bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1302: Targeting hormone receptor-dependent cancers with potent, selective and orally-available small molecule inhibitors of eIF4E
Authors: Chiang Gary G. , Parker Gregory S. , Hung Ivy N. , Goel Vikas K. , Staunton Jocelyn , Barrera Maria , Sung Eric , Parra Ana , Stumpf Craig R. , Chen Joan , Thompson Peggy A. , Nevarez Andreas , Wegerski Christopher J. , Parker Cody , Clarine Jeff , Sperry Samuel , Xiang Alan , Nilewski Christian , Packard Garrick K. , Urkalan Kaveri , Mukaiyama Takasuke , Michels Theo , Ernst Justin T. , Sprengeler Paul A. , Reich Siegfried H. , Webster Kevin R. 
Published: August 2019

Abstract
The PI3K/mTOR pathway is commonly dysregulated in many hormone receptor-dependent tumors and plays a key role in promoting tumor growth and mediating drug resistance. In particular, PI3K and mTORC1/2 inhibitors have been intensively studied in the treatment of hormone receptor-dependent cancers and have shown benefit in some clinical settings. However, issues such as dose-limiting toxicities and emergent resistance limit the broader utility of these inhibitors. The translation initiation factor eIF4E is essential for the translation of m7G-capped mRNA and is a key point of convergence for both the PI3K/mTOR and MAPK signaling pathways. We have designed a series of potent, selective and orally-available m7G cap-competitive inhibitors of eIF4E (eFT-4Ei) with favorable drug-like properties. These inhibitors bind to eIF4E either as its free form or with eIF4E-4EBP and eIF4F complexes within tumor cells and downregulate hormone receptor-dependent signaling. Ribosomal profiling of eIF4E inhibitor-treated tumor cells identified a subset of translationally regulated target genes that overlap with mTORC1/2 regulated genes, but also a unique set of translationally regulated target mRNAs. Consistent with this observation, our eIF4E inhibitors show some similarities yet several important differences from existing mTORC1 or mTORC1/2 dual inhibitors in both cellular and physiological assays. Finally, significant anti-tumor efficacy was observed with eIF4E inhibition in vitro and in vivo. Taken together, these results highlight the potential for targeting eIF4E as a novel therapeutic strategy to treat hormone-receptor dependent cancers.
Citation Format: Gary G. Chiang, Gregory S. Parker, Ivy N. Hung, Vikas K. Goel, Jocelyn Staunton, Maria Barrera, Eric Sung, Ana Parra, Craig R. Stumpf, Joan Chen, Peggy A. Thompson, Andreas Nevarez, Christopher J. Wegerski, Cody Parker, Jeff Clarine, Samuel Sperry, Alan Xiang, Christian Nilewski, Garrick K. Packard, Kaveri Urkalan, Takasuke Mukaiyama, Theo Michels, Justin T. Ernst, Paul A. Sprengeler, Siegfried H. Reich, Kevin R. Webster. Targeting hormone receptor-dependent cancers with potent, selective and orally-available small molecule inhibitors of eIF4E [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1302.
Abstract 1304: Aryl hydrocarbon receptor ligands 5F 203 and 3,3'-Diindolylmethane disrupt mammospheres derived from MCF-7 cells and induce tumor suppressor miR125b-2 expression
Authors: Brantley Eileen , Mavingire Nicole , Wooten Jonathan , Campbell Petreena 
Published: August 2019

Abstract
While anti-estrogen tamoxifen (Tam) effectively treats many patients with estrogen receptor positive (ER+) tumors, up to 40% experience relapse following resistance. Breast cancer stem cells (CSCs) within tumors greatly contribute to tamoxifen resistance (TamR) and exhibit unique molecular signatures that drive metastasis and promote relapse. Tumor suppressor miRNAs aid in suppressing breast cancer progression. We have previously shown that aryl hydrocarbon receptor (AhR)-ligand Aminoflavone disrupts the formation of spheres and inhibits the expression of putative stemness marker α6-integrin and α6-integrin-src-Akt signaling. We hypothesize that two AhR ligands, 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) and 3,3'-Diindolylmethane (DIM), exhibit anticancer properties in MCF-7 breast cancer cells by targeting the CSC population in an AhR-dependent fashion. We found that DIM and 5F 203 disrupted mammospheres derived from MCF-7 cells but demonstrated a reduced capacity to do so in mammospheres derived from AHR100 cells (MCF-7 variants that are AhR-unresponsive). Wound healing and colony forming assays respectively revealed that 5F 203 and DIM also decreased cell migration and cell proliferation in MCF-7 cells and to a much lesser extent in AhR100 cells. 5F 203 and DIM induced miR125b-2 expression and suppressed the expression of stemness-regulating genes such as α6-integrin, a predicted miR125b-2 target. The reduction in stemness-gene expression in MCF-7 cells was attenuated following pretreatment with AhR antagonist CH223191. These data suggest that AhR ligands such as DIM and 5F 203 confer their anticancer actions including those against breast CSCs in an AhR-dependent manner. Our data is expected to provide a rationale for the development of anticancer AhR ligands designed to combat ER+ breast cancer and decrease the risk of relapse.
