bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4170: Targeting androgen receptor overcomes resistance to tyrosine kinase inhibitors in advanced clear cell renal cell carcinoma
Authors: Adelaiye-Ogala Remi M. , Chintala Sreenivasulu , Orillion Ashley , Elbanna May , Elzey Ben , Damayanti Nur , Miles Kiersten M. , Kao Chinghai , Pettazzoni Piergiorgio , Draetta Giulio F. , Pili Roberto 
Published: July 2017

Abstract
Background: Advanced renal cell carcinoma (RCC) responds initially to anti-angiogenic therapies but eventually develop resistance which may be driven by the expression of key intratumoral pro-survival protein and overall kinome reprogramming. Androgen receptor (AR) expression has been reported in clear cell renal cell carcinoma (ccRCC) but its biological role remains elusive and its association with resistance to tyrosine kinase inhibitors (TKIs) has not been studied. Here we report the role of AR and its association with resistance to TKIs in advanced RCC. Methods: Human RCC cell lines; 786-0, 786-0R (with induced sunitinib resistance), ACHN, URMC2 (with intrinsic sunitinib resistance) were used to assess the combination effect of sunitinib and the AR antagonist enzalutamide in vitro. In vivo studies utilizing 786-0 tumors assessed the combination effect of enzalutamide and sunitinib following acquired resistance to sunitinib. AR expression was detected by qRT-PCR and Western blot analysis, and AR localization by immunofluorescence in treated and non-treated cells. Gene array was used to assess 93 AR associated genes in sensitive and resistant cells. Results: Quantitative RT-PCR data revealed a significant increase in AR expression with sunitinib resistance (&gt;100 folds; p&gt;0.001). In vitro and in vivo studies indicated significant increase in nuclear and cytoplasmic expression of AR with sunitinib treatment in resistant cells which was abrogated with single agent enzalutamide and combination treatment. More interestingly, combination treatment of enzalutamide and sunitinib significantly decreased cell growth and induced tumor regression in vitro and in vivo, respectively. Conclusion: Our data suggest the role of AR both in intrinsic and acquired sunitinib resistance in ccRCC and provide a rationale for combination strategies to restore TKI sensitivity that can be tested in the clinical setting.
Citation Format: Remi M. Adelaiye-Ogala, Sreenivasulu Chintala, Ashley Orillion, May Elbanna, Ben Elzey, Nur Damayanti, Kiersten M. Miles, Chinghai Kao, Piergiorgio Pettazzoni, Giulio F. Draetta, Roberto Pili. Targeting androgen receptor overcomes resistance to tyrosine kinase inhibitors in advanced clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4170. doi:10.1158/1538-7445.AM2017-4170
Abstract 4174: The impact of catechol estrogen metabolism on the proliferation rate and Docetaxel (DOC) resistance in hormone-responsive cancers
Authors: Tolba Mai F. , Omar Hany , Noreddin Ayman M. 
Published: July 2017

Abstract
Estrogen-responsive cancers such as breast cancer (BC) and prostate cancer (PC) are on the top of the most commonly diagnosed cancers in USA. Docetaxel (DOC) is considered the first-line of therapy for both metastatic BC and castration-resistant PC. However, its use in therapeutically effective doses is associated with significant toxic reactions and tumor resistance. Estrogens (E2) play an important role in the development and progression of both malignancies. Of special importance is that the catechol E2 metabolite, 4-hydroxyestradiol (4-OHE2) enhances the proliferation of both breast and prostate normal epithelial cells. The goal of this work is to investigate the relationship between catechol-E2 metabolism and cancer cells proliferation and response to DOC. Methods: The cells were exposed to serial concentrations of E2 and 4OHE2 (0.001-10 µM) to assess their effect on cells’ growth rate over 24-92 h. Cell proliferation assays were utilized to assess the density of viable cells at different time points. Cytotoxicity assays were performed to evaluate the median inhibitory concentration (IC50) of DOC alone or in the presence of 4OHE2. Results: Exposure of the estrogen receptor (ER)-positive BC cell line MCF-7 to 0.1 µM of 17-β-hydroxyestradiol (E2) for 3 days significantly boosted the cell proliferation rate compared to control group by about 27% (P&lt;0.05). Exposure of MCF-7 cells to the catechol estrogen metabolite 4-hydroxyestradiol (4OHE2) at 0.1µM for 3 days significally enhanced cell growth by about 31% (P&lt;0.001). Similarly, exposure of the androgen independent, ER-positive- advanced stage PC cells PC-3 to E2 (1 µM, 3 days) significantly enhanced the growth rate by 37% (P&lt;0.05). Moreover, our data showed that simultaneous exposure to 4OHE2 significantly antagonized the cytotoxic activity of DOC with subsequent increase in the IC50 of DOC by 18 folds (P&lt;0.006). Conclusion: these results indicate that altered E2 metabolism with subsequent accumulation of 4-OHE2 can enhance the proliferation rate of E2-responsive cancers in addition to hindering the cytotoxic activity of DOC with subsequent reduction in DOC potency. Further research is in progress to assess the potential merit of modulating the clearance of catechol E2 as a strategy to improve the cancer response to DOC. (This project is supported by Fulbright Scholar grant FY15/16 and L’Oreal-UNESCO for Women in Science-Levant and Egypt award for MFT).
Citation Format: Mai F. Tolba, Hany Omar, Ayman M. Noreddin. The impact of catechol estrogen metabolism on the proliferation rate and Docetaxel (DOC) resistance in hormone-responsive cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4174. doi:10.1158/1538-7445.AM2017-4174
Abstract 4176: Targeting TAM family members with antibody or small molecule inhibitors enhances therapeutic modalities of HNSCC
Authors: Black Nellie K. , Iida Mari , Rodems Tamara S. , Brand Toni M. , Kimple Randall J. , Wheeler Deric L. 
Published: July 2017

