bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1745: Inhibition of chemokine receptor 2 (CCR2) with a small molecule antagonist enhances the effectiveness of checkpoint inhibition by altering the tumor microenvironment in mouse colorectal tumors: Reducing tumor size and increasing long term survival
Authors: Campbell James J. , Janson Christine , Ertl Linda , Li Chris , Miao Zhenhua , Krasinski Antoni , Lui Rebecca , Mali Venkat , McMahon Jeffrey , Zheng Yibin , Wang Yu , Zang Xiaoping , Chhina Vicky , Vilalta Marta , Kumamoto Alice , Dang Ton , Liu Shirley , Yao Simon , Zhang Penglie , Schall Thomas J. , Singh Rajinder 
Published: August 2018

Abstract
Mouse CT26 colorectal tumors are heavily infiltrated by tumor-specific CD8 T cells, but nevertheless grow rapidly in Balb/c mice. These tumors are partially responsive to anti-PD-1 (α-PD-1) monoclonal antibody therapy, which suggests that an active suppression of the tumor-specific cytotoxic T cells exists in the untreated tumor. As chemokine receptor 2 (CCR2) is expressed by a potentially suppressive leukocyte subset within these tumors (monocytic myeloid derived suppressor cells aka M-MDSCs), we aimed to test whether CCR2 blockade could enhance the anti-tumor effects of α-PD-1.
We have found that the therapeutic effects of α-PD-1 therapy are appreciably enhanced by specific blockade of CCR2 via a small molecule antagonist. This combined α-PD-1/CCR2i approach significantly decreases overall tumor size and increases the proportion of long-term survivors, with more than 50% of the mice (up to 73%) showing complete regression of a previously established tumor. The effects of this combined therapy are dependent on the presence of CD8+ T cells, as tumors do not respond to the therapy in CD8-depleted mice. The anti-CT26 tumor response is specific: long term survivors are resistant to re-inoculation with the CT26 tumor (even without further dosing of either drug) but are not resistant to the 4T1 breast tumor. CCR2 antagonism alters the tumor microenvironment by reducing the number of M-MDSC per gram of tumor (a CCR2hi population phenotypically defined as CD11b+/Ly6G-/Ly6Chi). Reduction in tumor size is inversely proportional to the ratio of CD8 T cells to M-MDSC.
These data are consistent with a hypothesis that CCR2 antagonism enhances α-PD-1 therapy by preventing M-MDSC from accumulating within the tumor, thus reducing their suppressive effects on cytotoxic T cells.
Citation Format: James J. Campbell, Christine Janson, Linda Ertl, Chris Li, Zhenhua Miao, Antoni Krasinski, Rebecca Lui, Venkat Mali, Jeffrey McMahon, Yibin Zheng, Yu Wang, Xiaoping Zang, Vicky Chhina, Marta Vilalta, Alice Kumamoto, Ton Dang, Shirley Liu, Simon Yao, Penglie Zhang, Thomas J. Schall, Rajinder Singh. Inhibition of chemokine receptor 2 (CCR2) with a small molecule antagonist enhances the effectiveness of checkpoint inhibition by altering the tumor microenvironment in mouse colorectal tumors: Reducing tumor size and increasing long term survival [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 1745.
Abstract 1797: Characterization of a novel androgen receptor coregulator RIPK1
Authors: Hsu Cheng-Lung , Liu Jai-Shin , Lin Ting-Wei , Lin Chun-Cheng , Wu Wen-Guey 
Published: August 2018