Citation Format: Eileen Brantley, Nicole Mavingire, Jonathan Wooten, Petreena Campbell. Aryl hydrocarbon receptor ligands 5F 203 and 3,3'-Diindolylmethane disrupt mammospheres derived from MCF-7 cells and induce tumor suppressor miR125b-2 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1304.
Abstract 1305: Identification of signal transduction kinases inhibited by pan-RAF inhibitor belvarafenib using FRET imaging technique
Authors: Bae Dong-Jun , Kim Sang-Yeob , Byun JooYun , Bae InHwan , Ahn YoungGil , Kim YoungHoon , Suh Kwee Hyun 
Published: August 2019

Abstract
The mitogen-activated protein kinase (MAPK) pathway plays an important role for the survival and proliferation of tumor cells. For example, the activation of the MAPK pathway due to mutations in BRAF, NRAS and KRAS kinases is known to be the causes of various solid tumors and hematologic malignancies. Accordingly, there is a strong need for effective therapeutic drugs for treating cancers caused by genetic mutation of BRAF, NRAS or KRAS. Belvarafenib (HM95573 or GDC5573), currently in Phase 1 clinical trials, is a selective and orally bioavailable pan-RAF kinase inhibitor. When biochemically assayed for hundreds of kinases, Belvarafenib showed selectivity toward RAF family kinases, including strong inhibition activities for BRAF WT, BRAF mutants and CRAF. Previously, we reported that Belvarafenib strongly inhibits the growth of cancer cell lines with BRAF, NRAS or KRAS mutations and also shows excellent anticancer efficacy in animal models using the corresponding cancer cells. In this study, employing fluorescence resonance energy transfer (FRET) imaging, we examined which protein kinases involved in signal transduction are regulated by Belvarafenib and investigated the mechanism of action for the regulation in typical cancer cells harboring BRAF, NRAS or KRAS mutations such as A375 (melamona), SK-MEL-30 (Kwmelamona), HCT116 (CRC), and Calu-6 (NSCLC). Among the various protein kinases that can be involved in signal transduction, we identified with time-lapse FRET imaging that the phosphorylation of ERK, AKT and S6K are inhibited after the treatment of Belvarafenib in the above cancer cells of BRAF, NRAS or KRAS mutations. Of note, BRAF mutant selective inhibitors, Vemurafenib and Dabrafenib were not active in cancer cells of NRAS or KRAS mutations. These results correlate with the in vitro and in vivo anticancer activity in cancer cells of BRAF, NRAS or KRAS mutations. In conclusion, unlike Vemurafenib and Dabrafenib, the pan-RAF inhibitor Belvarafenib could be effective for treating the cancer caused by NRAS or KRAS mutations, as well as BRAF mutations.
Citation Format: Dong-Jun Bae, Sang-Yeob Kim, JooYun Byun, InHwan Bae, YoungGil Ahn, YoungHoon Kim, Kwee Hyun Suh. Identification of signal transduction kinases inhibited by pan-RAF inhibitor belvarafenib using FRET imaging technique [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1305.
