bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-A35: Discovery of a new kinase inhibitor targeting BRAF monomers and dimers
Authors: Cotto Rios Xiomaris M. , Agianian Paul , Wu Yang , Gavathiotis Evripidis 
Published: August 2018

Abstract
Increased activation of the RAS/RAF/MEK/ERK signaling pathway, through mutations in upstream activators or in components of the pathway, can lead to uncontrolled cellular growth and proliferation leading to tumor development. BRAF mutations are present in more than 50% of melanoma patients as well as in colorectal (5-10%), thyroid carcinomas (25-45%), hairy-cell leukemia (~100%) and less commonly in ovarian and lung malignancies. Specifically, activating BRAF mutation V600E in the kinase domain of BRAF accounts for almost 50% of melanoma. Although, FDA-approved RAF inhibitors vemurafenib and dabrafenib have elicited remarkable responses and improved survival of melanoma patients with BRAFV600E/K mutations, acquired resistance limits their effectiveness as patients relapse. Several studies have demonstrated that resistance in melanoma and other tumors involve increased formation of RAF dimers that are not effectively inhibited by clinical inhibitors. Hence, underscoring the need for improved RAF inhibitors. Toward this goal, we developed an in-cell-western assay to screen for small molecule kinase inhibitors of the ERK signaling pathway, using melanoma cells that express BRAFV600E monomers and dimers. Because several inhibitors have been identified to inhibit ERK signaling that led us to investigate the precise mechanism of inhibition. We performed structural characterization and biochemical analysis of the RAS/RAF/MEK/ERK signaling pathway in cells with different RAS/BRAF mutational background, expressing BRAF monomers and dimers. Our study enabled us to identify a kinase inhibitor that potently inhibits BRAF monomers and dimers, with distinct structural properties compared to current RAF inhibitors. Further development of this new class of RAF kinase inhibitor may lead to more effective ERK signaling inhibition and improved treatments for BRAF-dependent tumors.
Citation Format: Xiomaris M. Cotto Rios, Paul Agianian, Yang Wu, Evripidis Gavathiotis. Discovery of a new kinase inhibitor targeting BRAF monomers and dimers [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-A35.
Abstract LB-B20: High-affinity antisense oligonucleotides targeting Foxp3 inhibit immunosuppressive function of regulatory T cells and produce anti-tumor effects in syngeneic tumor models
Authors: Revenko Alexey S. , Sinclair Charles , Johnson Ben , Hettrick Lisa , Peter Alison , Staniszewska Anna , Hughes Adina , Sandin Linda , Taylor Molly , Klein Stephanie , Watt Andy , Monia Brett , Edbrooke Mark , MacLeod A. Robert 
Published: August 2018

