bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B021: Inhibition of β-catenin impairs triple-negative breast cancer (TNBC) cell migration and invasion by modulating aerobic glycolysis components
Authors: Prasad Chandra P. , Andersson Tommy 
Published: August 2018

Abstract
In the present study, we investigated the role of β-catenin on aerobic glycolysis in breast cancer cells and further evaluated its effects on triple-negative breast cancer (TNBC) cell migration and invasion. We used two metastatic TNBC cell lines, i.e., MDA-MB-468 and MDA-MB-231, and treated them with β-catenin antagonists (WNT5A and XAV939). Evaluation of glycolytic markers in WNT5A-expressing cell lines showed selective downregulation in the expression of β-catenin, platelet type-phosphofructokinase (PFKP), and lactate secretion, without affecting cell proliferation. Of the three phosphofructokinase isoform, we found that only PFKP expression was associated with decreased survival in breast cancer patients. We also found that the cause of PKFP and lactate downregulation was mediated by inhibition of β-catenin signaling, which is in accordance with the finding that β-catenin signaling positively regulates lactate production. Functionally, we showed that specific downregulation of β-catenin resulted in reduced lactate production accompanied by impaired TNBC cells migration and invasion. Finally, we demonstrated that apart from its inhibitory effect on lactate production, inhibition of β-catenin can also impair TNBC cell migration induced by exogenous lactate via downregulating monocarboxylate transporter 1 (MCT1). Overall, we demonstrated that inhibition of β-catenin-PFKP signaling axis impaired lactate production as well as its uptake from tumor microenvironment (via MCT1), thereby impairing TNBC cells' migration.
Citation Format: Chandra P. Prasad, Tommy Andersson. Inhibition of β-catenin impairs triple-negative breast cancer (TNBC) cell migration and invasion by modulating aerobic glycolysis components [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 B021.
Abstract B030: Neoadjuvant chemotherapy promotes macrophage-induced MenaINV-dependent pro-metastatic changes in breast tumors
Authors: Karagiannis George S. , Sharma Ved P. , Brizio Sara , Burt Joseph , Wang Yarong , Entenberg David , Smith Bryan , Flynn Daniel , Oktay Maja H. , Condeelis John 
Published: August 2018

Abstract
Neoadjuvant chemotherapy (NAC) is used for treatment of localized breast cancer to decrease tumor size and improve surgical outcome. However, our recent study has uncovered a previously unrecognized side effect of NAC, which involves the induction of pro-metastatic changes in the primary breast cancer microenvironment. In particular, NAC promotes the assembly of structures that serve as doorways for intravasation of tumor cells called tumor microenvironment of metastasis (TMEM), and increases the proportion of the highly invasive and migratory MenaINV-hi/Mena11alo (MenaCalc+) tumor cells, which utilize the TMEM sites for hematogenous dissemination (1). MenaINV expression in particular is associated with decreased sensitivity of cancer cells to receptor tyrosine-kinase (RTK) and tyrosine-kinase (TK) inhibitors and with dramatically increased TMEM-dependent intravasation. The mechanism behind these pro-metastatic changes was not known. Here we report that NAC induces increased levels of Tie2Hi macrophages in the tumors, resulting in increased contact between macrophages and tumor cells leading to MenaINV expression in the cancer cells, and MenaINV-dependent TMEM assembly and tumor cell intravasation. Furthermore, we demonstrate that the Tie2 switch control inhibitor rebastinib sufficiently suppresses Tie2 signaling in macrophages, thereby inhibiting increased levels of Tie2Hi macrophages in the tumor, resulting in decreased MenaINV expression in the cancer cells and decreased TMEM-associated tumor cell intravasation. Our work has uncovered a previously unrecognized mechanism behind pro-metastatic changes in response to cytotoxic chemotherapy, the markers that predict these changes (TMEM, MenaCalc and MenaINV), and shows that this mechanism could be addressed by combining chemotherapy with rebastinib. Reference: 1. Karagiannis GS, et al. Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Sci Transl Med 2017;9:aeen0026.
Citation Format: George S. Karagiannis, Ved P. Sharma, Sara Brizio, Joseph Burt, Yarong Wang, David Entenberg, Bryan Smith, Daniel Flynn, Maja H. Oktay, John Condeelis. Neoadjuvant chemotherapy promotes macrophage-induced MenaINV-dependent pro-metastatic changes in breast tumors [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 B030.
Abstract B053: GPER signaling inhibits melanoma and improves response to PD-1 blockade
Authors: Natale Christopher A. , Li Jinyang , Zhang Junqian , Dahal Ankit , Stanger Ben , Ridky Todd 
Published: August 2018