Abstract
Using bicalutamide-androgen receptor (AR) DNA binding domain-ligand binding domain as bait, we observed enrichment of FxxFY motif-containing peptides. Protein database searches revealed the presence of receptor-interacting protein kinase 1 (RIPK1) harboring one FxxFY motif. RIPK1 interacted directly with AR and suppressed AR transactivation in a dose-dependent manner. Domain mapping experiments showed that the FxxFY motif in RIPK1 is critical for interactions with AR and the death domain of RIPK1 plays a crucial role in its inhibitory effect on transactivation. In terms of tissue expression, RIPK1 levels were markedly higher in benign prostate hyperplasia and non-cancerous tissue regions relative to the tumor area. With the aid of computer modeling for screening of chemicals targeting activation function 2 (AF-2) of AR, we identified oxadiazole derivatives as good candidates and subsequently generated a small library of these compounds. A number of candidates could effectively suppress AR transactivation and AR-related functions in vitro and in vivo with tolerable toxicity via inhibiting AR-peptide, AR-coregulator and AR N-C interactions. Combination of these chemicals with antiandrogen had an additive suppressive effect on AR transcriptional activity. Our collective findings may pave the way in creating new strategies for the development and design of anti-AR drugs.
Citation Format: Cheng-Lung Hsu, Jai-Shin Liu, Ting-Wei Lin, Chun-Cheng Lin, Wen-Guey Wu. Characterization of a novel androgen receptor coregulator RIPK1 [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 1797.
Abstract 1799: ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct “alpha-cell signature” subgroup
Authors: Laddha Saurabh V. , Chan Chang S. , Lewis Peter , Koletsky Matthew , Robzyk Kenneth , Silva Edaise Da , Torres Paula J. , Untch Brian , Bose Promita , Chan Timothy , Klimstra David S. , Allis David C. , Tang Laura H. 
Published: August 2018

Abstract
Pancreatic neuroendocrine tumors (PanNETs) or islet cell tumors are a rare neuroendocrine malignancy with an annual incidence of less than 1 per 100,000 per year. Current classification scheme for PanNETs include grade and stage. While well-differentiated PanNETs can be successfully treated with surgery, there are few treatments for metastatic PanNETs. A greater understanding of the cells of origin of PanNETs, tumor progression and pathway pathogenesis may guide the development of novel therapeutic options. The most commonly mutated genes in PanNETs are ATRX, DAXX, and MEN1. Little is known about the cells-of-origin for non-functional neuroendocrine tumors. Here, we genotyped 64 PanNETs for mutations in ATRX, DAXX, and MEN1 and found 37 tumors (58%) carry mutations in these three genes (A-D-M mutant PanNETs) and this correlates with a worse clinical outcome than tumors carrying the wild-type alleles of all three genes (A-D-M WT PanNETs). We performed RNA sequencing (n=33) and Illumina 450K DNA methylation (n=32) analysis on randomly selected PanNETs to reveal two distinct subgroups with one group consisting exclusively of A-D-M mutant PanNETs. Pair-wise correlation of gene expression between all PanNETs, showed A-D-M mutant PanNETs are more homogeneous as a group than A-D-M WT PanNETs. Among A-D-M mutant PanNETs, mutants with the same genotype (mutations in ATRX/DAXX/MEN1) did not show greater gene expression correlation. Two biomarkers differentiating A-D-M mutant from A-D-M WT PanNETs were high ARX gene expression and low PDX1 gene expression with PDX1 promoter hyper-methylation in the A-D-M mutant PanNETs. Moreover, A-D-M mutant PanNETs had a gene expression signature similar to that of alpha cells (pval &lt; 0.009) of pancreatic islets including increased expression of HNF1A and its transcriptional target genes. We validated our subtype classification and A-D-M mutant panNET alpha signature using two independent PanNETs expression dataset. This gene expression profile suggests that A-D-M mutant PanNETs originate from or transdifferentiate into a distinct cell type similar to alpha cells.
Citation Format: Saurabh V. Laddha, Chang S. Chan, Peter Lewis, Matthew Koletsky, Kenneth Robzyk, Edaise Da Silva, Paula J. Torres, Brian Untch, Promita Bose, Timothy Chan, David S. Klimstra, David C. Allis, Laura H. Tang. ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct “alpha-cell signature” subgroup [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 1799.
Abstract 1805: Development of a selective androgen receptor degrader (SARD) for treatment of castration-resistant prostate cancer
Authors: Yao ZhongKe , Wardell Suzanne , Spasojevic Ivan , Norris John , Katzenellenbogen John , McDonnell Donald , Josan Jatinder S. 
Published: August 2018

