bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4878: RMC-4550, an allosteric inhibitor of SHP2: Synthesis, structure, and anti-tumor activity
Authors: Koltun Elena S. , Aay Naing , Buckl Andreas , Jogalekar Ashutosh S. , Kiss Gert , Marquez Abby , Mellem Kevin T. , Mordec Kasia , Saldajeno-Concar Mae , Semko Chris M. , Tibrewal Nidhi , Tzitzilonis Christos , Won Walter , Smith Jacqueline A. , Wilson Susan E. , Nichols Robert J. , Wang Zhengping , Wilds David , Singh Mallika , Gill Adrian L. 
Published: August 2018

Abstract
Genetic and pharmacologic evidence has shown that SHP2, a non-receptor protein tyrosine phosphatase (PTP) and scaffold protein encoded by the PTPN11 gene, is a convergent signal transduction node that integrates growth factor signals from multiple receptors to promote activation of RAS and its downstream effectors. Guided by structural insights from X-ray data, we describe a strategy aimed at the identification of a highly potent and selective allosteric SHP2 inhibitor series. Our efforts led to the discovery of RMC-4550, a potent and selective SHP2 inhibitor which exhibits a high quality, drug-like preclinical profile. RMC-4550 inhibits purified, activated full length human SHP2 with an IC50 of 1.55 nM, and has cellular IC50 of 39 nM in PC9 cells with a pERK readout. RMC-4550 has no detectable inhibitory activity up to 10 µM against the catalytic domain of SHP2, a panel of 14 additional protein phosphatases, and a panel of 468 protein kinases. RMC-4550 exhibits low to moderate cross species in vitro intrinsic clearance (3.6-24 µL/min/million cells) in hepatocytes, a high passive permeability (458 nm/s) and efflux ratio of 1. The ADME properties translate into favorable pharmacokinetic profiles in preclinical species. RMC-4550 has moderate to high bioavailability and has a half-life amenable for once daily oral administration. In the EGFR-driven KYSE-520 human esophageal cancer xenograft model, we observed a dose dependent efficacy consistent with target modulation, assessed by phospho-ERK inhibition in tumors. RMC-4550 is well tolerated at doses that achieved maximal and sustained efficacy in this model. RMC-4550 was synthesized in 5 linear (6 total) steps from the readily accessible or commercially available intermediates. The chemical structure and synthesis of RMC-4550, along with detailed structure-activity relationships will be presented. In summary, RMC-4550 exemplifies a novel class of potent allosteric inhibitors of SHP2 with an excellent drug like property profile.
Citation Format: Elena S. Koltun, Naing Aay, Andreas Buckl, Ashutosh S. Jogalekar, Gert Kiss, Abby Marquez, Kevin T. Mellem, Kasia Mordec, Mae Saldajeno-Concar, Chris M. Semko, Nidhi Tibrewal, Christos Tzitzilonis, Walter Won, Jacqueline A. Smith, Susan E. Wilson, Robert J. Nichols, Zhengping Wang, David Wilds, Mallika Singh, Adrian L. Gill. RMC-4550, an allosteric inhibitor of SHP2: Synthesis, structure, and anti-tumor 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 4878.
Abstract 4909: Adaptive oncology phase 1 study of first-in-class inhibitor of ataxia telangiectasia mutated protein kinase (ATM), in combination with olaparib
Authors: Chen Yingxue , Pass Martin , Bruna Nuria Bui , Stephens Christine , Pierce Andrew , Hanekom Wouter , Gabra Hani , Tomkinson Helen , Al-Huniti Nidal 
Published: August 2018