Abstract
Female sex and pregnancy are associated with reduced risk of melanoma and improved stage-specific survival; however, the mechanism underlying this apparent clinical benefit is unknown. We previously discovered that pregnancy-associated 17β-estradiol drives melanocyte differentiation by activating the nonclassical G-protein coupled estrogen receptor (GPER). Here, we show that pregnancy inhibits melanoma, and that transient GPER activation induces long-term changes in melanocytes, which are associated with increased cellular differentiation and resistance to melanoma. A selective GPER agonist induced c-Myc protein degradation, slowed tumor growth, and inhibited expression of immune-suppressive proteins, including PD-L1, suggesting that GPER signaling may render melanoma cells more vulnerable to immunotherapy. Systemically delivered GPER agonist was well tolerated, and cooperated with PD-1 blockade in melanoma-bearing mice to dramatically extend survival. These results thus define GPER as a target for differentiation-based melanoma therapy.
Citation Format: Christopher A. Natale, Jinyang Li, Junqian Zhang, Ankit Dahal, Ben Stanger, Todd Ridky. GPER signaling inhibits melanoma and improves response to PD-1 blockade [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 B053.
Abstract B076: A DREAM-world of approaches for predicting combination synergies in cancer
Authors: Dry Jonathan R. , Menden Michael , Saez Rodriguez Julio , Guinney Justin 
Published: August 2018

Abstract
Selecting the right drug combination for the right patient is a complex problem. Some success has been seen from preclinical screening and computational approaches combining molecular, drug and tumor properties to predict combination benefit within the tumor cell. However the context specificity and heterogeneity of drug resistance is often overlooked, leading to inappropriate assumptions of statistical power and resulting in poor translatability. Knowledge-aware approaches will be needed to augment pre-clinical statistical discovery but a huge variety of techniques exist, each offering different strengths. To test this world of methods, AstraZeneca partnered with DREAM, Sage Bionetworks and the Sanger Institute. We released over 11,000 test results from drug combinations in cancer cell lines for an incentivized crowd-sourcing challenge to develop computational models predicting synergistic drug combinations and biomarkers determining response. This became the highest participated of any DREAM challenge, with &gt;700 participants from diverse geographies and knowledge/skill specialties collectively contributing &gt;50,000 hours to the problem. Over 70 models were submitted, testing most machine learning algorithms alongside knowledge-driven approaches. The best models out-performed the state of the art, consistently predicting at an equivalent level to biological replication. Network techniques to select molecular markers most relevant to drug target biology improved prediction the most. Amongst results that could be validated in independent data, ERBB2/EGFR/EP300 variants were predictive for combinations inhibiting AKT+EGFR/ERBB, KRAS for BRAF+MAP2K, AR for AKT/SGK+MAP2K, and ESR1 for ESR1+AKT/PI3K. Alongside revealing interesting biology in our data and providing predictive models, the challenge has given clear direction to our future investment in computational methods for combination pharmacogenomics.
Citation Format: Jonathan R. Dry, Michael Menden, Julio Saez Rodriguez, Justin Guinney. A DREAM-world of approaches for predicting combination synergies in cancer [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 B076.
Abstract B100: Mutant KRAS-induced macrophage migration inhibitory factor (MIF) secretion promotes resistance to cetuximab in colorectal cancer
Authors: Jang Jee Eun , Kim Hwang-Phill , Han Sae Won , Kim Tae You 
Published: August 2018