Abstract 1309: Targeting GluN2C ion channels as a promising approach in the treatment of melanoma
Authors: Tabatabaee Hessam , Feng Yuchen , Yari Hamed , La Ting , Sherwin Simonne , Jin Lei , Lim Rebecca , Brichta Alan , Zhang Xu Dong 
Published: August 2019

Abstract
Ion channels are pore-forming integral membrane proteins that are known to have an impact on all hallmarks of cancer. Due to their expression on the surface of the cells, ion channels provide a distinct therapeutic target with more facilitated access from the extracellular milieu. NMDA receptors are a subtype of ligand-gated ion channels that express unique features including high calcium permeability as well as the requirement for binding of glutamate and the co-agonist glycine in order to be activated. Here we show that a glutamate ionotropic NMDA (N-methyl-D-aspartate) type ion channel, GluN2C is critically required for survival of human melanoma cells. Publicly available microarray data from Gene Expression Omnibus (GEO) were acquired in order to identify the differentially expressed ion channel genes in 127 melanoma patient samples relative to benign nevi or human epidermal melanocytes. Data exists into two major cohorts: First cohort consisted of 18 benign nevi and 45 melanoma (GSE3189), while second cohort contained 8 melanocytes and 82 melanoma (GSE29377). A bioinformatics approach was undertaken to determine commonly upregulated ion channels between the two cohorts. Subsequently, functional enrichment analysis along with pathway evaluation of these genes revealed GluN2C as a novel candidate for further investigation in this study. Upregulation of GluN2C was confirmed in a panel of melanoma cell lines and fresh melanoma isolates. Strikingly, silencing of GluN2C markedly reduced viability and clonogenicity in melanoma cells. Consistently, a pharmacological inhibitor of GluN2C potently killed melanoma cells with minimal effects on melanocytes and fibroblasts. Killing of melanoma cells by inhibition of GluN2C was not due to induction of apoptosis, since a general caspase inhibitor Z-VAD-FMK failed to rescue cells from dying. In contrast, the late stage autophagy inhibitor Bafilomycin A1 blocked the GluN2C induced cell death suggesting that killing of melanoma cells following inhibition of GluN2C is in part associated with induction of autophagy. Collectively, these results uncover a potential role for GluN2C ion channels in the pathogenesis of melanoma and suggest that these ion channels may constitute a promising target for melanoma treatment.
Citation Format: Hessam Tabatabaee, Yuchen Feng, Hamed Yari, Ting La, Simonne Sherwin, Lei Jin, Rebecca Lim, Alan Brichta, Xu Dong Zhang. Targeting GluN2C ion channels as a promising approach in the treatment of melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1309.
Abstract 1321: TPX-0022, a polypharmacology inhibitor of MET/CSF1R/SRC for treatment of cancers with abnormal HGF/MET signaling
Authors: Zhai Dayong , Rogers Evan , Deng Wei , Zhang Xin , Lee Dong , Ung Jane , Zhang Han , Liu Jing , Lu Yuelie , Huang John , Graber Armin , Zimmerman Zach , Lim John , Whitten Jeffrey , Cui J. Jean 
Published: August 2019

Abstract
Aberrant activation of the HGF/MET pathway has frequently been found in human cancers via MET mutation, gene amplification and translocation, as well as HGF paracrine or autocrine upregulation. The abnormal HGF/MET signaling not only acts as an oncogenic driver but also confers resistance to many cancer therapies, such as EGFR targeted therapy in NSCLC. One key downstream effector for activated MET is SRC, which is also involved in malignancy formation, tumor metastasis and drug resistance. In the tumor microenvironment, CSF1R plays an important role in regulation of tumor associated macrophages, which promote tumor progression and angiogenesis. Therefore, the polypharmacological inhibition of MET/SRC/CSF1R has great potential for more effectively targeting cancers with abnormal HGF/MET signaling via targeting both tumor intrinsic signaling and the tumor microenvironment. TPX-0022, a novel macrocyclic compound, has been designed and optimized to inhibit MET/CSF1R/SRC with enzymatic kinase inhibition IC50s of 0.14, 0.76 and 0.12 nM, respectively. TPX-0022 potently inhibited cell proliferation of the MET-amplified MKN-45 and SNU-5 gastric cancer cells, with IC50s &lt;0.2 nM, which ranked TPX-0022 as one of the most potent MET inhibitors. TPX-0022 caused suppression of MET auto-phosphorylation at an IC50 of approximately 0.3 nM in MKN-45 cell line. TPX-0022 also potently inhibited the phosphorylation of MET downstream signaling effectors, including AKT, ERK, STAT3 and PLCγ2 in a dose-dependent manner. In the cancer cell line- and patient-derived xenograft tumor models from gastric, lung and liver cancers harboring MET amplification or MET exon14 skipping mutations, TPX-0022 caused dramatic tumor regression and tumor growth inhibition, without overt abnormality and body weight loss in treated mice. Furthermore, the tumor inhibitory effect was associated with drastic inhibition of MET activity. Overall, TPX-0022 is a novel and potent MET inhibitor and has demonstrated desirable drug-like properties, a good preclinical safety profiles, that warrants further clinical development and an IND submission is currently planned.