Abstract
Current treatments for prostate cancer are centered on blocking androgen-signaling axis, which is the target of several clinical androgen receptor (AR) antagonists such as enzalutamide. Recent studies have shown that a single AR mutation (F876L) converts enzalutamide from an antagonist to an agonist—a fate shared by earlier antagonists as well such as bicalutamide and flutamide. While hormonal therapy is often successful in the initial stages of the disease, prostatic tumors inevitably become resistant to these therapeutics. Remarkably though, several mechanistic studies suggest that the androgen receptor signaling remains active even in these hormonal refractory cancers, which suggests that AR remains a viable target in the castration-resistant prostate cancers (CRPC). Thus, novel therapeutics that target and degrade AR could provide unique druggable opportunities for complete and more sustained AR inhibition in prostate cancers. Based on an AR-gelsolin interaction in a mammalian two-hybrid luciferase assay, we conducted a screen of an in-house library of 170,000 compounds, re-assayed and validated the top 2K hits. The top 500 hits were then characterized in a battery of assays such as AR-driven gene expression, inhibition of cell proliferation in WT and mutant cell lines, ChIP-seq, transcriptional and conformational profiling, and AR degradation studies. We have identified a selective androgen receptor degrader (SARD) series that shows efficacy against both WT and AR mutants. Further structure-activity relationship (SAR) studies revealed analogs with IC50 equivalent or superior to enzalutamide. In vivo studies are currently under way to evaluate the efficacy of the optimized lead in mouse tumor xenografts. These preclinical findings highlight the utility of SARDs as an effective therapeutic prostate tumor strategy in the context of AR mutations and overexpression that bestow resistance to the second-generation AR antagonists.
Citation Format: ZhongKe Yao, Suzanne Wardell, Ivan Spasojevic, John Norris, John Katzenellenbogen, Donald McDonnell, Jatinder S. Josan. Development of a selective androgen receptor degrader (SARD) for treatment of castration-resistant 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 1805.
Abstract 1809: Expression of genes in the nuclear receptor superfamily defines a set of prognostic biomarkers in endometrial cancer
Authors: Hoivik Erling A. , Tangen Ingvild L. , Mauland Karen M. , Halle Mari K. , Werner Henrica J. , Trovik Jone , Krakstad Camilla 
Published: August 2018

Abstract
The nuclear receptor (NR) superfamily in humans consists of 48 transcription factors that form a network to sense lipophilic molecules from the diet, metabolism and hormone production, which ultimately regulate development, circadian rhythm, metabolism, proliferation and differentiation in the normal state. In cancer, biomarker signatures that provide either prognostic or predictive information are useful when suggesting therapeutic strategies. However, when performing differential gene expression analysis on global datasets, there is little overlap among the gene sets identified, even among similar datasets of same cancers. The fourth-eight NRs in cancers could represent a unique predefined pan-cancer subset of potential biomarkers in gynecologic cancers. Of note, NRs, in particular, estrogen, progesterone and androgen receptors (ESR1, PGR, AR), are strongly involved in the progression of gynecologic cancers, as revealed by us and others exemplified by endometrial cancer. Further, NRs are appealing targets, as they are regulated by ligand-receptor interactions, and approximately 15% of all pharmacologic drugs target factors within this group. We investigate the association of NR expressions and clinical outcome, and reveal NR signatures that may provide useful information as a biomarker in gynecologic cancers, with emphasis on endometrial cancer.
Citation Format: Erling A. Hoivik, Ingvild L. Tangen, Karen M. Mauland, Mari K. Halle, Henrica J. Werner, Jone Trovik, Camilla Krakstad. Expression of genes in the nuclear receptor superfamily defines a set of prognostic biomarkers in endometrial 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 1809.
Abstract 1815: Massively parallel identification of conserved drug resistant mutations in kinases
Authors: Persky Nicole S. , Hernandez Desiree , Cordova Jonathon , Walker Amanda , Brenan Lisa , Piccioni Federica , Pantel Sasha , Lee Yenarae , Goodale Amy , Yang Xiaoping , Mitsuishi Yoichiro , Carmo Mariana Do , Zhu Cong , Andreev Aleksandr , Root David E. , Johannessen Cory M. 
Published: August 2018