Abstract
The tumor microenvironment is recognized as developing crosstalk between different cells by secretion of growth factors and cytokines, thus providing oncogenic signals enhancing tumor progression and drug resistance. Here, we hypothesized that tumor cells carrying KRAS mutation-induced cytokines may have a critical role in intercellular communication between microenvironment and tumor cells. We first investigated biologic evidence of secreted cytokines in KRAS mutant type (KRAS MT) cell lines. We explored the roles of cytokine that cell morphology, colony-formation ability, and wound-healing ability were enhanced when KRAS wild-type (KRAS WT) cell lines were exposed to conditioned media (CM) from KRAS MT cells, and we found macrophage migration inhibitory factor (MIF) was highly expressed in KRAS MT cells by analysis of proteomics. We also observed secreted MIF level between KRAS WT and MT cell lines, and it was highly secreted in KRAS MT cell lines. In addition, compared with patients whose KRAS mutation was not harbored, MIF expression was higher in patients who have KRAS mutation. The predictive marker of KRAS mutation in colorectal cancer patients is associated with resistance to antiepidermal growth factor receptor (EGFR) antibody cetuximab. Following the hypothesis, we investigated that secreted cytokines have an effect on the cetuximab resistance to surrounding cells including KRAS WT cells. Treatment of CM from KRAS MT cells led to cetuximab resistance in KRAS WT cells and MIF blockade prevented cetuximab resistance. Also, CM from knockout in KRAS MT cells by using CRISPR/Cas9 system resulted in sensitizing to cetuximab resistance compared with CM from KRAS MT cells. In conclusion, we demonstrated for the first time that MIF promotes the cetuximab resistance of KRAS WT colorectal cancer cells, and this effect is mediated by paracrine and autocrine signaling-induced activation of the intracellular AKT signaling pathways and regulated by NF-kb transcription factor through oncogenic KRAS mutation and MIF overexpression, respectively. These findings suggest that MIF may be a promising predictive biomarker for the cetuximab resistance of KRAS wild-type colorectal cancer patients.
Citation Format: Jee Eun Jang, Hwang-Phill Kim, Sae Won Han, Tae You Kim. Mutant KRAS-induced macrophage migration inhibitory factor (MIF) secretion promotes resistance to cetuximab in colorectal cancer [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 B100.
Abstract B121: The benefits of bispecific mAb2 antibodies targeting EGFR and HGF
Authors: Leung Kin-Mei 
Published: August 2018

Abstract
F-star’s Modular Antibody TechnologyTM platform introduces a novel antigen binding site into the constant (Fc) region of an antibody to create a so-called FcabTM (an Fc-domain with antigen binding activity). The resulting Fcab is then combined with variable region (Fab) of an existing antibody to generate a full-length bispecific antibody or mAb2TM. Here we show how Fcabs targeting epidermal growth factor receptor (EGFR) are utilized to generate mAb2 molecules that bind specifically EGFR and hepatocyte growth factor (HGF). The EGFR/HGF bispecifics inhibit cell proliferation in vitro and show antitumor activity in patient-derived xenograft (PDX) models in vivo. The mAb2 molecules show superior inhibition of tumor growth compared to combination treatments in tumors with specific molecular profiles, suggesting novel biology of the bispecific.
Citation Format: Kin-Mei Leung. The benefits of bispecific mAb2 antibodies targeting EGFR and HGF [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 B121.
Abstract B157: Effect of HGF concentration on c-Met phosphorylation and inhibition in paracrine-activated tumor cells
Authors: Hughes Veronica S. , Siemann Dietmar W. 
Published: August 2018

Abstract
c-Met is a receptor tyrosine kinase critical for embryogenesis and liver repair. In tumors, including breast, prostate, glioblastoma, and thyroid cancer, Met protein levels are often elevated and associated with disease progression and metastasis. The c-Met pathway is activated by the endogenous ligand hepatocyte growth factor (HGF). HGF is produced by mesenchymal cells and binds to the c-Met protein, leading to phosphorylation and upregulation of a variety of downstream signaling pathways that result in increased tumor cell migration, proliferation, survival, and induction of angiogenesis. Consequently, there has been significant interest in the development of c-Met inhibitors as anticancer therapeutics. The efficacy of such agents usually initially are determined in vitro utilizing HGF concentrations of 25-50 ng/mL. However, HGF serum levels in humans typically range from 0.4-0.8 ng/mL. To examine the impact of exogenous HGF levels on c-Met inhibitor activity, human prostate (PC-3, DU145) and lung (A549) cancer cell lines were utilized in this study. These cell lines have been previously characterized as paracrine-activated: cell lines that express the c-Met receptor, but not HGF. In the presence of 25-50 ng/mL HGF, these cell lines demonstrated a reduction in migration, invasion, and phosphorylation of Met after treatment with the small-molecule c-Met inhibitor BMS-777607. However, such antitumor efficacy was absent when these paracrine-activated cell lines were treated with BMS-777607 in the presence of physiologically normal concentrations of HGF (0.4-0.8 ng/mL). A human HGF-expressing mouse model has been developed for xenograft studies of human c-Met inhibition, on the basis that mouse HGF does not activate human c-Met. However, we found that mouse HGF was able to induce phosphorylation of Met in the human DU145 cell line. In vivo, DU145 xenografts in NSG mice treated with BMS-777607 showed no reduction in c-Met phosphorylation unless the mice were administered exogenous HGF during tumor growth. Taken together, these findings indicate that the utilization of nonphysiologic concentrations of HGF in tissue culture evaluations of c-Met targeting agents may result in an overestimation of agent activity not likely to be observed in the tumor microenvironment.
Citation Format: Veronica S. Hughes, Dietmar W. Siemann. Effect of HGF concentration on c-Met phosphorylation and inhibition in paracrine-activated tumor cells [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 B157.
Abstract B162: Highly selective, orally available CDK7 inhibitor for cancer therapy
Authors: Jeon Yeejin , Yu Donghoon , Seo Mooyoung , Kim June , Shin Jaehee , Kang Hwankyu , Ahn Jiye , Choi Jinho , Ahn Seohyun , Kim Jaeseung , Nam Kiyean 
Published: August 2018

