bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2654: Immunologic and prognostic correlates of WISP1 in prostate cancer
Authors: Gaudreau Pierre-Olivier , Clairefond Sylvie , Boulay Pierre-Luc , Chrobak Pavel , Allard Bertrand , Pommey Sandra , Saad Fred , Young Marian , Stagg John 
Published: August 2018

Abstract
Background: Avoidance of immune destruction and tumor-promoting inflammation are equally important cancer hallmarks. In the context of prostate cancer, inflammatory markers and high levels of immune infiltrates have been associated with shorter biochemical recurrence (BCR)-free survival. WNT1 Inducible Signaling Pathway (WISP1) has been implicated in prostate cancer metastasis and the regulation of inflammation in diverse benign diseases. Thus, the objectives of this study were: 1) to assess the prognostic value of WISP1 in human prostate cancer, and 2) to determine the association of WISP1 to the inflammatory landscape specific to this disease.
Methods: A tumor microarray (TMA) was constructed with radical prostatectomy specimens of 285 prostate cancer patients. Multicolor manual immunofluorescence (IF) was performed to simultaneously detect WISP1, CD8 and cytokeratins 8 and 18. WISP1 expression levels were determined by the mean fluorescence intensity (MFI) in stromal, epithelial, cytoplasmic and nuclear (DAPI) areas in each core, and CD8+ cell density was determined for each compartment by dividing cell count by the percentage of the core occupied by the compartment. Finally, the prostate cancer TCGA dataset (n = 548) was used to validate the prognostic value of WISP1 mRNA expression, as well as its association to CD8+ lymphocytes using previously validated gene signatures (Becht et al., 2016).
Results: IF analyses of our TMA revealed that high levels of WISP1 in normal adjacent epithelium are significantly associated with shorter BCR-free survival in Kaplan-Meier (log-rank = 4.246, p = 0.039) and univariate Cox regression analyses (hazard ratio = 1.477; p = 0.042), but not in multivariate Cox regression analyses (hazard ratio = 1.381; p = 0.101). Furthermore, a significant correlation was found between WISP1 expression and CD8+ cell density. Gene expression analyses further showed that WISP1-high prostate tumors are associated with a CD8+ lymphocyte gene enrichment profile, and confirmed that patients with WISP1-high prostate tumors have reduced BCR-free survival (Wilcoxon rank, p = 0.003).
Conclusions: Overall, our results support a negative prognostic association for WISP1 as well as a proinflammatory role. WISP1 may represent a relevant target for the improvement of prostate cancer immunotherapy.
Citation Format: Pierre-Olivier Gaudreau, Sylvie Clairefond, Pierre-Luc Boulay, Pavel Chrobak, Bertrand Allard, Sandra Pommey, Fred Saad, Marian Young, John Stagg. Immunologic and prognostic correlates of WISP1 in 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 2654.
