bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4642: Personalized cancer-specific protein corona affects the therapeutic impact of nanoparticles
Authors: Corbo Claudia , Mahmoudi Morteza , Farokhzad Omid C. 
Published: August 2018

Abstract
Despite recent progress in nanomedicine, there is still a lack of efficient nanotherapeutics for cancer treatment. When nanoparticles (NPs) are injected, they circulate the bloodstream and interact with biomolecules, creating a biomolecular shell. This shell of biomolecules surrounding the NPs consists mostly of proteins and is referred to as the protein corona (PC). The PC composition depends on various factors, including, but not limited to i) surface properties of NPs (e.g. surface chemistry and charge), and ii) experimental parameters (e.g. incubation time, pH, temperature). The impact of these factors on the formation of the PC has been widely investigated and is nowadays well known. However, the effects of the biological milieu (e.g. patient's health status, plasma vs serum) on the PC formation and composition have been underexamined and still need to be deeply clarified. Recently, it has been demonstrated that the protein pattern constituting the PC of NPs exposed to plasma of cancer patients is different than that of the PC formed by exposure of NPs to healthy plasma. These variations can be miniscule but crucial in the fate of NPs. In fact, NPs surrounded by a PC lose their synthetic identity and acquire a new biological identity responsible for their biological destiny (cell targeting, accumulation, immune response). In this work, we have studied the PCs formed around NPs using plasmas of patients with one of eight cancers to gain insights into the cancer-related variations of the PC composition and into their potential effects on the therapeutic efficacy of NPs. Our results confirmed that the same NPs incubated with plasmas of patients affected by different tumors have distinct PCs. Overall, this is the first wide study unveiling the specific PCs formed around NPs using plasmas of eight cancers. This comprehensive report acts as a tool for researchers in nanomedicine to design personalized nanotherapeutics in a cancer-specific manner for clinical applications. Methods: Silica NPs were incubated with plasma of healthy subjects and cancer patients. NPs in the study were 100 nm in size and the PCs in each subject's plasma were characterized and compared using SDS-PAGE and LC-MS/MS. Plasmas of patients with one of 8 cancers have been employed: breast, rectum, lung, kidney, thyroid, uterine, bladder, ovary.
Citation Format: Claudia Corbo, Morteza Mahmoudi, Omid C. Farokhzad. Personalized cancer-specific protein corona affects the therapeutic impact of nanoparticles [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 4642.
Abstract 4713: BET bromodomain inhibition synergizes with PD-1 blockade to facilitate anti-tumor response in Kras-mutant non-small cell lung cancer
Authors: Adeegbe Dennis O. , Liu Shengwu , Bowden Michaela , Hammerman Peter S. , Bradner James E. , Rustgi Anil K. , Bass Adam J. , Freeman Gordon J. , Chen Huawei , Wong kwok-Kin 
Published: August 2018

Abstract
KRAS mutation is present in about 30% of human lung adenocarcinomas. While recent advances in targeted therapy have shown great promise, KRAS remains undruggable and concurrent alterations in tumor suppressors render KRAS mutant tumors even more resistant to existing therapies. Contributing to the refractoriness of KRAS mutant tumors harboring these co-mutations are immunosuppressive mechanisms such as increased presence of suppressive Tregs in tumors and elevated expression of the inhibitory receptor PD-1 on tumor-infiltrating T cells. BET bromodomain inhibitors demonstrate clinical benefit in hematologic malignancies, and prior reports demonstrate their Treg-disruptive effects in a NSCLC model. Targeting PD-1 inhibitory signals through anti-PD-1 antibody blockade has also shown substantial therapeutic impact in lung cancer although these outcomes are still limited to a minor pool of patients. We therefore hypothesized that the BET bromodomain inhibitor JQ1 would synergize with PD-1 blockade to promote robust anti-tumor response in lung cancer. In the present study, using Kras+/LSL-G12D; Trp53L/L (KP) mouse models of non-small cell lung cancer, we identified cooperative effects among JQ1 and anti-PD-1 that included reduced numbers of tumor-infiltrated Tregs and enhanced activation of tumor-infiltrating T cells, which exhibited a Th1 cytokine profile that favored their demonstrated improved effector function. Furthermore, lung-tumor-bearing mice under this combinatorial treatment regimen showed robust and long-lasting anti-tumor responses compared to either agent alone, culminating in substantial improvement in the survival of treated mice. Thus, combining BET bromodomain inhibition with immune checkpoint blockade offers a promising therapeutic approach for solid malignancies such as lung adenocarcinoma.
Citation Format: Dennis O. Adeegbe, Shengwu Liu, Michaela Bowden, Peter S. Hammerman, James E. Bradner, Anil K. Rustgi, Adam J. Bass, Gordon J. Freeman, Huawei Chen, kwok-Kin Wong. BET bromodomain inhibition synergizes with PD-1 blockade to facilitate anti-tumor response in Kras-mutant non-small cell lung 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 4713.
Abstract 4744: Disruption of Clever-1 in macrophages activates the innate immune response and mediates tumor rejection
Authors: Viitala Miro , Virtakoivu Reetta , Tadayon Sina , Jalkanen Sirpa , Hollmén Maija 
Published: August 2018