Abstract
Cyclin-dependent kinase 7 (CDK7) has dual functions in cell: 1) CDK-activating kinase (CAK) that regulates cell cycle progression by phosphorylation of CDK1, CDK2, and CDK4/6, and 2) a component of transcription factor II H (TFIIH) that regulates transcriptional initiation through phosphorylation of RNA polymerase II C-terminal domain (CTD). Here we present orally available, selective CDK7 inhibitors that show distinct mechanism of action in different cancer cell lines. In some cell lines, compounds exert anti-CAK activity leading to cell cycle arrest, and in others, show transcription inhibitor activity leading to apoptosis. The differential roles of CDK7 seem to be a basis for good specificities of selective CDK7 inhibitors in cancer cell line panel, showing big difference in cytotoxic activity between responding and nonresponding cells. Lead compounds have been optimized for drug-like properties, high potency, and good selectivity and desirable pharmacokinetic profile to achieve antitumor activity. The lead compound shows good activity in mouse models through oral administration without gross adverse findings. Final optimization is under way for candidate nomination.
Citation Format: Yeejin Jeon, Donghoon Yu, Mooyoung Seo, June Kim, Jaehee Shin, Hwankyu Kang, Jiye Ahn, Jinho Choi, Seohyun Ahn, Jaeseung Kim, Kiyean Nam. Highly selective, orally available CDK7 inhibitor for cancer therapy [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 B162.
Abstract B163: Identification and preclinical characterisation of VER-250840, a potent, selective Chk1 inhibitor with in vivo oral single-agent antitumor activity
Authors: Wayne Joanne , Stokes Stephen , Foloppe Nicolas , Browne Helen , Brooks Teresa , Benwell Karen , Baker Lisa , Daniels Zoe , Fiumana Andrea , Graham Christopher , Macias Alba , Maddox Daniel , McKenna Sean , Northfield Christopher , Ray Stuart , Simmonite Heather , Stefaniak Emma , Webb Paul , Wood Mike , Massey Andrew 
Published: August 2018