Abstract 2662: Indenoisoquinoline topoisomerase I inhibitors target the DNA G-quadruplex formed in the c-Myc promoter and cause MYC downregulation
Authors: Wang Kaibo , Elsayed Mohamed S. A. , Wu Guanhui , Cushman Mark , Yang Danzhou 
Published: August 2018

Abstract
The inhibition of DNA topoisomerase I (Top1) has proven to be a successful approach toward the design of anticancer agents. Indenoisoquinoline derivatives have been designed and developed as Top1 inhibitors and can overcome some shortcomings associated with the camptothecin Top1 inhibitors, resulting in three indenoisoquinoline compounds, indotecan (LMP 400), indimitecan (LMP776), and LMP744 entering Phase I clinical trials at the National Cancer Institute. However, some active indenoisoquinolines did not show potent Top1 inhibition, suggesting a separate mechanism of action. c-Myc is one of the most commonly deregulated genes in human cancers; a DNA G-quadruplex (G4) formed in the proximal promoter region of c-Myc has been found to function as a transcriptional silencer and be amenable to small molecule targeting. As indenoisoquinolines share structure similarity to our c-Myc G-quadruplex (MycG4)-interactive compounds, we hypothesized that indenoisoquinolines could stabilize MycG4 and downregulate MYC transcription. Using a fluorescence resonance energy transfer (FRET) assay, we examined the MycG4 stabilization activity of 56 indenoisoquinoline compounds that we previously developed as Top1 inhibitors. Notably, 26 of the 56 compounds decreased the fluorescence intensity by at least 50%, and the 10 most potent compounds reduced fluorescence intensities by over 70%, indicating that these indenoisoquinolines are effective MycG4 stabilizers. The identified compounds were further characterized by fluorescence anisotropy, circular dichroism, and nuclear magnetic resonance for MycG4 interactions, followed by western blot assays for MYC downregulation. Significantly, the compounds with good MycG4 binding activity and affinity exhibited significant dose-dependent reduction of MYC expression, indicating that targeting the c-Myc promoter G-quadruplex is a likely mechanism of action for these active anticancer compounds. Furthermore, some active indenoisoquinolines exhibited both MYC downregulation and Top1 inhibition, suggesting that dual targeting c-Myc G-quadruplex and Top1 may represent a novel mechanism of action for anticancer drug design.
Citation Format: Kaibo Wang, Mohamed S. A. Elsayed, Guanhui Wu, Mark Cushman, Danzhou Yang. Indenoisoquinoline topoisomerase I inhibitors target the DNA G-quadruplex formed in the c-Myc promoter and cause MYC downregulation [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 2662.
Abstract 2666: Subtype-selective lethal molecules disrupt the regulatory module that drives high-risk neuroblastoma
Authors: Stokes Michael E. , Vasciaveo Alessandro , Small Jonnell Candice , Rajbhandari Presha , Lopez Gonzalo , Califano Andrea , Stockwell Brent R. 
Published: August 2018

Abstract
Neuroblastoma (NBL) is a tumor that is derived from the developing neural crest, resulting in approximately 15% of pediatric cancer deaths. This cancer is characterized by multiple tumor subtypes that vary in their aggressiveness and clinical prognosis. Though MYCN amplification is associated with an aggressive subtype and poor prognosis, recent molecular classification identified a novel aggressive subtype driven by a mesenchymal gene signature. To understand the molecular mechanisms underpinning each subtype, network-based analysis identified key transcriptional regulators for each subtype that act in concert to drive tumor pathology. We hypothesize that chemical inhibitors disrupting this regulatory module will have greater chance of success in vivo, by targeting the specific drivers of the tumor subtype. In an effort to identify subtype-selective lethal molecules that could be developed into targeted therapies, we screened ~5500 bioactive molecules across a panel of four NBL cell lines representing either MycNAMP or the newly identified mesenchymal subtype (MESN). A number of subtype selective compounds were identified, and their effect on the regulatory module was evaluated using high-throughput transcriptome analysis (PLATE-Seq) (Bush EC et al., 2017) followed by Virtual Inference of Protein activity by Enriched Regulon (VIPER) analysis (Alvarez MJ et al., 2016). This analysis revealed 15 compounds that exhibited greater potency in MycNAMP cells, and inverted the MR signature that characterizes this subtype. Compounds that reverted the signature caused destabilization of MycN through diverse mechanisms, highlighting new therapeutic approaches to targeting the MycNAMP subtype. This screening strategy also identified MESN-selective compounds, including multiple statin drugs that inhibit mevalonate biosynthesis in cells. The subtype-selectivity of these well-studied drugs is being used to define their lethal mechanisms in the MESN subtype, and to understand how MycNAMP cells evade their inhibitory effects. Our multifaceted approach, including cell line-selective chemical screening coupled with high-throughput transcriptome and network analysis, can serve as a framework for future drug discovery in a variety of cancers.