Abstract
Macrophages are considered the main obstacles for successful cancer treatment since they can dampen anti-tumor immune responses and promote tumor progression and resistance formation. Macrophages are highly eligible candidates for targeted therapies since these cells are abundantly present in various tumors, they are very plastic and can be converted into pro-inflammatory macrophages supporting T cell activation and tumor rejection. Clever-1 (also known as Stabilin-1) is a multifunctional molecule conferring scavenging ability on a subset of alternatively activated macrophages. The aim of this study is to uncover previously unknown functions of Clever-1 in the regulation of macrophage-mediated anti-tumor immune responses and develop anti-Clever-1 therapy into clinical use for those suffering from refractory, untreatable solid tumors.
By using in vivo tumor models and sophisticated immunological assays, our data show that mice carrying a macrophage-specific genetic deletion of Clever-1 (Lyz2-Cre/Stab1fl/fl) reject implanted Lewis lung carcinoma and EL4 lymphoma tumors. Macrophage Clever-1 deficiency induced proliferation of Ly6Chi monocytes in the tumor microenvironment but impaired their maturation and polarization into tumorigenic Ly6Clo macrophages. Tumors in Lyz2-Cre/Stab1fl/fl mice consisted almost completely of proliferating CD8 T cells with an exhausted PD-1+Lag3+ phenotype two weeks after implantation. Functionally, Clever-1 depleted macrophages showed enhanced pro-inflammatory responses following TLR activation with a shift in IL-12/IL-10 secretion levels. This was due to enhanced activation of mTORC1 and NFκB signaling, which resulted in increased secretion of TNFα in steady state and after LPS induction.
In conclusion, our data show an important function of Clever-1 in controlling macrophage mediated local immune responses. Moreover, our data supports Clever-1 targeting as a novel approach to increase host defenses against immune compromised tumors and promotes anti-Clever-1 immunotherapy into clinical trials where it may have benefits in comparison with currently available immune activating drugs.
Citation Format: Miro Viitala, Reetta Virtakoivu, Sina Tadayon, Sirpa Jalkanen, Maija Hollmén. Disruption of Clever-1 in macrophages activates the innate immune response and mediates tumor rejection [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 4744.
Abstract 4835: UD-017, a novel highly selective and orally active CDK7 inhibitor, shows a significant anticancer activity in patient-derived cancers
Authors: Matsushita Takashi , Ogi Sayaka , Onuma Kazuhiro , Sunamoto Hidetoshi , Ogawa Ayumi , Hasegawa Toru , Tokunaga Yasunori , Aga Yasuhiro , Ushiyama Shigeru 
Published: August 2018