Abstract
Regulatory T cells (Treg) contribute to the progression of cancer through suppression of specific anti-tumor effector immune responses. Therefore, inhibition of Treg function is an attractive approach for cancer immunotherapy. However, despite substantial effort, specific inhibition of Tregs remains a challenge. Foxp3 is a Treg-specific transcription factor required for their development and function. We employed next-generation antisense inhibitors (Gen 2.5 cEt-modified ASOs) to selectively inhibit Foxp3 expression in mouse Treg cells and evaluated consequences of ASO-mediated Foxp3 knock-down in vitro and in vivo. Mouse Foxp3-specific ASOs produced potent dose-dependent reductions in Foxp3 mRNA and protein in mouse Tregs in vitro without the use of transfection reagents. Reductions of Foxp3 in mouse Tregs was associated with loss of expression of immunosuppressive markers as well as loss of immunosuppressive function in vitro. Systemically delivered unformulated cEt-modified mouse Foxp3 ASOs reduced Foxp3 mRNA and protein in Tregs in normal mice. Importantly, this inhibition, in contrast to the phenotype of Foxp3 KO mice, was not associated with a significant autoimmune phenotype. When mouse Foxp3 ASOs were administered to syngeneic tumor-bearing mice they produced significant Foxp3 mRNA and protein knockdown in tumor-infiltrating Tregs. The growth of tumors in mouse Foxp3 ASO-treated animals was significantly attenuated with a fraction of animals (25%-50%) achieving complete regressions. Anti-tumor activity of mouse Foxp3 ASOs was associated with immunophenotype changes consistent with the increased anti-tumor immune response. Overall these data demonstrate that regulatory T cells can be effectively targeted by ASOs and that Foxp3 ASOs represent a potentially attractive therapeutic approach in cancer immunotherapy.
Citation Format: Alexey S. Revenko, Charles Sinclair, Ben Johnson, Lisa Hettrick, Alison Peter, Anna Staniszewska, Adina Hughes, Linda Sandin, Molly Taylor, Stephanie Klein, Andy Watt, Brett Monia, Mark Edbrooke, A. Robert MacLeod. High-affinity antisense oligonucleotides targeting Foxp3 inhibit immunosuppressive function of regulatory T cells and produce anti-tumor effects in syngeneic tumor models [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-B20.
Abstract LB-B22: TNBC kinase prioritization for targeted therapy after chemotherapy resistance
Authors: Lim Bora , Park In Ah , Wang Ying , Bollu Lakshmi , Brown Powel , Baggerly Keith , Meric-Bernstam Funda , Ueno Naoto 
Published: August 2018

Abstract
Introduction: Triple negative breast cancer accounts for 10-15% of all breast cancers yet contribute to high recurrence and metastasis that leads to the death of patients. Lack of molecular therapeutic target for TNBC leaves the chemotherapy as only available options while many develop resistance to chemotherapeutics, leaving patients with TNBC at risk of accumulative toxicities and death. Thus, it is critical to identify unique molecular kinases that contribute to chemotherapy resistance. We hypothesize that differential level of kinase expression stratified based on the chemotherapy response, to discover putative targets. Methods and Material: We performed an in silico search of kinases using mRNA microarray data that are expressed with higher proportion in TNBC patient samples based on the chemotherapeutic response, to identify kinases that contribute to the resistance to neoadjuvant chemotherapy using mRNA sequencing data of 132 patients with TNBC. We then prioritize the putative resistance related kinases, based on priority scoring system we have developed, to select the top candidate kinase for further therapeutics development. Result: Eleven kinases were differentially expressed between the pCR and non-pCR patients samples at baseline, and prioritized based on our scoring system. MELK was selected as a top target kinase given the highest score and biological validation, and currently available inhibitor. Pre-clinical studies of MELK has shown efficacy in vitro and in vivo models. Conclusion: First in human trial of oral MELK inhibitor is currently launched to be tested in actual clinical setting in patients with TNBC, that will offer the opportunity for us to validate our prioritization scoring system and pre-clinical validation. Further clinical validation, which is ongoing, will support our in silico screening followed by a prioritization to select kinase inhibitor development in chemotherapy resistant TNBC.
Citation Format: Bora Lim, In Ah Park, Ying Wang, Lakshmi Bollu, Powel Brown, Keith Baggerly, Funda Meric-Bernstam, Naoto Ueno. TNBC kinase prioritization for targeted therapy after chemotherapy resistance [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-B22.
Abstract LB-B32: Modulation of the Hedgehog signaling pathway in models of basal cell carcinoma by ATP-competitive PKCi inhibitors
Authors: Roffey Jon , Dillon Christian , Oro Anthony E. , Mirza Amar N. , Sarin Kavita Y. , Aasi Sumaira Z. , Parker Peter J. , Riou Philippe , Barton Caroline , Patel Bhavisha , Barton Caroline , Turnbull Andrew , Stanway Emma , Fowler Katherine , Ott Gregory , Ator Mark 
Published: August 2018