Citation Format: Michael E. Stokes, Alessandro Vasciaveo, Jonnell Candice Small, Presha Rajbhandari, Gonzalo Lopez, Andrea Califano, Brent R. Stockwell. Subtype-selective lethal molecules disrupt the regulatory module that drives high-risk neuroblastoma [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 2666.
Abstract 2677: A natural product-derived Compound A effectively targets both cancer stem and non-stem cells in NSCLC
Authors: Hyun Seung Yeob , Le Huong T. , Cho Jaebeom , Min Hye-Young , Lee Ho-Young 
Published: August 2018

Abstract
Cancer stem-like cells (CSCs) contribute to tumor recurrence and chemoresistance. Hence, strategies eradicating CSCs are crucial for effective anticancer therapies. Here, we demonstrate transcriptional upregulation of the heat shock proteins (Hsp90 and Hsp70) and their co-chaperones and enhanced activities of the Hsp system in both non-CSCs and CSCs in non-small cell lung cancer (NSCLC) cells. Genetic and pharmacologic strategies targeting Hsps eliminated both CSCs and non-CSCs of NSCLC, suggesting the functional role of the Hsp system in the two populations in NSCLC. We further identified Compound A, a natural product-derived compound, as a novel Hsp70 inhibitor eliminating both the CSC and non-CSC populations in NSCLC. Compound A inhibited the sphere-forming ability of NSCLC CSCs by inducing apoptosis. Compound A also suppressed the viability and colony-forming abilities of NSCLC cells (non-CSCs) and their sublines carrying acquired chemoresistance by inducing apoptosis with minimal toxicity in normal cells derived from various organs. Mechanistically, Compound A disrupted Hsp70 function by binding to the ATP-binding pockets of Hsp70. These data suggest the rationale to target the Hsp system for controlling both CSCs and non-CSCs in NSCLC and the potential of Compound A as a natural Hsp70 inhibitor to eliminate the two populations with limited toxicities.
Citation Format: Seung Yeob Hyun, Huong T. Le, Jaebeom Cho, Hye-Young Min, Ho-Young Lee. A natural product-derived Compound A effectively targets both cancer stem and non-stem cells in NSCLC [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 2677.
Abstract 268: Combined inhibition of cyclooxygenase with docosahexaenoic acid augments apoptosis in KRAS mutant non-small cell lung cancer cells
Authors: Amissah Felix , Jones Kylee J. , Poku Rosemary A. 
Published: August 2018

Abstract
Cyclooxygenase (COX) inhibitors are widely used in the treatment of various inflammatory disorders. Their antiproliferative effects have also been widely reported. This health benefit of COX inhibitors is limited by some potential adverse effects, including gastrointestinal irritation. Docosahexaenoic (DHA), commonly derived from fish oils, is also known to possess anticancer effects. We examined whether COX inhibitors (aspirin and diclofenac) combined with DHA would synergize their antiproliferative activity. This would allow for a decrease in the amounts of each compound used for chemoprevention, which may likely decrease the risk of adverse effects. While treatment with DHA resulted in concentration-dependent cell death in K-Ras mutant (A549 and NCI-H1573) lung cancer cells (EC50 of 5.5 µM and 9.5 µM), combination with diclofenac resulted in relatively more significant reduction in cell viability (EC50 of 3.7 µM and 3.2 µM) and cell proliferation (p&lt;0.0001). In addition, the combination treatment was more effective in inhibiting clonogenic cell growth and inducing apoptosis with a significant increase in proapoptotic proteins (p&lt;0.001). Furthermore, the combination treatment yielded more marked inhibition of K-Ras expression as well as altered localization in the cell membrane. These data point to the promising chemopreventive potential of combining low doses of COX inhibitors with DHA with a possible decrease in their adverse effects.
Citation Format: Felix Amissah, Kylee J. Jones, Rosemary A. Poku. Combined inhibition of cyclooxygenase with docosahexaenoic acid augments apoptosis in KRAS mutant non-small cell lung 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 268.