Abstract
Background: AZD0156 is a highly selective first oral ATM inhibitor in the clinic. Coordinating DNA single and double strand break repair, AZD0156 enhances the preclinical activity of olaparib, leading to its development as an antitumor agent in combination. We report here results from an ongoing phase 1 adaptive dose escalation study of AZD0156 in combination with olaparib.
Methods: This phase I study is to assess the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of escalating doses of AZD0156 in combination with olaparib in patients with advanced malignancies. AZD0156 is mainly metabolized by CYP3A and FMO, which undergo genetic polymorphism. The flexible language incorporated in the protocol also allow rapid dose escalation beyond subtherapeutic doses.
Results: PK data from the first 2 dose cohorts were lower than predicted and the AZD0156 dose was increased 4 X and dosing changed from QD (daily) to BD (twice daily). The mean terminal half-life of AZD0156 was 9-12 hours and PK was dose proportional. No significant drug-drug interactions (DDI) were observed with olaparib. Minor toxicities included nausea, vomiting and anemia in about 40% of patients in all cohorts. Grade 3 and 4 hematologic toxicities were observed in AZD0156 120mg BD with olaparib 200mg BD, and this dose level was considered intolerable. At doses of AZD0156 of 30 and 60mg BD, active target engagement was demonstrated. PK profile was similar across FMO genotype.
Conclusion: Hematologic toxicities, consistent with the mode of action, emerged as dose-limiting toxicities of AZD0156 in combination with olaparib. Pharmacologically active doses of AZD0156 with olaparib were achieved more quickly in patients by using real-time PK, real-time genotyping, safety, DDI assessment, and PK/PD modelling.
Citation Format: Yingxue Chen, Martin Pass, Nuria Bui Bruna, Christine Stephens, Andrew Pierce, Wouter Hanekom, Hani Gabra, Helen Tomkinson, Nidal Al-Huniti. Adaptive oncology phase 1 study of first-in-class inhibitor of ataxia telangiectasia mutated protein kinase (ATM), in combination with olaparib [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 4909.
Abstract 5022: Precision medicine: High-throughput 3D bioprinting of embedded multicellular cancer spheroids
Authors: Atapattu Lakmali , Utama Robert , O'Mahony Aiden , Fife Christopher , Baek Jongho , Allard Théophile , O'Mahony Kieran , Ribeiro Julio , Gaus Katharina , Gooding Justin , Kavallaris Maria 
Published: August 2018

Abstract
Three-dimensional (3D) cancer cell models, such as 3D multicellular spheroids, are superior models of in vivo systems than the more popular two-dimensional (2D) cell culture. 3D cancer spheroids provide a closer reflection of tumor gene expression and biology than 2D cultures. This is particularly relevant for drug development and precision medicine programs were cell culture conditions that better reflect the 3D tumor environments, including matrix stiffness, would be highly advantageous. A key challenge for the routine application of embedded 3D cancer spheroids in precision and drug programs is the lack of high throughput and uniform production of spheroids in a biocompatible matrix. To address this, we have developed a high-throughput method of producing 3D multicellular cancer spheroids embedded inside a tissue-like matrix using a custom-built drop-on-demand 3D bioprinter. The 3D bioprinter is capable of printing a cell-suspension ink with up to 300 million cells/mL and a cell viability greater than 95%. We have validated the 3D bioprinting using glioblastoma, neuroblastoma and lung cancer cells. The 3D bioprinted spheroids were confirmed to maintain all the biological characteristics typically found in a cancer spheroid. In particular, the 3D bioprinted cancer spheroids were shown to be viable and proliferating, preserved the apoptotic and cancer-stemness characteristics and using super-resolution lattice-light sheet microscopy, we showed the spheroids maintained the same structural integrity as manually formed spheroids. The potential application of the 3D bioprinted spheroids for high-throughput drug screening in 3D environments was demonstrated using doxorubicin as the model drug. 3D-bioprinting of patient-derived cancer cells for precision medicine applications is now underway. High-throughput embedded 3D bioprinting has enormous potential to accelerate precision medicine, drug discovery and cancer biology.
Citation Format: Lakmali Atapattu, Robert Utama, Aiden O'Mahony, Christopher Fife, Jongho Baek, Théophile Allard, Kieran O'Mahony, Julio Ribeiro, Katharina Gaus, Justin Gooding, Maria Kavallaris. Precision medicine: High-throughput 3D bioprinting of embedded multicellular cancer spheroids [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 5022.
Abstract 5133: Lipids and suppressive functions of MDSC in cancer
Authors: Veglia Filippo , Tyurin Vladimir A. , Kagan Valerian E. , Gabrilovich Dmitry 
Published: August 2018

