed by MRI every two months (range 210-1036 days) with standard imaging and diffusion tensor imaging until tumor progression.
Results: Progression-free survival (PFS) was significantly longer in the subgroup treated by TTFields (mean 784 days ± 163 SD) as compared to standard therapy alone (443 days ± 249). No difference was detected between groups in the initial mean diffusivity values measured within the affected white matter near the resection cavity. However the linear regression slope describing mean diffusivity in this region over serial measurements was higher in the subgroup treated by TTFields than in the other group (5.43 ± 2.4 versus -3.77 ± 11.8). Furthermore, we detected significant positive correlation between mean diffusivity slope and PFS.
Discussion: Our data demonstrate increasing mean diffusivity in the affected white matter of glioblastoma patients, which is favorable with positive correlation to PFS seen in steeper regression slopes. The patients treated with TTFields showed greater PFS in comparison to those who did not receive TTFields. There was a corresponding increase in mean diffusivity in the affected white matter of these patients. In the group that received standard therapy, the increase was not as apparent and, if present, the slope was not as steep. Changes in mean diffusivity likely reflect changes in tumor density in the white matter.
Citation Format: Josef Vymazal, Radovan Zacek, Jan Sroubek, Jan Klener, Aaron M. Rulseh. Quantitative MR measurements in glioblastoma patients: Mean diffusivity with tumor treating fields plus standard therapy versus standard treatment alone [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT097.
Abstract CT103: Rationale for flat dosing of AZD9150 by population pharmacokinetic analysis
Authors: Tong Xiao , Mugundu Ganesh , Scott Martin , Cook Carl , Lyne Paul , Al-Huniti Nidal , Xu Hongmei 
Published: August 2018

Abstract
Objective: AZD9150 (ISIS 481464) is a 16-nucleotide oligonucleotide antisense molecule designed to reduce expression of human STAT3 protein by targeted down-regulation of STAT3 messenger RNA and is currently in clinical development in advanced solid tumors. The recommended Phase 2 dose (RP2D) for AZD9150 is 3 mg/kg, dosed based on ideal body weight (IBW) with three loading doses on day 1, 3 and 5 in week 1 followed by weekly dosing thereafter. The objective of the current analysis was to assess the effect of body size on AZD9150 pharmacokinetics (PK) to determine the appropriate dosing approach using population PK modeling.
Methods: PK and demographics data from 3 phase I/II studies (481464-CS1 [NCT01563302], D5660C00001 [NCT01839604], D5660C00004 [NCT02499328]) in total of 126 patients with diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma (HCC) and squamous-cell carcinoma in head and neck (SCCHN), receiving doses ranging from 1 to 4 mg/kg as monotherapy or in combination with durvalumab, were used in the population PK analysis. Both 2-compartment and 3-compartment structure PK models were tested in the analysis. Patient characteristics including age, ideal body weight (IBW), race and sex were explored as covariates on relevant AZD9150 PK parameters in an automated forward inclusion followed by backward elimination procedure through use of the stepwise covariate modelling. Once a final model was identified, simulations (n=1000, body weight distribution 30 to 100 kg) were conducted to compare AZD9150 exposures at the RP2D of 3 mg/kg versus a flat dose of 200 mg.
Results: A 2-compartment model with linear elimination well described the data. None of the covariates (inc. IBW) were found to significantly impact AZD9150 PK. The final PK model parameter estimate for clearance (CL), central volume of distribution (V1) and peripheral volume of distribution (V2) are 3.11 L/h, 5.56 L and 87.3 L, respectively. Model based simulations demonstrate that systemic exposure of AZD9150 was similar between 3 mg/kg versus 200 mg dose with slightly less overall between-patients variability with the flat dosing regimen.
Conclusion: Population PK modeling supports the potential switch of dosing approach from 3 mg/kg dose to a flat dose of 200 mg. The AZD9150 flat dosing rationale and schedule has been granted approval by FDA (for IND 137525) and also by MHRA (for BISCAY trial) as the first protocol / IMPD to be approved in the EU. Flat dose of 200 mg is currently being evaluated in ongoing clinical studies.
Citation Format: Xiao Tong, Ganesh Mugundu, Martin Scott, Carl Cook, Paul Lyne, Nidal Al-Huniti, Hongmei Xu. Rationale for flat dosing of AZD9150 by population pharmacokinetic analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT103.