Abstract 2692: Elucidation of the pre-B-cell receptor signaling network in acute lymphocytic leukemia cells
Authors: Walter Roland , Kouidri Khouloud , Peter Jessica , Pape Martine , Merschen Laura , Haeupl Bjoern , Doebele Carmen , Serve Hubert , Yi Yanlong , Urlaub Henning , Oellerich Thomas 
Published: August 2018

Abstract
Antigen receptors transduce complex signals and thereby control important cell fate decisions of the B-lineage including differentiation, proliferation and B-cell survival. The initial steps of B-cell development take place in the bone marrow, and the first dependency of a developing B-cell on antigen receptor signaling occurs at the pre-B-cell stage where expression of the pre-BCR is essential for cell survival. In contrast to B-cell-receptor (BCR) signaling, the nature of pre-BCR signals is far less characterized. It is believed that pre-BCRs transduce a constitutive baseline signal that is essential for survival and differentiation of pre-B-cells into immature B-cells. Since pre-BCRs are crucial regulators of pre-B-cell survival and differentiation, it is not surprising that dysregulation of pre-BCR signaling is observed in acute lymphocytic leukemia (ALL) cells where it contributes to survival of the malignant cell clones. To identify drug targets in the pre-BCR signaling network, we have systematically characterized pre-BCR signaling in two pre-BCR-dependent ALL cell lines by quantitative phosphoproteomics. Because pre-BCRs transduce a constitutive baseline signal, we interfered with pre-BCR signaling by either Syk inhibitor treatment or by an inducible shRNA-mediated knock-down of the pre-BCR component Ig-α to monitor pre-BCR-dependent signals. We identified and quantified more than 15,000 phospho-sites. Among these sites, more than 500 were regulated upon interference with pre-BCR signaling. Although the upstream components are shared between pre-BCRs and BCRs, the wiring of their downstream signals occurred to be different which is reflected by our finding that the majority of the identified pre-BCR signaling effectors have not been described in the context of BCR signaling in mature B-cells or lymphomas. Finally, we have identified vulnerabilities in the pre-BCR signaling network by intersecting our phosphoproteomic data with data from loss-of-function CRISPR-Cas9 screens for essential genes in ALL cell lines. Taken together, this study provides a comprehensive dataset for pre-BCR signaling and identifies effector proteins that are relevant for the regulation of ALL cell survival and proliferation.
Citation Format: Roland Walter, Khouloud Kouidri, Jessica Peter, Martine Pape, Laura Merschen, Bjoern Haeupl, Carmen Doebele, Hubert Serve, Yanlong Yi, Henning Urlaub, Thomas Oellerich. Elucidation of the pre-B-cell receptor signaling network in acute lymphocytic leukemia 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 2692.
Abstract 2695: Quantitative phosphoproteome analysis identifies novel functional pathways of tumor suppressor DLC1 in estrogen receptor-positive breast cancer
Authors: Gökmen-Polar Yesim , True Jason D. , Vieth Edyta , Gu Yuan , Gu Xiaoping , Qi Guihong D. , Mosley Amber L. , Badve Sunil 
Published: August 2018

Abstract
Deleted in Liver Cancer-1 (DLC1), a member of the RhoGAP family of proteins, functions as a tumor suppressor in several cancers including breast cancer. However, its clinical relevance is unclear in breast cancer. In this study, expression of DLC1 was correlated with prognosis using publicly available breast cancer gene expression datasets and quantitative polymerase chain reaction (qPCR) in cohorts of Estrogen Receptor-positive (ER+) breast cancer. Mutation and methylation status of DLC1 were assessed in these datasets including The Cancer Genome Atlas (TCGA). To seek further insights in understanding the role of DLC1 in ER+ breast cancer, we developed a knock-in model of DLC1 in T47D breast cancer cells. Label-free global proteomic and TiO2 phosphopeptide enrichment assays were performed and validated using Western blotting. Data are available via ProteomeXchange with identifier PXD008220. Here, we report that low expression of DLC1 correlates with poor prognosis in patients with ER+ breast cancer with further decrease in metastatic lesions. Analysis of the TCGA data showed that down regulation of DLC1 is not due to methylation or mutations. Stable knock-in of DLC1-full-length inhibits cell colony formation significantly in vitro compared to its control counterpart. 6726 phosphopeptides were quantified by phosphoproteomics analysis in both conditons, whereas 205 and 122 were unique to DLC1 knock-in and T47D-control cells, respectively. Pathway analysis using DAVID showed the top three significant clusters of differentially identified phosphopeptides involving cell-cell adhesion, mRNA processing and splicing, and transcription regulation. Decreased phosphorylation of epithelial cell transforming sequence 2 (ECT2) at the residue T359, critical for its active conformational change, was validated. In conclusion, this data suggests that high expression of DLC1 reduces cell growth and is associated with favorable prognosis. Our results document an inverse relation between ECT2 phosphorylation and DLC1 expression, promising a novel strategy for treating ER+ breast cancer.