Citation Format: Dayong Zhai, Evan Rogers, Wei Deng, Xin Zhang, Dong Lee, Jane Ung, Han Zhang, Jing Liu, Yuelie Lu, John Huang, Armin Graber, Zach Zimmerman, John Lim, Jeffrey Whitten, J. Jean Cui. TPX-0022, a polypharmacology inhibitor of MET/CSF1R/SRC for treatment of cancers with abnormal HGF/MET signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1321.
Abstract 1328: Exploring the pharmacokinetic-pharmacodynamic relationships of AZD3229, a novel and selective inhibitor of cKIT, in a range of mouse xenograft models of gastrointestinal stromal tumors
Authors: Reddy Venkatesh Pilla , Smith Aaron , Grondine Michael , Anjum Rana , Jones Rhys D. 
Published: August 2019

Abstract
cKIT belongs a family of transmembrane tyrosine kinase growth factor receptors and gain of function mutations result in constitutive c-KIT activation that provide an important pathogenic role in gastrointestinal stromal tumors (GIST). AZD3229 is a highly potent and selective oral best-in-class KIT inhibitor that is active against a wide spectrum of primary and secondary KIT mutations that are known to confer resistance to standard of care agents. AZD3229 demonstrates rapid, extensive and sustained inhibition of KIT signaling in preclinical xenograft models with KIT primary exon 11 del mutations and primary/secondary ATP-binding pocket mutations (GIST 430/654A and patient-derived xenograft (PDX) model of KIT V654A, HGiXF-106) and A-loop mutations (PDX model of KIT Y823D, HGiXF-105 and Ba/F3 KIT D816H). In these models, AZD3229 results in anti-tumour activity (tumour regressions ranging from -60% to -99 % TGI) when dosed orally up to 20 mg/kg BID.
The objective of this PK-PD modeling work was to (1) establish the PK-PD-Efficacy relationship for AZD3229 across the four cell-lines and PDX mouse models tested; (2) to confirm the extent and duration of pKIT inhibition required for optimal efficacy, as defined by tumor regressions.
Inhibition of KIT phosphorylation observed with AZD3229 shows a direct relationship to free mouse plasma concentration and an estimated in vivo EC90 was estimated for each model (Ba/F3 D816H = 20 nM; GIST 430/V654A= 43 nM; HGiX-106 = 76 nM; HGiX-105 = 4 nM). No change in the extent of inhibition of KIT phosphorylation was observed on repeat dosing. Optimal efficacy is observed when sustained inhibition of pKIT, &gt;90% is achieved over the dosing interval.
Conclusion: Exploring the in vivo activity and PK-PD relationship in multiple cell-line derived xenograft and PDX models harboring different mutations provides a benchmark from which to anchor human dose predictions that partly reflect the spectrum of responses likely to be seen in GIST patients.
Citation Format: Venkatesh Pilla Reddy, Aaron Smith, Michael Grondine, Rana Anjum, Rhys D. Jones. Exploring the pharmacokinetic-pharmacodynamic relationships of AZD3229, a novel and selective inhibitor of cKIT, in a range of mouse xenograft models of gastrointestinal stromal tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1328.
Abstract 133: The role of the calcium-sensing receptor (CaSR) in the adaptation of breast cancer cells in high Ca2+ microenvironments
Authors: Beasley Heather K. , Actkins Ky'Era V. , Widatalla Sarrah E. , Whalen Diva S. , Williams Stephen D. , Korolkova Olga Y. , Sakwe Amos M. 