Abstract
Radiation, cisplatin, and cetuximab are clinical therapeutics used in the treatment of head and neck squamous cell carcinoma (HNSCC). Despite clinical success with these modalities, development of both intrinsic and acquired resistance is an emerging problem in the management of HNSCC. Thus, identifying and targeting molecules driving this drug resistance is essential for improving efficacy of treatment approaches.
Recent studies have identified a role for the TAM family of receptor tyrosine kinases (Tyro, Axl, and Mer) in tumor biology, especially the Axl receptor in promoting tumor growth and metastasis. Previously, we identified Axl as a logical molecular target in HNSCC and indicated that it may play a pivotal role in resistance to radiation, cisplatin, and cetuximab. In the current study, we advanced these early findings into pre-clinical models using patient-derived xenografts (PDXs). We have shown that small molecules targeting Axl can enhance therapy in PDXs that express high levels of Axl and have been identified as resistant to radiation, cisplatin, and cetuximab. Current studies are focusing on antibody-based targeting of Axl using PDXs and genetically-modified models of resistance. Furthermore, studies focused on co-targeting of Axl and Mer in vitro and in vivo have shown striking results and denote the importance of establishing logical approaches to target TAMs in the management of HNSCC.
Finally, investigations into the molecular mechanisms of how Axl signaling can lead to resistance have underscored the importance of tyrosine 821 (Y821) of Axl. Overexpression of Axl rendered cetuximab sensitive lines resistant, but cell lines overexpressing Axl-Y821F retained their sensitivity to cetuximab. Advancing this line of study in vivo indicated that tumors expressing Axl were resistant to cetuximab whereas tumors harboring the Y821 mutation were sensitive demonstrating that signals emanating from Y821 may be critical for cetuximab resistant pathways.
Collectively, the studies presented herein identify the TAM family of receptors as key players in radiation, cisplatin, and cetuximab resistance. These results provide rationale for the clinical targeting of TAM receptors to enhance the therapeutic modalities used in treating HNSCC.
Citation Format: Nellie K. Black, Mari Iida, Tamara S. Rodems, Toni M. Brand, Randall J. Kimple, Deric L. Wheeler. Targeting TAM family members with antibody or small molecule inhibitors enhances therapeutic modalities of HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4176. doi:10.1158/1538-7445.AM2017-4176
Abstract 423: Detection of genetic alterations to predict the chemotherapeutic responses in unresectable pancreatic ductal adenocarcinomas
Authors: Park Joo Kyung , Lee Kwang Hyuck , Park Donghyun , Park Woong-Yang , Son Dae-Soon , Lee Jong Kyun , Lee Kyu Taek 
Published: July 2017

