bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3663: Discovery of sulfonamide-piperidinones as potent inhibitors of the MDM2-p53 protein-protein interaction
Authors: Li Zhihong , Fu Jiasheng , Rew Yosup , Gribble Michael W. , Canon Jude , Chen Ada , Eksterowicz John , Huang Xin , Jin Lixia , Lo Mei-Chu , McGee Lawrence R. , Osgood Tao , Saiki Anne Y. , Shaffer Paul , Sun Daqing , Wortman Sarah , Ye Qiuping , Yu Dongyin , Zhao Xiaoning , Zhou Jing , Oliner Jonathan D. , Olson Steve H. , Medina Julio C. 
Published: August 2015

Abstract
The p53 tumor suppressor is controlled by MDM2, which binds p53 and negatively regulates its transcriptional activity and stability. Many tumors overproduce MDM2 to impair p53 function. Therefore, restoration of p53 activity by inhibiting p53-MDM2 binding represents an attractive, novel approach to cancer therapy. We previously reported the discovery of AM-8553, a potent and selective piperidinone inhibitor of the MDM2-p53 interaction (Rew et al. J. Med. Chem. 2012, 55, 4936). We report here continued optimization of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface that led to the discovery of a variety of extremely potent sulfonamides such as 14 with an IC50 of 5.3 nM in the cell proliferation assay. The compound 14 interacts specifically with the p53-binding pocket of MDM2 and releases the p53 protein from negative control. Treatment of cancer cells expressing wild-type p53 with sulfonamide 14 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest and apoptosis. The compound 14 showed excellent efficacy and caused tumor regression in the SJSA-1 tumor xenograft model.
Citation Format: Zhihong Li, Jiasheng Fu, Yosup Rew, Michael W. Gribble, Jude Canon, Ada Chen, John Eksterowicz, Xin Huang, Lixia Jin, Mei-Chu Lo, Lawrence R. McGee, Tao Osgood, Anne Y. Saiki, Paul Shaffer, Daqing Sun, Sarah Wortman, Qiuping Ye, Dongyin Yu, Xiaoning Zhao, Jing Zhou, Jonathan D. Oliner, Steve H. Olson, Julio C. Medina. Discovery of sulfonamide-piperidinones as potent inhibitors of the MDM2-p53 protein-protein interaction. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3663. doi:10.1158/1538-7445.AM2015-3663
Abstract 3695: Discovery of probes to evaluate the disruption of the protein-protein interactions mediated by RPA70N
Authors: Waterson Alex G. , Kennedy Phillip , Patrone James D. , Pelz Nicholas F. , Frank Andreas O. , Vangamudi Bhavatarini , Camper DeMarco V. , Souza-Fagundes Elaine M. , Feldkamp Michael D. , Olejniczak Edward T. , Rossanese Olivia W. , Chazin Walter J. , Fesik Stephen W. 
Published: August 2015

Abstract
Replication Protein A (RPA) is a major regulator of checkpoint activation and enhanced DNA repair in cancer cells. In response to genotoxic stress, the RPA complex binds to and protects ssDNA while serving as a scaffold to recruit critical checkpoint and DNA-damage response proteins through the N-terminal region of the 70 kDa subunit of RPA (RPA70N). RNAi against RPA has shown an expected toxicity against cancer cell lines. However, specific disruption of the RPA protein-protein interactions mediated by the RPA70N domain has the potential to produce selective killing of cancer cells without of cytotoxicity due to interference with its ssDNA-binding function. In order to accurately examine the therapeutic relevance of the inhibition of RPA function, we have sought to discover potent probe molecules that disrupt the interactions between RPA70N and its binding partners.
Here we describe the discovery of molecules to probe RPA function using complementary fragment-based and traditional high-throughput screening techniques. SAR studies and structure-based design concepts used to optimize the lead series of interest will be discussed along with the biochemical and cellular results obtained with the compounds.
Citation Format: Alex G. Waterson, Phillip Kennedy, James D. Patrone, Nicholas F. Pelz, Andreas O. Frank, Bhavatarini Vangamudi, DeMarco V. Camper, Elaine M. Souza-Fagundes, Michael D. Feldkamp, Edward T. Olejniczak, Olivia W. Rossanese, Walter J. Chazin, Stephen W. Fesik. Discovery of probes to evaluate the disruption of the protein-protein interactions mediated by RPA70N. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3695. doi:10.1158/1538-7445.AM2015-3695
Abstract 3706: Risk of bladder and kidney cancers in end-stage renal disease patients: a nationwide, population-based study in Taiwan
Authors: Kao Wei-Tang , Shen Cheng-Huang , Kiu Kee-Thai , Chen Hsin-An , Wu Chia-Chang , Wang Yuan-Hung 
Published: August 2015