Abstract
Myeloid derived suppressor cells (MDSC) play an important role in the regulation of anti-tumor responses and their presence in cancer patients correlates with a poor prognosis. MDSC contribute to the failure of cancer therapies and favor tumor progression and metastasis. However, despite the recent advances in understanding the biology of MDSC, the mechanisms driving their expansion and suppressive function are not yet well defined. Polymorphonuclear, PMN-MDSC is by far the largest population of MDSC. Here, we found that PMN-MDSC from tumor bearing mice and from cancer patients have higher amount of lipids than their counterpart (neutrophils) in tumor free mice and healthy donors, respectively. The content of lipids in PMN-MDSC was much higher in MDSC infiltrating the tumor, and the accumulation of lipids in PMN-MDSC was caused by the uptake of extracellular lipids. Lipid profile of PMN-MDSC demonstrated accumulation of oxidized fatty acids as part of triglycerides and phospholipids. We demonstrated that fatty acids accumulated by PMN-MDSC are oxidized by myeloperoxidase (MPO) and reactive oxygen species (ROS) generated by Nox2. Genetic ablation of MPO or ROS in MDSC results in a drastic reduction of lipid oxidation and in an impaired ability of MDSC to suppress CD8 T cell responses. In line with these findings, unsaturated fatty acids, highly susceptible to oxidation, favor the expansion of highly suppressive MDSC from hematopoietic progenitors in vitro, contrary to non-oxidizable saturated fatty acids. Together, our data suggest that MDSC have increased ability to pick up lipids from the microenvironment and to oxidize them via their potent oxidative machinery. In turn oxygenated lipids contribute to the suppressive activity of MDSC. In conclusion, the regulation of the oxidation of lipids in MDSC could be an attractive therapeutic strategy in cancer.
Citation Format: Filippo Veglia, Vladimir A. Tyurin, Valerian E. Kagan, Dmitry Gabrilovich. Lipids and suppressive functions of MDSC in 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 5133.
Abstract 5236: ARV-110: An androgen receptor PROTAC degrader for prostate cancer
Authors: Neklesa Taavi , Snyder Lawrence B. , Willard Ryan R. , Vitale Nicholas , Raina Kanak , Pizzano Jennifer , Gordon Deborah , Bookbinder Mark , Macaluso Jennifer , Dong Hanqing , Liu Zheng , Ferraro Caterina , Wang Gan , Wang Jing , Crews Craig M. , Houston John , Crew Andrew P. , Taylor Ian 
Published: August 2018

Abstract
The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology. Here we report an orally bioavailable small molecule ARV-110 that leads to ubiquitination and degradation of AR. ARV-110 completely degrades AR in all cell lines tested, with an observed 50% degradation concentration (DC50) &lt; 1 nM. PROTAC-mediated AR degradation suppresses the expression of the AR-target genes PSA and FKBP5, inhibits AR-dependent cell proliferation, and induces potent apoptosis in VCaP cells. ARV-110 degrades clinically relevant mutant AR proteins and retains activity in a high androgen environment. In mouse xenograft studies, greater than 90% AR degradation is observed at a 1 mg/kg PO QD dose. Significant inhibition of tumor growth and AR signaling can be achieved in both an intact and castrate setting. Further, ARV-110 demonstrates in vivo efficacy and reduction of oncogenic Erg protein in a long term, castrate, enzalutamide-resistant VCaP tumor model. DMPK and exploratory toxicology studies show robust oral, dose proportional drug exposure in rodent and non-rodent species. In summary, we report preclinical data on ARV-110, an orally bioavailable androgen receptor PROTAC degrader that demonstrates efficacy in enzalutamide-resistant prostate cancer.
Citation Format: Taavi Neklesa, Lawrence B. Snyder, Ryan R. Willard, Nicholas Vitale, Kanak Raina, Jennifer Pizzano, Deborah Gordon, Mark Bookbinder, Jennifer Macaluso, Hanqing Dong, Zheng Liu, Caterina Ferraro, Gan Wang, Jing Wang, Craig M. Crews, John Houston, Andrew P. Crew, Ian Taylor. ARV-110: An androgen receptor PROTAC degrader for 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 5236.
Abstract 5395: MicroRNA-196b-3p identified from serum microRNA expression profiling is a potential diagnostic biomarker for gastritis and early gastric cancer
Authors: Fujii Atsushi , Nambara Sho , Kuroda Yosuke , Ito Shuhei , Eguchi Hidetoshi , Masuda Takaaki , Otsuka Takao , Nakamura Masafumi , Mimori Koshi 
Published: August 2018