Abstract
Background & Aims: Next-generation sequencing (NGS) that enables the analyses of massively parallel sequences of DNA can advance the understanding of the underlying molecular pathophysiologies of cancer. Such recent genomic analyses have revealed a complex mutational landscape for PDACs. The aims of this study were to investigate the genomic profile to predict the chemotherapy response in unresectable PDACs.
Methods: The total of 80 pathologically confirmed PDACs were enrolled and genomic DNA was extracted and quality control metrics of DNA analytes were measured. The specimens that passed a quality control test underwent targeted deep sequencing using a customized cancer panel (CancerSCAN) enriched in the exons of 83 genes.
Results: Clinical prognostic factors associated with survival in PDAC were gender, tumor mass size, stage and chemotherapy response rate. (P=0.078, 0.009, 0.052 and &lt;0.001, respectively). Multivariate Cox proportional-hazards analysis revealed chemotherapy response rate (P &lt; 0.001, hazard ratio (HR) = 1.908, 95% CI, 1.281 to 2.840) is an independent prognostic factor. There were 56 (71%) and 9 (11%) study patients who underwent gemcitabine based chemotherapy and FOLFIRINOX respectively. Response rate of study patients were as follows; CR+PR 14 (20%), SD (27%) and PD 28 (41%). There were only 9 (16%) and 4 (50%) patients who had CR+PR response gemcitabine based chemotherapy and FOLFIRINOX respectively.
Conclusion: Targeted sequencing using EUS-FNA specimens in PDAC showed excellent compatibilities to analyze genomic profiles of PDACs. Furthermore, novel genes associated with survival, metastasis and chemotherapy response in PDAC were identified.
Citation Format: Joo Kyung Park, Kwang Hyuck Lee, Donghyun Park, Woong-Yang Park, Dae-Soon Son, Jong Kyun Lee, Kyu Taek Lee. Detection of genetic alterations to predict the chemotherapeutic responses in unresectable pancreatic ductal adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 423. doi:10.1158/1538-7445.AM2017-423
Abstract 4232: Gastrointestinal stromal tumor: Retrospective analysis of 44 cases of center of reference in eastern Algeria
Authors: Boukhalfa Soufyane Ali , Filali Tah 
Published: July 2017

Abstract
Aim: To analyze the clinicopathologic characteristics, prognostic factors, and treatment of gastrointestinal stromal tumors (GISTs).
Methods: We conducted a retrospective analysis of all cases of GISTs treated in the Medical Oncology Unit from 2010 through 2015.
Results: We analyzed 44 patients with a median age of 49.43 years (17-76 years) with sex ratio 1:1. The main symptom was abdominal pain. Thirty patients had limited-stage disease and 14 patients had metastatic disease. We observed 90% of the immunohistochemistry exams were positive for CD117 (c-Kit+). The most frequent location was in the stomach (45%), the high-risk group was predominant (50%) and the average tumor size is 12.84 cm. Surgery was considered R0 (extensive) in 75% of the cases and the main sites of metastases were liver and peritoneum.25 patients received imatinib 400 mg qDay in adjuvant setting,5 patients in neoadjuvant, 13 patients in palliative and 1 patient had best supportive care. A total of 44 patients were followed up for 1 to 78 months.6 patients (13 %) developed recurrence or metastasis during or after adjuvant treatment. Two patients had surgery after neoadjuvant treatment(40%). 4 patients treated in second line with imatinib 800 mg qDay, 5 patients with sunitinib and 2 patients rechallenged in third line with imatinib 800 mg qDay.
Conclusion: Our patients presented mainly in the form of high-risk disease, Surgery is the mainstay treatment when GISTs are localized, Adjuvant therapy is used depending their risk of relapse. In the advanced disease, tyrosine kinase inhibitors have substantially improved the prognosis of GISTs.
Note: This abstract was not presented at the meeting.
Citation Format: Soufyane Ali Boukhalfa, Tah Filali. Gastrointestinal stromal tumor: Retrospective analysis of 44 cases of center of reference in eastern Algeria [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4232. doi:10.1158/1538-7445.AM2017-4232
Abstract 425: SMRT® Sequencing of full-length androgen receptor isoforms in prostate cancer reveals previously hidden drug resistant variants
Authors: Kohli Manish , Ho Yeung , Hillman David W. , Etten Jamie L. Van , Henzler Christine , Yang Rendong , Li Yingming , Tseng Elizabeth , Hon Ting , Clark Tyson A. , Wang Liguo , Silverstein Kevin , Wang Liewei , Dehm Scott M. 
Published: July 2017