Abstract
Background: Cyclin dependent kinase 7 (CDK7) is an attractive target for anticancer drugs due to its dual roles, cell cycle regulation and gene transcription/RNA processing. We synthesized UD-017, a small-molecule, highly selective, orally active CDK7 inhibitor with a novel chemotype. In this study, we characterized anticancer activities of UD-017 in vitro and in vivo using patient-derived (PD) cancer cells.
Methods: We first evaluated an antiproliferative activity of UD-017 broadly in a panel of cancer cell assay including patient-derived 3-dimensional tumor clonogenic assay. To verify the potential of c-Myc expression as a biomarker, we investigated the correlation between c-Myc expression levels and anticancer activity in vitro and in vivo using a colorectal cancer cell. In the main part, anticancer efficacy of UD-017 was investigated in vivo in PD-xenograft (PDX) models using representative PD cancer cells.
Results: In antiproliferative panel assays using over 100 cancer cell lines, UD-017 broadly inhibited a wide range of cancer cells from colon, breast, lung, kidney, blood, pancreas, osteosarcoma, sarcoma and urinary bladder cancers. Especially, UD-017 showed high sensitivity in solid tumor such as non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), gastric, osteosarcoma and sarcoma cells with IC50s of 10-200 nM. UD-017 showed a good correlation of c-Myc expression levels with antiproliferative activity using colorectal cancer cells in vitro, and UD-017 reduced the intratumoral MYC mRNA levels by an administration at 100 mg/kg in a HCT-116 xenograft model in mice. In PDX models, UD-017 showed strong inhibition and even regression of tumor growth, and the tumors were almost disappeared on day 14 without body weight loss in non-small cell lung cancer (LXFL1121). In a pleuramesothelioma (PXF541) PDX model, UD-017 also showed regressive effect, and in gastric cancer (GXA3067) and sarcoma (SXFS117) PDX models, UD-017 completely inhibited the tumor growth.
Conclusions: We propose UD-017 as a novel type of anticancer drug that shows complete antitumor responses in patient-derived xenograft models of diverse cancer types. c-Myc expression in cancer cells may be a biomarker for the antitumor effect of UD-017. These data support the rationale for further advancing towards clinical development.
Citation Format: Takashi Matsushita, Sayaka Ogi, Kazuhiro Onuma, Hidetoshi Sunamoto, Ayumi Ogawa, Toru Hasegawa, Yasunori Tokunaga, Yasuhiro Aga, Shigeru Ushiyama. UD-017, a novel highly selective and orally active CDK7 inhibitor, shows a significant anticancer activity in patient-derived cancers [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 4835.
Abstract 4857: Discovery of PF-06855800, a SAM competitive PRMT5 inhibitor with potent antitumor activity
Authors: Mcalpine Indrawan J. , Tatlock John , Billitti Joseph , Braganza John , Brooun Alexei , Ya-Li Deng , Hirakawa Brad , Jensen-Pergakes Kristen , Kumpf Robert , Liu Wei , Maegley Karen , McTigue Michele , Patman Ryan , Rui Eugene , Scales Stephanie , Spiegel Noah , Tran-Dubé Michelle , Wang Fen , Wang Zhenxiong , Yamazaki Shinji , Zhang Tao , Wythes Martin 
Published: August 2018

Abstract
Protein arginine methyltransferase 5 (PRMT5) is the primary type II arginine methyltransferase responsible for symmetric dimethylation of protein arginine residues. PRMT5 utilizes S-adenosylmethionine (SAM) to methylate a number of cytoplasmic and nuclear substrates that are involved in tumorigenesis. A number of these substrates affect a variety of biologic functions including RNA splicing, transcriptional regulation and translation, all of which are dysregulated in cancer. The discovery of adenosine as an efficient inhibitor of PRMT5 catalyzed a medicinal chemistry effort aimed at nucleoside optimization. Protein structure-based and ligand property-based design were combined to deliver molecules with desirable potency, selectivity and ADME properties. Here we will describe a series of deazapurine nucleoside analogues that culminate in the identification of PF-06855800, a SAM competitive PRMT5 inhibitor with antiproliferative activity in both in vitro and in vivo models.
Citation Format: Indrawan J. Mcalpine, John Tatlock, Joseph Billitti, John Braganza, Alexei Brooun, Deng Ya-Li, Brad Hirakawa, Kristen Jensen-Pergakes, Robert Kumpf, Wei Liu, Karen Maegley, Michele McTigue, Ryan Patman, Eugene Rui, Stephanie Scales, Noah Spiegel, Michelle Tran-Dubé, Fen Wang, Zhenxiong Wang, Shinji Yamazaki, Tao Zhang, Martin Wythes. Discovery of PF-06855800, a SAM competitive PRMT5 inhibitor with potent antitumor activity [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 4857.
Abstract 4859: JNJ-64619178, a selective and pseudo-irreversible PRMT5 inhibitor with potent in vitro and in vivo activity, demonstrated in several lung cancer models
Authors: Wu Tongfei , Millar Hillary , Gaffney Dana , Beke Lijs , Mannens Geert , Vinken Petra , Sommers Ivan , Thuring Jan-Willem , Sun Weimei , Moy Christopher , Pande Vineet , Zhou Junguo , Haddish-Berhane Nahor , Salvati Mark , Laquerre Sylvie , Lorenzi Matthew V. , Brehmer Dirk 
Published: August 2018