Abstract
Background: Gastric cancer is one of the most common forms of cancer worldwide. The progression of chronic atrophic gastritis (CAG) is involved in gastric carcinogenesis. With the progression of chronic atrophic gastritis, the risk of gastric cancer increased in a stepwise fashion. Non-invasive tools for early gastric cancer are required to improve the prognosis. MicroRNAs (miRNAs), a class of small non-coding RNAs of 19-22 nucleotides in length, function as post-transcriptional regulators by directly cleaving target messenger RNA or translational repression. MiRNAs in serum have been shown to be potential biomarkers in various type of cancers and several miRNAs have been reported in gastric cancer. The purpose of present study was to identify a serum miRNA expression profile that can serve as a novel diagnostic biomarker for early gastric cancer.
Materials and Method: We defined a normal gastric mucosa as grade0, CAG classified C-1, 2 in Kimura-Takemoto classification as grade1, CAG classified C-3, O-1 in Kimura-Takemoto classification as grade2, and CAG classified O-2, 3 in Kimura-Takemoto classification as grade3. We obtained 344 serum samples, which gathered from 19 health people (grade0), 125 patients with chronic atrophic gastritis (grade1: 54, grade2: 36, grade3: 35), and 200 patients with early gastric cancer. The miRNAs were extracted from serums and miRNA microarray analysis was performed. In the discovery phase, we analyzed 71 cases (grade0: 11, grade1: 20, grade2: 20, grade3: 20). Next, in the training phase, we analyzed 73 cases (grade0: 8, grade1: 34, grade2: 16, grade3: 15). Then, we analyzed 200 early gastric cancer serum samples.
Result: The microarray analysis identified a profile of miRNA (miRNA-196b-3p) as a biomarker for early gastric cancer. The analysis results showed that the expression level of the serum miRNA was correlated to degree of CAG and carcinogenesis. When compared with grade0,1,2 and grade3, the area under the receiver operating characteristic (ROC) curve of this serum miRNA signature was 0.730 and 0.763 for the two sets of serum samples. There was significant difference in serum value of miRNA-196b-3p between grade1-3 and early gastric cancer (p=0.003). Conclusion: Serum miRNA-196b-3p is good biomarker for early gastric cancer.
Citation Format: Atsushi Fujii, Sho Nambara, Yosuke Kuroda, Shuhei Ito, Hidetoshi Eguchi, Takaaki Masuda, Takao Otsuka, Masafumi Nakamura, Koshi Mimori. MicroRNA-196b-3p identified from serum microRNA expression profiling is a potential diagnostic biomarker for gastritis and early gastric 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 5395.
Abstract 5629: Preclinical characterization of Sym023 a human anti-TIM3 antibody with a novel mechanism of action
Authors: Lindsted Trine , Gad Monika , Grandal Michael V. , Frölich Camilla , Bhatia Vikram K. , Gjetting Torben , Lantto Johan , Horak Ivan D. , Kragh Michael , Koefoed Klaus , Pedersen Mikkel W. 
Published: August 2018

Abstract
Immunotherapy has become a major focus of research in oncology and blockade of immune checkpoints such as cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4) and programmed cell death protein 1 (PD1) has been some of the most successful immunotherapies. The next wave of immunomodulatory targets that are being explored for cancer therapy include T cell immunoglobulin and mucin domain protein 3 (TIM3). TIM3 is constitutively expressed on cells of myeloid origin whereas the TIM3 expression is induced on T-cells upon activation. The exact function of TIM3 on the different immune cells is not clear and may be context dependent suggesting that TIM3 is not a classical immune check-point.
Sym023 is a human anti-TIM3 antibody, which binds human TIM3 and cross-reacts with cynomolgus monkey TIM3. Sym023 blocks binding of phosphatidyl serine but not galectin 9 and stimulates T-cell proliferation in mixed lymphocyte reactions and tumor growth inhibition in vivo. Here, we present data demonstrating that ligation of TIM3 by Sym023 increase cytokine production and T cell proliferation in vitro through a novel mechanism of action.
Citation Format: Trine Lindsted, Monika Gad, Michael V. Grandal, Camilla Frölich, Vikram K. Bhatia, Torben Gjetting, Johan Lantto, Ivan D. Horak, Michael Kragh, Klaus Koefoed, Mikkel W. Pedersen. Preclinical characterization of Sym023 a human anti-TIM3 antibody with a novel mechanism of action [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 5629.
Abstract 5754: Hypoxia-induced tumor plasticity and immune resistance involves an alteration of target recognition by a mechanism involving TGF-beta signaling
Authors: Terry Stephane , Buart Stephanie , Thiery Jean-Paul , Mami-Chouaib Fathia , Chouaib Salem 
Published: August 2018