Abstract
Drug resistant mutations that arise in therapeutic targets often limit clinical responses. However, the discovery of such mutations has historically been performed one gene or mutation at a time, often over decades of experimental and clinical testing, limiting our understanding of conserved mechanisms of drug resistance.
We hypothesized that deep mutational scanning of canonical kinases may expedite this process and identify novel conserved elements that cause drug resistance when mutated (similar to the well-studied “Gatekeeper” residue). To test this, we generated cDNA-expression libraries containing all possible amino acid substitutions in CDK6, CDK4, ERK2, and EGFR. We screened each library against clinically utilized, ATP-competitive small molecule inhibitors. We then mapped the phenotypic data for over 40,000 missense mutations onto the aligned crystal structures of each protein and searched for shared structural attributes associated with drug resistance.
This analysis revealed 4 equivalent amino acid sites whose mutation conferred drug resistance to ATP-competitive inhibitors in all of our screens: the Gatekeeper residue, as well as three uncharacterized residues. One of these sites, which we have termed the “Keymaster”, was additionally found to cause resistance in published data sets of sub-saturation BRAF, HER2, BCR-ABL, and MEK1 mutagenesis screens against their respective inhibitors. We confirmed that drug resistant phenotypes are caused by these alterations utilizing growth assays and protein target phosphorylation detection assays. Mechanistically, we show preliminary evidence that Keymaster-mutant proteins are competent for drug binding, but may display elevated basal activity. Consistent with our findings, we additionally identified mutations at Keymaster residues in reported patient tumors in a number of oncogene kinases, suggesting that Keymaster mutations could be drivers of tumorigenesis, as well as drug resistance. These efforts may prove useful for characterizing somatic kinase mutations of unknown function, designing next-generation therapeutics and deepening our understanding of kinase regulation.
Citation Format: Nicole S. Persky, Desiree Hernandez, Jonathon Cordova, Amanda Walker, Lisa Brenan, Federica Piccioni, Sasha Pantel, Yenarae Lee, Amy Goodale, Xiaoping Yang, Yoichiro Mitsuishi, Mariana Do Carmo, Cong Zhu, Aleksandr Andreev, David E. Root, Cory M. Johannessen. Massively parallel identification of conserved drug resistant mutations in kinases [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 1815.
Abstract 1822: Emergence of MET D1228N mutation as a resistance mechanism following an exceptional response to crizotinib in a MET-amplified triple-negative breast cancer patient
Authors: Parsons Benjamin M. , Meier David R. , Gurda Grzegorz T. , Lofgren Kristopher A. , Kenny Paraic A. 
Published: August 2018

Abstract
The MET proto-oncogene encodes a receptor tyrosine kinase which is activated by Hepatocyte Growth Factor binding. Recent reports have described single agent activity for crizotinib in MET-amplified or mutant lung adenocarcinoma, squamous cell carcinoma and papillary renal cell carcinoma. Here we describe a stage IV triple-negative breast cancer patient in her early forties, previously treated with doxorubicin/cyclophosphamide, carboplatin/paclitaxel and with capecitabine. PET/CT imaging after progression on capecitabine revealed extensive metastatic disease including a large left pleural effusion, bilateral hypermetabolic nodular pleural implants, innumerable bilateral lung nodules and widespread mildly hyper-metabolic skeletal metastases in the ribs, spine and pelvis. A next-generation sequencing assay detected a 30-fold amplification of MET. MET amplification, overexpression and hyperactivity was confirmed by FISH and by immunohistochemistry for total MET and phospho-MET, respectively. Single agent crizotinib (250 mg, twice daily) was well-tolerated. Immunostaining of a biopsy taken after 9 days of treatment showed elimination of active phosphorylated MET, demonstrating in-tumor crizotinib efficacy at the clinical dose. CT imaging at 10 weeks showed a resolution of her metastatic disease, meeting RECIST 1.1 criteria for a complete response. This response was sustained at 22 weeks. At 37 weeks, the patient progressed in the pleura. An ultrasound guided biopsy revealed a robust resurgence of MET phosphorylation while still taking crizotinib, suggesting an alteration rendering MET recalcitrant to crizotinib. Next generation sequencing revealed a MET D1228N mutation, previously implicated in crizotinib resistance in lung cancer. This mutation was not detected in the pre-crizotinib biopsy (locus sequenced at 6300x) suggesting de novo acquisition in response to crizotinib. Transition from this type I MET inhibitor to a type II inhibitor (cabozantinib, initially 60 mg/day, later 100 mg/day) resulted in clinically stable disease for a period of 7 weeks, at which point the patient again progressed. Although MET-amplification is rare in breast cancer (~0.6% of cases), these data indicate that substantial clinical benefit may be achieved using single agent MET inhibition however the optimal selection of second-line agents to use upon progression will be critical.
Citation Format: Benjamin M. Parsons, David R. Meier, Grzegorz T. Gurda, Kristopher A. Lofgren, Paraic A. Kenny. Emergence of MET D1228N mutation as a resistance mechanism following an exceptional response to crizotinib in a MET-amplified triple-negative breast cancer patient [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 1822.
Abstract 1832: Acquired resistance mechanisms to afatinib in lung cancer cells harboring HER2 alterations
Authors: Torigoe Hidejiro , Shien Kazuhiko , Takeda Tatsuaki , Yoshioka Takahiro , Namba Kei , Sato Hiroki , Suzawa Ken , Yamamoto Hiromasa , Soh Junichi , Sakaguchi Masakiyo , Tomida Shuta , Miyoshi Shinichiro , Toyooka Shinichi 
Published: August 2018