Published: August 2019

Abstract
Cancer-induced hypercalcemia (CIH) is common in cancer patients with metastatic disease and in up to 30% of cases without metastasis. During malignancy, tumor cells secrete factors such as parathyroid hormone related protein (PTHrP) that causes the destruction of bone tissue, or osteolysis. The resulting persistent osteolysis leads to a progressive increase in systemic calcium or CIH. High circulating Ca2+ is sensed by the calcium-sensing receptor (CaSR), which plays a significant role in maintaining Ca2+ homeostasis, and also stimulates the secretion of PTHrP which promotes tumor cell proliferation and motility. Moreover, more than 200 mutations including single nucleotide polymorphisms (SNPs) in the CaSR gene have been described, including the inactivating A986S CaSR at rs1801725 and Q1011E CaSR at rs1801726 SNPs with reduced sensitivity to Ca2+ . Although the CaSR is the major cell surface Ca2+ sensor in most cell types, its function in the Ca2+ rich bone microenvironment remains unclear. We show that high Ca2+ adaptation of MDA-MB-231 cells, did not lead to altered expression of the receptor in the surviving cells. However, the receptor was desensitized to high Ca2+ and the cells were more motile and formed larger colonies in 3D cultures. Meanwhile, gene expression profiling of triple negative breast cancer cells (TNBC) cells transiently exposed to high Ca2+ reveals the expression of early response genes and Ca2+ -inducible genes with known functions in tumor growth and/or motility. Since breast cancer (BC) frequently metastasizes to skeletal tissues, these data suggest that BC cells that successfully colonize the bone microenvironment undergo high Ca2+ adaptation or priming via the expression of high Ca2+ inducible genes that facilitate cell growth and/or motility.
Citation Format: Heather K. Beasley, Ky'Era V. Actkins, Sarrah E. Widatalla, Diva S. Whalen, Stephen D. Williams, Olga Y. Korolkova, Amos M. Sakwe. The role of the calcium-sensing receptor (CaSR) in the adaptation of breast cancer cells in high Ca2+ microenvironments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 133.
Abstract 1343: SNPs in the NFKB alternative pathway genes CD40, BAFFR and LTβR in CRC
Authors: Antonacopoulou Anna , Kottorou Anastasia , Koutras Angelos , Dimitrakopoulos Foteinos-Ioannis , Makatsoris Thomas , Kalofonos Haralabos P. 
Published: August 2019

Abstract
We sought to assess the role of single nucleotide polymorphisms (SNPs) in genes of the alternative NF-KB pathway, important in regulating different aspects of immune functions in colorectal cancer (CRC). The study comprised DNA samples from 418 patients with CRC and 299 age-matched healthy individuals. Genotyping was performed with real time PCR followed by high resolution melt curve analysis for the following SNPs: CD40 rs1883832 (C/T), BAFFR rs7290134 (A/G), LTβR rs10849448 (A/G). Genotypes of random samples were confirmed by sequencing. Genotype frequencies differed between CRC and healthy individuals for CD40 rs1883832 and LTβR rs10849448 (p = 0.001 and p = 0.016, respectively) but were similar for BAFFR rs7290134. The LTβR rs10849448 G allele was more frequent in CRC patients compared to healthy controls and increased risk for CRC by 61% (p = 0.024). Moreover, the G allele was found more frequently in stage D patients compared to stages A and C while the A allele was more prevalent in stage B patients (p = 0.007). Additionally, most patients with grade III tumors were G allele carriers whereas the majority of grade I tumors were AA homozygotes (p = 0.019). The CD40 rs1883832 T allele was less frequent in CRC patients and reduced risk for CRC by 71% (p = 0.027). The CD40 rs1883832 SNP proved to be a prognostic factor for PFS with the CC individuals displaying a longer PFS compared to T carriers (p = 0.045). The BAFFR rs7290134 SNP was independent of all clinical parameters evaluated. Primary site was independent of genotypes for all three SNPs. SNPs within genes of receptors of the NF-KB alternative pathway, CD40 rs1883832 and LTβR rs10849448, influence PFS and risk for CRC development. Additionally, particular genotypes correlated with stage and grade.
Citation Format: Anna Antonacopoulou, Anastasia Kottorou, Angelos Koutras, Foteinos-Ioannis Dimitrakopoulos, Thomas Makatsoris, Haralabos P. Kalofonos. SNPs in the NFKB alternative pathway genes CD40, BAFFR and LTβR in CRC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1343.