Abstract
We will describe for the first time the optimization and pharmacological characterisation of azaquinazoline based ATP-competitive inhibitors of the aPKC isoforms. The serine/threonine kinase protein kinase C iota (PKCι) and protein kinase C zeta (PKCζ) together define the atypical sub-class of the protein kinase C superfamily (aPKC). Both isoforms have emerged as master regulators of cellular polarity with PKCι implicated in the maintenance of aberrant Hedgehog (HH) pathway activity in basal cell carcinoma (BCC). Common activating mutations in the HH signalling pathway drive BCC growth through the transcription factor GLI. Inhibitors of membrane protein smoothened (SMO) are clinically effective suppressors of HH signalling in BCC. However, acquired and de novo resistance to SMO inhibitors poses severe limitations to the clinical use of these agents. PKCι has been shown to directly activate GLI1 in BCC and has been linked to SMO inhibitor resistance making a strong case for the development of a selective PKCι inhibitor. Insights from structural biology identified critical amino acid residues in the PKCι binding pocket that could be exploited through structure-based drug design to optimise inhibitor potency and selectivity over structurally related kinase targets. The phosphorylation status of the known PKCι proximal substrate LLGL2 was used as a cellular pharmacodynamic biomarker and to demonstrate in vivo PKCι inhibition. To investigate the effects of PKCι inhibitors on the HH pathway a panel of compounds covering a diversity of chemotypes were profiled using a Hedgehog pathway GLI1 reporter assay in an engineered NIH3T3 cell line. Murine and human BCC cells, dependent on HH signalling for survival, were sensitive to PKCι inhibitor treatment with concomitant dose and time dependent effects on the expression of the HH pathway activity biomarker GLI1. Taken together, these results have therapeutic implications making a strong case for further evaluation of PKCι inhibitors in the setting of SMO-inhibitor-resistant BCC cancers.
Citation Format: Jon Roffey, Christian Dillon, Anthony E. Oro, Amar N. Mirza, Kavita Y. Sarin, Sumaira Z. Aasi, Peter J. Parker, Philippe Riou, Caroline Barton, Bhavisha Patel, Caroline Barton, Andrew Turnbull, Emma Stanway, Katherine Fowler, Gregory Ott, Mark Ator. Modulation of the Hedgehog signaling pathway in models of basal cell carcinoma by ATP-competitive PKCi inhibitors [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-B32.
Abstract 100: Interleukin 1 receptor type II upregulates MMP1 expression and increases motility of keratinocytes cells
Authors: Wang Hsiu-Hua , Lee Te-Chang 
Published: August 2018

Abstract
We have shown that long-term exposure to low doses of inorganic arsenite (iAs) induced malignant transformation of non-tumorigenic human keratinocytes, HaCaT cells. We further demonstrated that enhanced expression of a decoy type II receptor of interleukin-1 (IL1R2) in transformed keratinocytes mediated through IL-6 and VEGFR to increase the migration and invasion activities, indicating the oncogenic potential of IL1R2. In this present study, we further explored how IL1R2 enhances the cell motility in human keratinocytes. As described earlier, long-term and low dose iAs (0, 0.5 and 1 μM) exposed HaCaT cells were designated as HaCaT A0, A1 and A2 cells, respectively. The tumorigenic cell line, T4R2, was derived from the tumor in mice implanted with HaCaT A2 cells. By growing HaCaT A0, A1, A2 and T4R2 cells on an organotypic culture system using basal medium, we found that T4R2 cells formed multilayered morphology. By aid of siRNA and ectopic expression techniques, we further demonstrated that increased expression of IL1R2 in T4R2 cells was associated with increased matrix metalloproteinase-1 (MMP1) and enhanced cell motility. The roles of MMP1 on supporting the organotypic growth of T4R2 cells were confirmed by using the stably MMP1-silenced T4R2 cells (T4R2-shMMP1). The cell motility of T4R2-shMMP1 cells was also significantly reduced. Furthermore, IL1R2-induced MMP1 upregulation was remarkably inhibited by inhibitors of MAPK/ERK signaling. Our present results revealed that MMP1 was one of downstream targets of IL1R2 which plays a crucial role on the progression of malignancy. Therefore, IL1R2 may be a target for cancer intervention.
Citation Format: Hsiu-Hua Wang, Te-Chang Lee. Interleukin 1 receptor type II upregulates MMP1 expression and increases motility of keratinocytes 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 100.
Abstract 1003: Improving the functional taxonomy of breast cancer-associated fibroblasts by single-cell RNA sequencing reveals clinically relevant cellular subsets
Authors: Bartoschek Michael , Pietras Kristian 
Published: August 2018