Abstract
Chronic kidney disease (CKD) was the tenth leading cause of death in Taiwan. as the fifth stage of progressive CKD. Various therapeutic modalities including hemodialysis (HD),peritoneal dialysis (PD) and renal transplantation (RT) modify the risks of systemic chronic diseases in end-stage renal disease (ESRD) patients remains unclear.
A total of 18,081 newly diagnosed ESRD patients and 54,243 controls matched for age, gender and index date were recruited from the National Health Insurance Research Database in Taiwan. The ESRD status was confirmed by the registry of catastrophic illness. The incidence of cancer was identified through cross-referencing with the National Cancer Registry Database. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by a Cox proportional hazards model. Kaplan-Meier method were used for all analyses. Significant higher incidence rate ratios (IRRs) of bladder cancer of 7.0, 9.5 and 14.4 were found for ESRD patients undergoing HD, PD and RT, respectively. The IRRs of kidney cancer also represent a similar risk pattern. We observed that significant bladder cancer risks were observed among ESRD patients undergoing HD (HR = 10.0), PD (HR = 12.8) and RT (17.7) after the adjustment for age, gender and co-morbidities. In addition, significant kidney cancer risks of 11.2, 17.1 and 33.7 were also found for ESRD patients undergoing HD, PD and RT, respectively. In conclusion, different therapeutic modalities could modify the risks of bladder and kidney cancers in ESRD patients in Taiwan.
Citation Format: Wei-Tang Kao, Cheng-Huang Shen, Kee-Thai Kiu, Hsin-An Chen, Chia-Chang Wu, Yuan-Hung Wang. Risk of bladder and kidney cancers in end-stage renal disease patients: a nationwide, population-based study in Taiwan. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3706. doi:10.1158/1538-7445.AM2015-3706
Abstract 3713: Second malignant neoplasms after non-CNS embryonal tumors in North America
Authors: Zong Xuchen , Pole Jason D. , Grundy Paul , Mahmud Salaheddin M. , Parker Louise , Hung Rayjean J. 
Published: August 2015

Abstract
Background: Childhood cancer survivors are known to face an increased risk of adverse medical conditions related to the initial disease or cancer treatment; however, few studies have quantified the risk of second malignant neoplasms (SMNs) among survivors of childhood non-CNS embryonal cancer due to its rarity. In this study, we combined data from the U.S. and Canada to investigate the risk of SMNs.
Methods: Data from 13,107 survivors of childhood non-CNS embryonal tumors reported to the Surveillance Epidemiology and End Results (SEER) program in the U.S. and 8 population-based cancer registries in Canada (between 1973 to 2010) were analyzed. We calculated standardized incidence ratios (SIRs) for all types of second primaries by type of first primary, age at first cancer diagnosis, and follow-up duration. Expected numbers of SMNs were obtained by applying age-, sex-, calendar year-, and registry-specific cancer incidence rates to person-years contributed by these cancer survivors.
Results: One hundred and ninety SMNs were reported over 134,548 person-years of follow-up, with bone and joint cancer and leukemia being the most common SMNs (19% and 16% respectively). The SIR for all SMNs combined was 6.4 (95% CI: 5.53-7.35). Most site-specific SIRs were significantly increased, ranging from 36.4 (95% CI: 25.5-49.2) for bone and joint cancer, to 3.1 (95% CI: 1.54-5.2) for brain tumor. Among all the survivors, those who survived rhabdomyosarcoma carried the greatest risk of SMN development with SIR of 11.5 (95% CI: 8.7-14.6). Bone and joint tumors were mostly seen among retinoblastoma survivors, reflecting a markedly risk of 139.3 (95% CI: 85-207). When stratified by follow-up period, we observed that the risk patterns varied by SMN site. For example, the risk for a second malignancy in the thyroid remained significantly increased even after 20 years of follow-up, whereas the elevated risk of secondary leukemia persisted for 10 years but decreased rapidly afterwards. Details of stratified analyses by first primary tumor site, age at first diagnosis, and follow-up duration will be presented.
Conclusion: Survivors of childhood non-CNS embryonal tumors have increased risks of developing SMNs compared to the general population. Increased surveillance may explain the elevated risks within the first few years of the initial diagnosis, but treatment effects and shared etiology most likely account for the excess risk later in life.
Citation Format: Xuchen Zong, Jason D. Pole, Paul Grundy, Salaheddin M. Mahmud, Louise Parker, Rayjean J. Hung. Second malignant neoplasms after non-CNS embryonal tumors in North America. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3713. doi:10.1158/1538-7445.AM2015-3713
Abstract 3720: Diabetes and prostate cancer (CaP): Clinical characteristics and disparity in outcomes
Authors: Spangler Elaine , Zeigler-Johnson Charnita , Mitchell Jonathan , Rebbeck Timothy 
Published: August 2015