Abstract
PRMT5 is a type II methyltransferase that symmetrically di-methylates arginine residues on proteins involved in signal transduction and cellular transcription. For example, PRMT5 acts as the enzymatic machinery of the methylosome complex, crucial for spliceosome assembly and activity. Although not frequently mutated or amplified in tumors, an elevated PRMT5 protein level that leads to higher methylosome activity and promotes epithelial–mesenchymal transition, has recently been correlated with a poor survival of cancer patients.
The PRMT5 inhibitor JNJ-64619178 has been selected as a clinical candidate based on its high selectivity and potency, paired with favorable oral pharmacokinetics and safety properties.
JNJ-64619178 binds simultaneously to the SAM- and protein substrate- binding pockets of the PRMT5/MEP50 complex with a pseudo-irreversible mode-of-action. Chemical proteomics, methylomics and RNA-sequencing analyses of PRMT5 inhibitor treated cell line samples support the current biological understanding of PRMT5 as a regulator of alternative splicing events.
JNJ-64619178 showed potent and broad inhibition of cellular growth, observed in several cell line panels that represent diverse cancer histologies. Ongoing investigations will explore the potential synthetic lethal correlation between PRMT5 inhibition and cancer driver pathways, including those addicted to altered splicing.
Oral administration of JNJ-64619178 resulted in efficient inhibition of di-methylation of SMD1/3 proteins, components of the splicing machinery and direct substrates of the methylosome, in several human NSCLC and SCLC cancer mouse xenograft models. JNJ-64619178 demonstrated dose-dependent tumor growth inhibition and regression in several human NSCLC and SCLC cancer mouse xenograft models with sustained blockage of tumor re-growth after dosing cessation.
In summary, JNJ-64619178 has a favorable pre-clinical profile supporting clinical testing in patients with lung cancer and other malignancies.
Citation Format: Tongfei Wu, Hillary Millar, Dana Gaffney, Lijs Beke, Geert Mannens, Petra Vinken, Ivan Sommers, Jan-Willem Thuring, Weimei Sun, Christopher Moy, Vineet Pande, Junguo Zhou, Nahor Haddish-Berhane, Mark Salvati, Sylvie Laquerre, Matthew V. Lorenzi, Dirk Brehmer. JNJ-64619178, a selective and pseudo-irreversible PRMT5 inhibitor with potent in vitro and in vivo activity, demonstrated in several lung cancer models [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 4859.
Abstract 5038: Ready to use 3D spheroid cultures as a standard tool to screen for compounds targeting cancer
Authors: Martin Angel Garcia , Leis Olatz , Gumuzio Juan , Prieto Inés , Ruiz Estibaliz 
Published: August 2018

Abstract
The cancer stem cell (CSC) concept has important implications not only for our understanding of carcinogenesis, but also for the development of cancer therapeutics. There is a growing body of preclinical evidence showing that cancer stem cells contribute to chemotherapy and radiation resistance in breast cancer. The use of drugs that interfere with stem cell self-renewal represents the strategy of choice for novel effective anti-cancer treatments, but also a great challenge because cancer stem cells and their normal counterparts share many pathways. The biology of cancer stem cells has proven complex and difficult to translate into effective therapeutic strategies. The question arises as: how do we test compounds for anti-cancer stem cell activity? The answer is: phenotypic screening. There are indeed several functional assays well validated in the scientific literature that have been used for years associated to the ability of cancer cells to demonstrate stem cell behavior. The most relevant is the 3D tumor spheroid assay. This assay has been used to uncover and culture stem cells from many tissues as well as from tumors. There are multiple reports now that show that spheroid derived cells are enriched in tumor initiating or cancer stem cells, derived from cell lines and from natural fresh tumors as well. Here we describe the use of 3D spheroid models to profile compound activity against cancer stem cells. Furthermore, a case of compounds preventing hypoxia-inducible transcription factor (HIFs) activity is presented. Recently, HIF transcription factor biology has been linked to pathways that regulate stem cell self-renewal and pluripotency, suggesting a new mechanism whereby HIF proteins may drive tumor growth, through the generation of tumour-initiating cells or cancer stem cells. Therefore, targeting the HIF pathway may provide a novel therapeutic avenue to target cancer stem cells. We demonstrate that interfering with HIF pathway activation prevents mammosphere formation, validated through indenpendent confirmation through Sox2 promoter activation, Aldefluor® assay and in vivo proof-of concept experiments targeting tumor initiation.
Citation Format: Angel Garcia Martin, Olatz Leis, Juan Gumuzio, Inés Prieto, Estibaliz Ruiz. Ready to use 3D spheroid cultures as a standard tool to screen for compounds targeting 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 5038.
Abstract 5309: Determining EGFR and STK11 mutational status in lung adenocarcinoma histopathology images using deep learning
Authors: Coudray Nicolas , Moreira Andre L. , Sakellaropoulos Theodore , Fenyö David , Razavian Narges , Tsirigos Aristotelis 
Published: August 2018