Abstract
Aim: The traditional tumor cell-centric view of cancer has been replaced in the past years with the appreciation of the importance of the tumor microenvironment for the malignant phenotype. Cancer-associated fibroblasts (CAFs) are the main constituent of the breast tumor microenvironment, although the exact origin and role of CAF subpopulations in disease initiation, progression and response to treatment remain unclear. Therefore, cancer therapies targeting CAFs are not available.
Methods: Here, we delineate the heterogeneity of CAFs through single-cell RNA sequencing of 768 EPCAM-CD31-CD45-NG2- cells from the MMTV-PyMT mouse model of breast cancer.
Results and discussion: Unbiased transcriptional clustering and differential gene expression analysis revealed four populations, with functionally distinct transcriptional profiles. The existence of these cell populations was further validated by immunostaining in experimental and human tumors revealing a preferential localization of each CAF subtype within the tumor microenvironment. Gene profiles specific to each CAF subpopulation held prognostic capability in clinical cohorts and correlated to known functional gene profiles. Our high-resolution comparison of single-cell transcriptomes in CAFs reveals previously unappreciated functional diversity within the tumor microenvironment.
Conclusions: Ultimately, our delineation of an improved taxonomy of breast CAFs reveals a previously unappreciated functional diversity within the tumor microenvironment and opens the possibility for biomarker-driven development of new drugs for precision medicine.
Citation Format: Michael Bartoschek, Kristian Pietras. Improving the functional taxonomy of breast cancer-associated fibroblasts by single-cell RNA sequencing reveals clinically relevant cellular subsets [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 1003.
Abstract 1004: Tuft cell chemosensory signaling during pancreatic ductal adenocarcinoma
Authors: Hoffman Megan T. , Crawford Howard 
Published: August 2018

Abstract
Pancreatic ductal adenocarcinoma (PDA) is the second most common cause of cancer death in the US with a 10% 5-year survival rate and, as such, is one of the most common deadly cancers. PDA is characterized by a robust stromal reaction, a large portion of which is composed of infiltrating immune cells. This inflammatory response has been previously shown to promote both the initiation and progression of PDA. Current research has been to understand the interaction between tumor cells and infiltrating immune cells and the contribution to cancer progression. In this work we focus on a specific cell population present in the epithelium during pancreatic tumorigenesis called a tuft cell. Tuft cells have been found in luminal surfaces throughout the body, most notably characterized in the intestine where these cells have been shown to directly regulate the immune response to parasitic infection, but have also been found in the nasal, respiratory and bladder epithelium. These solitary chemosensory cells, as they are also known, use a common chemosensory pathway, previously characterized in type-II taste cells, in order to interact with the luminal environment. Interestingly, tuft cells in the metaplastic pancreas uniquely express TRPM5 and alpha-gustducin, both components of the chemosensory cascade, suggesting these cells have the potential to mediate a response to extracellular signals. Pancreatic tuft cells also make an array of cytokines and immunomodulatory factors that can directly alter the immune response in the tumor microenvironment. These data leads us to hypothesize that tuft cells utilize the chemosensory response pathway to remodel the tumor microenvironment in PDA. In order to answer this question, we ablated a key protein in the chemosensory cascade, alpha-gustducin, and found that this loss increases aggressiveness in a model of pancreatitis-associated tumorigenesis. We are currently exploring differences in the tumor microenvironment that may explain these results.
Citation Format: Megan T. Hoffman, Howard Crawford. Tuft cell chemosensory signaling during pancreatic ductal adenocarcinoma [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 1004.
Abstract 102: RUNX3 inhibits invasiveness and stemness through downregulation of Gli-1 in colon cancer cells
Authors: Kim Bo Ram , Na Yoo Jin , Kim Jung Lim , Jeong Soyeon , Park Seong Hae , Jo Min Jee , Jeong YoonA , Lee Dae-Hee , Oh Sang Cheul 
Published: August 2018