Abstract
Prostate cancer is the most frequently diagnosed male cancer. For prostate cancer that has progressed to an advanced or metastatic stage, androgen deprivation therapy (ADT) is the standard of care. ADT inhibits activity of the androgen receptor (AR), a master regulator transcription factor in normal and cancerous prostate cells. The major limitation of ADT is the development of castration-resistant prostate cancer (CRPC), which is almost invariably due to transcriptional re-activation of the AR. One mechanism of AR transcriptional re-activation is expression of AR-V7, a truncated, constitutively active AR variant (AR-V) arising from alternative AR pre-mRNA splicing. Noteworthy, AR-V7 is being developed as a predictive biomarker of primary resistance to androgen receptor (AR)-targeted therapies in CRPC. Multiple additional AR-V species are expressed in clinical CRPC, but the extent to which these may be co-expressed with AR-V7 or predict resistance is not known. Here we utilized long read sequencing to identify and quantify AR isoforms expressed in CRPC. To unambiguously characterize all AR isoforms, we prepared Iso-Seq™ libraries via 3’ rapid amplification of cDNA ends (RACE) with RNA isolated from prostate cancer cell lines and xenograft tissues using a forward primer anchored in AR exon 1. 3’RACE reactions were subjected to single molecule, real-time (SMRT®) long-read sequencing with a Pacific Biosciences RSII System. Our work identified AR-V9 as a truncated isoform that is frequently co-expressed with AR-V7 in CRPC. Mechanistically, our work re-annotated AR-V7 and AR-V9 mRNAs, showing these two species shared a common 3’ terminal exon containing separate splice acceptor sites. Taking into account this new information, novel siRNAs and antibodies which could distinguish between AR-V7 and AR-V9 were designed, validated and used to measure the relative expression of these two AR isoforms in CRPC cells with a view to determining the potential of AR-V9 as a predictive biomarker of primary resistance to AR-targeted therapies.
Citation Format: Manish Kohli, Yeung Ho, David W. Hillman, Jamie L. Van Etten, Christine Henzler, Rendong Yang, Yingming Li, Elizabeth Tseng, Ting Hon, Tyson A. Clark, Liguo Wang, Kevin Silverstein, Liewei Wang, Scott M. Dehm. SMRT® Sequencing of full-length androgen receptor isoforms in prostate cancer reveals previously hidden drug resistant variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 425. doi:10.1158/1538-7445.AM2017-425
Abstract 4255: Associations of coffee consumption and caffeine intake with mammographic breast density
Authors: Yaghjyan Lusine , Colditz Graham , Rosner Bernard , Gasparova Aleksandra , Tamimi Rulla 
Published: July 2017

Abstract
Purpose: Previous studies suggest that coffee consumption and caffeine intake may be associated with reduced breast cancer risk which may result from stimulating effect of coffee on estrogen metabolism enzymes and subsequent changes in bioavailable estrogen. We investigated the association of coffee consumption and caffeine intake with mammographic density by woman’s menopausal status and, in postmenopausal women, by hormone therapy (HT).
Methods: This study included 4,130 cancer-free women within the Nurses’ Health Study and Nurses’ Health Study II cohorts. Percent breast density (PD), absolute dense and non-dense areas were measured from digitized film mammograms using a computer-assisted thresholding technique; all measures were square-root transformed for the analysis to improve normality. Diet was assessed with a food frequency questionnaire; average cumulative coffee/caffeine consumption was calculated using data available from all the questionnaires preceding the mammogram date. Information regarding breast cancer risk factors was obtained from baseline or biennial questionnaires closest to the mammogram date. We used generalized linear regression to quantify associations between exposures and breast density measures, adjusted for potential confounders. Associations were examined separately for regular coffee, decaffeinated coffee, total coffee, and energy-adjusted caffeine intake.
Results: In multivariable analyses, decaffeinated coffee was positively associated with PD in premenopausal women (2+ cups/day: β=0.23, p-trend=0.03). In postmenopausal women, decaffeinated and total coffee were inversely associated with PD (decaffeinated coffee 2+ cups/day: β=-0.24, p-trend=0.04; total coffee 4+ cups/day: β=-0.17). These associations appeared to be driven by the inverse associations of these exposures with absolute dense area. Among current HT users (n=980), regular coffee and caffeine intake were inversely associated with PD (regular coffee 4+ cups/day: β=-0.29, p-trend&lt;0.01; caffeine 4th vs. 1st quartile: β=-0.32, p-trend&lt;0.01). Among past users (n=430), decaffeinated coffee was inversely associated with PD (2+ cups/day β=-0.70, p-trend=0.02).
Conclusions: Our findings suggest that among current HT users, regular coffee and caffeine are inversely associated with mammographic percent breast density.
Citation Format: Lusine Yaghjyan, Graham Colditz, Bernard Rosner, Aleksandra Gasparova, Rulla Tamimi. Associations of coffee consumption and caffeine intake with mammographic breast density [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4255. doi:10.1158/1538-7445.AM2017-4255
Abstract 4282: Germline TP53 p.R337H mutations and Li-Fraumeni syndrome: A new variant form of the disease
Authors: Freycon Claire , Andrade Kelvin César De , Yacouba Amina , Formiga Maria Nirvana , Bittar Camila , Santiago Karina Miranda , Savage Sharon , Ashton-Prolla Patricia , Hainaut Pierre , Achatz Maria Isabel 
Published: July 2017