Abstract
To characterize a tumor and suggest appropriate treatments, pathologists rely on the visual assessment of histopathology slides as well as molecular profiling of the tumors. This is especially true in lung adenocarcinoma cases where targeted therapies exist for tumors with EGFR mutations. In this work, we studied the use of deep learning approaches to classify lung cancer histopathology images and predict the mutational status of frequently mutated genes.
To achieve these tasks, more than 1600 scanned histopathology slides, obtained from TCGA, were separated into independent training, validation and test sets. They were then tiled into 512x512 pixel windows, and the training set was used to feed the inception v3 convolutional neural network developed by Google. The resulting model was evaluated on the test set, and the generated per-tile probabilities were aggregated to generate a per-slide classification score. We based our study on whole-slide images of adenocarcinoma, squamous cells carcinoma and normal lung tissues and the neural network was trained on several tasks: first, the goal was to identify normal from tumor regions, and then, once the tumor regions were identified, it was trained to identify adenocarcinoma versus squamous cell carcinoma. Finally, the neural network was trained predict the mutational status of the most frequently mutated genes in lung adenocarcinoma.
After verifying that the trained network properly identifies tumor slides compared to normal tissue (AUC=0.99) and distinguishes adenocarcinomas from squamous cell carcinomas (AUC=0.95), the network was trained to simultaneously identify different mutations. It achieved AUC scores of 0.82 and 0.86 for STK11 and EGFR respectively, showing that mutations in these two genes may confer specific macroscopic features, visible in histopathology images, and that a deep convolutional neural network can be trained to recognize those features.
Our results demonstrate that, given the availability of sufficient data, convolutional neural networks learn to perform complex diagnoses and thus assist pathologists in their work.
Citation Format: Nicolas Coudray, Andre L. Moreira, Theodore Sakellaropoulos, David Fenyö, Narges Razavian, Aristotelis Tsirigos. Determining EGFR and STK11 mutational status in lung adenocarcinoma histopathology images using deep learning [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 5309.
Abstract 5327: DNA methylation loss in late-replicating domains is linked to mitotic cell division
Authors: Zhou Wanding , Dinh Huy Q. , Ramjan Zachary , Weisenberger Daniel J. , Nicolet Charles M. , Shen Hui , Laird Peter W. , Berman Benjamin P. 
Published: August 2018

Abstract
DNA methylation loss occurs frequently in cancer genomes, primarily within lamina-associated, late-replicating regions termed Partially Methylated Domains (PMDs). We profiled 39 diverse primary tumors and 8 matched adjacent tissues using Whole-Genome Bisulfite Sequencing (WGBS), and analyzed them alongside 343 additional human and 206 mouse WGBS datasets. We identified a local CpG sequence context associated with preferential hypomethylation in PMDs. Analysis of CpGs in this context (“Solo-WCGWs”) revealed previously undetected PMD hypomethylation in almost all healthy tissue types. PMD hypomethylation increases with age in both fetal and postnatal tissues, appearing to track accumulation of cell divisions beginning early in life. In cancer, the degree of PMD hypomethylation correlates with somatic mutation density and expression of cell-cycle dependent genes, reinforcing its mitotic clock-like role. We propose that late replication leads to progressive methylation loss throughout an individual's lifespan, potentially contributing to the onset of cancer and acting as a biomarker for cellular aging.
Citation Format: Wanding Zhou, Huy Q. Dinh, Zachary Ramjan, Daniel J. Weisenberger, Charles M. Nicolet, Hui Shen, Peter W. Laird, Benjamin P. Berman. DNA methylation loss in late-replicating domains is linked to mitotic cell division [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 5327.