Abstract
Disabled tumor suppressor genes and hyperactive oncogenes contribute considerably to cell fates during cancer development via genetic alterations such as somatic mutations. To date, little is known about how tumor suppressor genes react to diverse oncogenes during tumor progress. Our previous report showed that RUNX3 inhibits metastasis by preventing vascular endothelial growth factor (VEGF) secretion and suppressed endothelial cell growth and tube formation in colorectal cancer. Hedgehog signaling is crucial for the physiological maintenance and self-renewal of stem cells, and its deregulation is responsible for their tumor development. The mechanisms that inhibit this pathway during the proliferation are poorly understood. Here, we show that the tumor suppressor RUNX3 modulates tumorigenesis in response to cancer cells induced by inhibition by oncogene Gli-1 ubiquitination. Moreover, we demonstrated that RUNX3 and Gli-1 expression had inverse correlation in colorectal cancer cells and tissues. We observed a direct interaction between RUNX3 and Gli-1, promoting ubiquitination of Gli-1 at the intracellular level. The increased ubiquitination of Gli-1 was induced through the E3 ligase β-TrCP. This novel RUNX3-dependent regulatory loop may limit the extent and duration of Hedgehog signaling during extension of tumor initiation capacity. Base on this research, a search for agents that can induce RUNX3 might result in new and effective therapies for colorectal cancer.
Citation Format: Bo Ram Kim, Yoo Jin Na, Jung Lim Kim, Soyeon Jeong, Seong Hae Park, Min Jee Jo, YoonA Jeong, Dae-Hee Lee, Sang Cheul Oh. RUNX3 inhibits invasiveness and stemness through downregulation of Gli-1 in colon 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 102.
Abstract 1028: Patient-derived xenografts undergo mouse-specific tumor evolution
Authors: Ben-David Uri , Ha Gavin , Tseng Yuen-Yi , Greenwald Noah F. , Oh Coyin , Shih Juliann , McFarland James M. , Wong Bang , Boehm Jesse S. , Beroukhim Rameen , Golub Todd R. 
Published: August 2018

Abstract
Patient-derived xenografts (PDXs) have become a prominent cancer model system, as they are presumed to faithfully represent the genomic features of primary tumors. Here we monitored the dynamics of copy number alterations (CNAs) in 1,110 PDX samples across 24 cancer types. We observed rapid accumulation of CNAs during PDX passaging, often due to selection of pre-existing minor clones. CNA acquisition in PDXs was correlated with the tissue-specific levels of aneuploidy and genetic heterogeneity observed in primary tumors. However, the particular CNAs acquired during PDX passaging differed from those acquired during tumor evolution in patients. Several CNAs recurrently observed in primary tumors gradually disappeared in PDXs, indicating that events undergoing positive selection in humans can become dispensable during propagation in mice. Importantly, the genomic stability of PDXs was associated with their response to chemotherapy and targeted drugs. These findings have important implications for PDX-based modeling of human cancer.
Citation Format: Uri Ben-David, Gavin Ha, Yuen-Yi Tseng, Noah F. Greenwald, Coyin Oh, Juliann Shih, James M. McFarland, Bang Wong, Jesse S. Boehm, Rameen Beroukhim, Todd R. Golub. Patient-derived xenografts undergo mouse-specific tumor evolution [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 1028.