Abstract
On sustaining damage to their DNA, cells employ a sophisticated mechanism of detection and repair, termed the DNA damage response (DDR). As a critical component of the DDR and G2/M checkpoint, Chk1 kinase represents an attractive target for cancer therapy. We have utilized a structure-based drug design approach to identify and develop VER-250840, a novel, orally active inhibitor of the checkpoint kinase, Chk1. VER-250840 exhibited sub-nM potency against Chk1 kinase with exquisite selectivity over an extensive and diverse panel of kinases. In vitro, VER-250840 inhibited Chk1 autophosphorylation with an IC50 of 1.0 nM and increased the number of S-phase tumor cells staining positive for pan-nuclear γH2AX with an EC50 of 7 - 27 nM. Accumulated genomic DNA damage by Chk1 inhibition led to irreversible cell cycle arrest, inhibition of tumor cell proliferation, increased replication stress, and cell death in both 2D culture and multicellular tumor spheroids. In an in vivo A2058 tumor xenograft PD study, VER-250840 demonstrated rapid and sustained inhibition of Chk1 auto-phosphorylation within 30 minutes of oral administration. Doses of 10 mg/kg and higher PO resulted in greater than 90% inhibition of tumor pChk1 (S296) over 24 hours. In SKOV3 in vivo models, VER-250840 inhibited Chk1 auto-phosphorylation, modulated other biomarkers of replication stress and DNA damage, and exhibited moderate antitumor activity with minimal toxicity when administered orally on a 21-day once-daily schedule. Work is ongoing to further optimize in vivo efficacy. In conclusion, VER-250840 demonstrates potent and selective activity as a monotherapy both in vitro and in vivo. From these findings, further evaluation and optimization of this novel kinase inhibitor is justly merited.
Citation Format: Joanne Wayne, Stephen Stokes, Nicolas Foloppe, Helen Browne, Teresa Brooks, Karen Benwell, Lisa Baker, Zoe Daniels, Andrea Fiumana, Christopher Graham, Alba Macias, Daniel Maddox, Sean McKenna, Christopher Northfield, Stuart Ray, Heather Simmonite, Emma Stefaniak, Paul Webb, Mike Wood, Andrew Massey. Identification and preclinical characterisation of VER-250840, a potent, selective Chk1 inhibitor with in vivo oral single-agent antitumor activity [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 B163.
Abstract B185: TPX-0005, a supreme ROS1 inhibitor, overcomes crizotinib-resistant ROS1 mutations including solvent front mutation G2032R and gatekeeper mutation L2026M
Authors: Cui J. Jean , Zhai Dayong , Deng Wei , Rogers Evan , Huang Zhongdong , Whitten Jeffrey , Lim John , Li Yishan 
Published: August 2018

Abstract
The fusion kinases of ROS1 and ALK have been identified as oncogene drivers in small portions of many malignancies, especially in non-small cell lung cancer (NSCLC). ALK/ROS1/MET inhibitor crizotinib has been approved by the US Food and Drug Administration for the treatment of ALK or ROS1-positive non-small cell lung cancer in 2011 and 2016, respectively. The emergence of drug resistance presents a major issue for targeted therapy. Although ceritinib, alectinib, and brigatinib have been approved for crizotinib-refractory ALK+ patients with NSCLC, treatment options for patients with ROS1+ NSCLC are limited, especially for crizotinib-refractory patients. Ceritinib and entectinib demonstrated clinical efficacy only in crizotinib-naïve ROS1+ patients. The most common resistance mechanisms to crizotinib treatment in ROS1+ NSCLC is the solvent front mutation ROS1 G2032R and gatekeeper mutation ROS1 L2026M. TPX-0005, a novel three-dimensional macrocycle with a much smaller size than current ROS1 inhibitors in the clinic, was designed to overcome clinical resistance mutations systematically. TPX-0005 potently inhibited both wild type and mutant ROS1s including solvent front mutations and gatekeeper mutations. TPX-0005 showed pico-molar activity against ROS1 kinase (IC50 0.076 nM) in Reaction Biology kinase assay. The comparison of TPX-0005 with other ROS1 inhibitors in Ba/F3 cell proliferation assays is presented in the table. In the xenograft tumor model studies, TPX-0005 dramatically caused tumor regression in the tumors carrying WT or solvent-front mutated ROS1 fusion gene. Overall, TPX-0005 demonstrated desired drug-like properties, good safety profile, and is a supreme ROS1 inhibitor against WT and various mutated ROS1s. A phase 1/2 clinical trial of TPX-0005 is actively being pursued (NCT03093116). CD74-ROS1 Ba/F3 Cell Proliferation Assay IC50 (nM)InhibitorWTG2032RD2033NL2026MS1986FS1986YTPX-0005&lt;0.28.40.210&lt;0.2&lt;0.2Crizotinib9.71402139606.420.919Lorlatinib0.5262.42.4ND0.30.3Entrectinib25.42404ND2026NDNDCeritinib131.92000NDND14.226.9Brigatinib28.61385167.1211527.724.6Cabozantinib1.060.70.129.1NDND
ND: not determined.
Citation Format: J. Jean Cui, Dayong Zhai, Wei Deng, Evan Rogers, Zhongdong Huang, Jeffrey Whitten, John Lim, Yishan Li. TPX-0005, a supreme ROS1 inhibitor, overcomes crizotinib-resistant ROS1 mutations including solvent front mutation G2032R and gatekeeper mutation L2026M [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 B185.