Abstract
The founder germline TP53 mutation, p.R337H, was detected in South and Southern Brazil in families with Li-Fraumeni Syndrome (LFS). The aim of this study was to estimate the burden and patterns of cancer in p.R337H carriers and other germline TP53 mutations. We analyzed data on 539 individuals from the LFS/LFL database from A.C. Camargo Cancer Center in São Paulo, Brazil and compared to International Agency for Research on Cancer (IARC) germline TP53 mutations database (R17). A total of 144 p.R337H carriers have developed 147 cancers (16.7% multiple primaries). The most frequent malignancies were soft tissue sarcoma (STS; 25.9%), breast cancer (24.5%) and adrenocortical carcinoma (ACC; 17.7%). Compared to IARC database, p.R337H carriers had a higher risk of ACC and STS, a lower risk of brain tumors and osteosarcomas (P&lt;0.01). Patients with p.R337H were at risk for developing thyroid and kidney cancers. The median age at diagnosis was 43 years in p.R337H carriers, 30 in other mutations carriers and 65 in the general population. The overall penetrance was similar in both groups until age 12 years. Penetrance was lower in p.R337H carriers (27% at 30 years, 55% at 60 years). The lifetime penetrance was significantly higher in females (79%) than in males (48%). p.R337H-associated disease resembles LFS until age 12, and then diverges, with differences in men and women and a predisposition to cancers that are not part of the LFS spectrum. These observations suggest that p.R337H could predispose to a variant form of LFS.
Citation Format: Claire Freycon, Kelvin César De Andrade, Amina Yacouba, Maria Nirvana Formiga, Camila Bittar, Karina Miranda Santiago, Sharon Savage, Patricia Ashton-Prolla, Pierre Hainaut, Maria Isabel Achatz. Germline TP53 p.R337H mutations and Li-Fraumeni syndrome: A new variant form of the disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4282. doi:10.1158/1538-7445.AM2017-4282
Abstract 4284: Gate keeping role for endometrial cancer about Lynch syndrome by surgeon
Authors: Kim Min Kyu , Kwon Min Jung , Yun Min Jeong 
Published: July 2017

Abstract
Background: It is well known that Lynch syndrome increases risk of endometrial and colorectal cancer. There is not much study about detecting Lynch syndrome patient fast among Korean population by gynecologic oncology surgeon. We undertook this study to investigate this.
Methods: A review of endometrial cancer patients who was counseled about Lynch syndrome in Department of Obstetrics and gynecology, Samsung Changwon Hospital by single surgeon was done. Clinical information was extracted from the medical record including age, family and personal history of cancer, immunohistochemistry(IHC), microsatellite instability test(MSI), and gene sequencing results. Risk management and posttest education after result were offered about risk reducing options and cascade testing for affected individual
Results: App patient was 16.There were two germline mutations (both MSH2) (c.23C&gt;T (p.Thr8Met), c.187delG (p.Val63*).Both were negative for MSH2 IHC, But no patient matched criteria of Amsterdam. Four variation of unknown significance (VUS) was found (Three MSH2 and One MLH1).Among those all were abnormal in IHC and there was only one Amsterdam criteria matched patient. There were two unstable MSI patients, one was MSH2 germline mutation and the other was MSH2 VUS. Median age was 57(41~76).Most cases were endometrioid type (11/16, 69 %).Seventy five percent were stage I(12/16).
Conclusion: Two MSH2 germline mutation patients among this population was found. Gynecologic oncology surgeon can be adapted to develop the ability to assess and evaluate genetic risk among endometrial cancer.
Citation Format: Min Kyu Kim, Min Jung Kwon, Min Jeong Yun. Gate keeping role for endometrial cancer about Lynch syndrome by surgeon [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4284. doi:10.1158/1538-7445.AM2017-4284