Citation Format: Yesim Gökmen-Polar, Jason D. True, Edyta Vieth, Yuan Gu, Xiaoping Gu, Guihong D. Qi, Amber L. Mosley, Sunil Badve. Quantitative phosphoproteome analysis identifies novel functional pathways of tumor suppressor DLC1 in estrogen receptor-positive breast 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 2695.
Abstract 27: Regulating Rac1 signaling proteins influences migratory and protrusive behaviors of metastatic breast cancer cells in aligned, 3D collagen and collagen-like matrices
Authors: Doorn Rachel Van , Szulczewski Joseph , Ponik Suzanne 
Published: August 2018

Abstract
Breast cancer is the most commonly diagnosed cancer in women, with one out of every eight women being diagnosed in their lifetime. Our lab has previously shown that aligned collagen promotes tumor progression to metastatic disease, and predicts poor prognosis for breast cancer patients. Aligned collagen increases the persistence of cellular migration by limiting the number of protrusions from the cell body. The regulation of Rac1 and Rho proteins are important for cell motility through formation of lamelliepodia. Deregulation of these proteins and those upstream of Rac1, can result in cancer cell migration, invasion and metastases. Understanding how these proteins are regulated in different 3D collagen tumor microenvironments is important for determining phenotypes of invasive breast cancers. Inhibition of cell motility through the Rac1 pathway may limit cancer cell migration and prevent metastatic disease. While many studies have investigated cell migration in 2D, little is known regarding the cellular mechanisms that regulate both breast cancer cell migration and protrusive events in 3D aligned collagen. In vitro models will be used to recapitulate 3D aligned, and random collagen environments and assess the mechanisms of cell migration and protrusion dynamics by live-cell, time-lapse microscopy. Previous work from our group determined that MDA-MB-231 cells seeded into collagen environments had fewer protrusions, which localized in the directions of collagen alignment, when migrating along aligned fibers compared to MDA-MB-231 cells in the random collagen matrices. Preliminary data demonstrates that signaling proteins upstream of Rac1 such as, small GTPases, DOCK180 and FilGAP, dictate cellular protrusions and migratory persistence. MDA-MB-231 cell lines with doxycycline-induced knock-down Rac1 GTPase activating protein (GAP), FilGAP, and guanine nucleotide exchange factor (GEF), DOCK180, demonstrate that the regulation of Rac1 activity through these specific proteins plays a role in breast cancer cell migration and protrusion dynamics in an aligned collagen environment. Understanding the regulation of breast cancer cell migration in aligned and random 3D collagen environments will enhance the current understanding of progression to metastatic disease on a cellular level.
Citation Format: Rachel Van Doorn, Joseph Szulczewski, Suzanne Ponik. Regulating Rac1 signaling proteins influences migratory and protrusive behaviors of metastatic breast cancer cells in aligned, 3D collagen and collagen-like matrices [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 27.