Abstract
Human epidermal growth factor receptor 2 (HER2) plays an important role in the pathogenesis of various cancers. HER2 alterations have been suggested to be a therapeutic target in non-small cell lung cancer (NSCLC), just as in breast and gastric cancers. We previously reported that the pan-HER inhibitor afatinib could be a useful therapeutic agent as HER2-targeted therapy for patients with NSCLC harboring HER2 alterations. However, acquired resistance to afatinib was observed in the clinical setting, similar to the case for other HER inhibitors. Thus, elucidation of the mechanisms underlying the development of acquired drug resistance and exploring means to overcome acquired drug resistance are important issues in the treatment of NSCLC. In this study, we experimentally established afatinib-resistant cell lines from NSCLC cell lines harboring HER2 alterations (Calu3, H2170, and H1781), by stepwise-escalation or high-concentration exposure methods, and investigated the mechanisms underlying the acquisition of drug resistance. The established cell lines showed several unique afatinib-resistance mechanisms, including MET amplification, loss of HER2 amplification and gene expression, epithelial-to-mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)-like features. The afatinib-resistant cell lines showing MET amplification were sensitive to the combination of afatinib plus crizotinib (a MET inhibitor), both in vitro and in vivo. The resistant cell lines with the loss of HER2 amplification obtained MEK inhibitors sensitivity in vitro and in vivo. Other resistant cell lines that showed EMT or had acquired CSC-like features remained sensitive to docetaxel, like the parental cells. These findings may provide clues to countering the resistance to afatinib in NSCLC patients with HER2 alterations.
Citation Format: Hidejiro Torigoe, Kazuhiko Shien, Tatsuaki Takeda, Takahiro Yoshioka, Kei Namba, Hiroki Sato, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Masakiyo Sakaguchi, Shuta Tomida, Shinichiro Miyoshi, Shinichi Toyooka. Acquired resistance mechanisms to afatinib in lung cancer cells harboring HER2 alterations [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 1832.
Abstract 1838: A pre-existing rare PIK3CAE545K subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling
Authors: Romano Gabriele , Chen Pei-Ling , Song Ping , McQuade Jennifer , Liang Roger , Liu Mingguang , Roh Whijae , Duose Dzifa , Carapeto Fernando , Li Jun , Teh Jessica , Aplin Andrew , Chen Merry , Zhang Jianhua , Lazar Alexander , Futreal P Andrew , Amaria Rodabe , Zhang David , Wargo Jennifer , Kwong Lawrence N. 
Published: August 2018

Abstract
Combined MEK and CDK4/6 inhibition (MEKi+CDK4i) has shown promising clinical outcomes in NRAS mutant melanoma patients. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi+CDK4i therapy but subsequently developed resistance. Whole exome sequencing and functional validation identified an acquired PIK3CAE545K mutation as conferring drug resistance. We demonstrate that PIK3CAE545K pre-existed in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multi-region sampling due to PIK3CAE545K being non-uniformly distributed. This resistant population rapidly expanded after the initiation of MEKi+CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy. Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CAE545K-induced resistance. These results demonstrate that comprehensive analysis of pre-treatment samples can reveal rare pre-existing resistant subpopulations and posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways.
Citation Format: Gabriele Romano, Pei-Ling Chen, Ping Song, Jennifer McQuade, Roger Liang, Mingguang Liu, Whijae Roh, Dzifa Duose, Fernando Carapeto, Jun Li, Jessica Teh, Andrew Aplin, Merry Chen, Jianhua Zhang, Alexander Lazar, P Andrew Futreal, Rodabe Amaria, David Zhang, Jennifer Wargo, Lawrence N. Kwong. A pre-existing rare PIK3CAE545K subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 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 1838.