Abstract
Backgound: Hypoxia is known to shape the tumor microenvironment of developing tumors and contributes to both tumor progression and escape to immune surveillance. Previous work using non-small cell lung carcinoma cells (NSCLC) showed that hypoxia promotes epithelial-mesenchymal transition (EMT) in a fraction of carcinoma cells and that acquisition of a more mesenchymal (Mes) phenotype by certain cancer subclones correlates with an increased propensity to resist cytotoxic T lymphocytes (CTL) attacks as compared to more Epithelial (Epi) cancer subclones. Moreover, numerous studies identified alterations or loss of major histocompatibility complex (MHC) class I as a potential mechanism of tumor escape in cancer. Here, we asked whether hypoxia-induced EMT could regulate MHC class I expression and whether that could impact on resistance to CTL-mediated killing.
Methods and Results : By comparing CMH class I in various NSCLC cancer subclones that have experienced hypoxic stress, we found that cancer clones with enhanced Mes features have a reduced expression of CMH class I molecules, as compared to those with a more Epi phenotype. Transient siRNA knockdown of hypoxia effectors HIF-1α or HIF-2α did not affect the expression of CMH class I molecules suggesting that EMT effectors, rather that HIFs, directly regulate CMH class I expression. Among EMT effectors, TGF-β expression was found to be highly upregulated in Mes cancer clones. Moreover, treatment of these cells with TGF-βR inhibitors markedly upregulated CMH class I expression. and as target cells, increases their susceptibility to CTL-mediated killing. However, blocking of TGF-β using Ab to TGF-β during the coculture time had no significant effects on CTL-mediated killing. This suggests that the observed changes in target cell susceptibility occurs through TGF-β-mediated repression of MHC class I rather than by cancer cell production of TGF-β affecting CTL effector functions. Conclusions: These results suggest that the increase in TGF-β signaling, especially found in EMTed Mes carcinoma cells in response to hypoxic stress, contributes to downregulate CMH class I expression in these cells while coinciding with a reduced susceptibilty to CTL attacks. The development of agents targeting hypoxia or EMT components should provide new therapeutic opportunities in combination with current approaches.
Citation Format: Stephane Terry, Stephanie Buart, Jean-Paul Thiery, Fathia Mami-Chouaib, Salem Chouaib. Hypoxia-induced tumor plasticity and immune resistance involves an alteration of target recognition by a mechanism involving TGF-beta signaling [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 5754.
Abstract 5811: Evaluation of antitumor efficacy of CA102N, H-Nim and hyaluronic acid (HA) conjugate, alone or in combination with 5-fluorouracil (5-FU) in in vivo human colorectal cancer models
Authors: Tchaparian Eskouhie , Lin Louis 
Published: August 2018

Abstract
CA102N is a conjugate of HA and H-Nim (N-(4-Amino-2-phenoxyphenyl, methanesulfonamide), a derivative of cyclooxygenase-2 inhibitor Nimesulide, and a CD44 receptor targeted system currently in preclinical development for metastatic colorectal cancer. The in vivo antitumor activities of CA102N was evaluated singly or combined with 5-FU in CR5038 (Patient Derived Xenograft (PDX) and HT29 Xenograft models. Inhibitory activity was assessed according to tumor-volume changes. CA102N (i.v. 200mg/kg, BIW) monotherapy did not show significant tumor growth inhibition at either the end of the treatment (21 days) or prolonged observational (45 days) period, in CR5038 PDX-SCID metastatic model in comparison to vehicle control or 5-FU (i.v. 50mg/kg, QW). Notably, the combination therapy displayed a marked reduction in tumor growth (&gt;70%) compared to 5-FU alone (p=0.0003) or vehicle control (p&lt;0.0001) in addition to prolonged median survival (p&lt;0.05). Alternatively, HT29 xenografts nude mice were found to have significantly reduced tumor burden treated with either single agents CA102N (400 mg/kg, QW) or 5-FU (50 mg/kg, QW), (p&lt;0.012) compared to control vehicle. The drug combination further displayed a synergistic antitumoral effect and greater median survival (p &lt;0.05) in HT29 model. CA102N was well tolerated alone or in the combination therapy. Based on the results of this study, combined treatment of CA102N and 5-FU resulted in a complete response at the regimen given. The combination of CA102N and 5-FU represents a promising potential therapeutic strategy and a new approach to reverse drug resistant in the treatment of colorectal cancer. Studies presently are ongoing to further evaluate its efficacy in CT26 murine colorectal models.
Citation Format: Eskouhie Tchaparian, Louis Lin. Evaluation of antitumor efficacy of CA102N, H-Nim and hyaluronic acid (HA) conjugate, alone or in combination with 5-fluorouracil (5-FU) in in vivo human colorectal 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 5811.