Abstract
Introduction: Disparities in prostate cancer (CaP) outcomes are poorly understood, but are likely caused by multiple factors. The presence of comorbidities may contribute to disparate outcomes in at least two ways: by altering the biological course of disease, and by influencing overall survival probabilities that impact treatment decisions. Diabetes has been associated with CaP in a variety of settings, and there is evidence that AA men suffer from diabetes at a higher rate than men of other races. We examined whether presence of diabetes is related to prostate cancer recurrence measured by post-prostatectomy biochemical (PSA) failure (BF).
Materials and methods: A prospective cohort of 554 European Americans (EA) and 184 African American (AA) CaP cases from the University of Pennsylvania were studied. We performed survival analysis for BF to evaluate the effect of diabetes on using Cox proportional hazards models adjusting for age, race, obesity, and Kattan score. Median post-prostatectomy follow-up was 40 months.
Results: Prevalence of diabetes was 6.3% overall (12% in AA and 5% in EA, p&lt;0.0001). AA men were more likely to be obese then EA men (33% vs. 19%, p = 0.001). During post-prostatectomy follow-up, 52 (28%) AA and 187 (33%) EA men experienced BF; 47 (9%) diabetic men and 691 (5%) non-diabetic men experienced BF. Diabetic men were twice as likely to experience BF as men without diabetes (HR = 2.2, 95% CI: 1.26-3.92). Diabetes had a significant effect in both EA (HR = 2.1, 95% CI: 1.02-4.37) and AA (HR = 3.4, 95% CI: 1.16-10.0).
Conclusions. Being diabetic at time of CaP diagnosis increased the risk of prostate cancer recurrence, even after accounting for obesity and age. This effect was significant for both AA and EA, but the effect of diabetes appeared to be greater in AA. Diabetes may an important predictor of post-prostatectomy CaP outcomes.
Citation Format: Elaine Spangler, Charnita Zeigler-Johnson, Jonathan Mitchell, Timothy Rebbeck. Diabetes and prostate cancer (CaP): Clinical characteristics and disparity in outcomes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3720. doi:10.1158/1538-7445.AM2015-3720
Abstract 3732: Detecting germline PTEN mutations among at-risk cancer patients: An age and gender-specific cost effectiveness analysis
Authors: Ngeow Joanne , Liu Chang , Zhou Ke , Frick Kevin , Matchar David B. , Eng Charis 
Published: August 2015

Abstract
Introduction
Cowden syndrome (CS) is an autosomal dominant disorder characterized by benign and malignant tumours. One-quarter of patients diagnosed with CS have pathogenic germline PTEN mutations, which increase risks of breast, thyroid, uterine, renal and other cancers. PTEN testing and regular, intensive cancer surveillance allow for early detection and treatment of these cancers for mutation positive patients and their relatives. Individual CS-related features, however, occur commonly in the general population, making it challenging for clinicians to identify CS-like patients to offer PTEN testing.
Methods:
We calculated the cost per mutation detected and analyzed the cost-effectiveness of performing selected PTEN testing among CS-like patients using a semi-quantitative score [PTEN-Cleveland Clinic (CC) score] compared with existing diagnostic criteria. In our model, first-degree relatives of the patients with detected PTEN mutations are offered PTEN testing. All individuals with detected PTEN mutations receive cancer surveillance.
Findings:
CC score at a threshold of 15 (CC15) allows costs ranging from $3,720 to 4,573 to detect one PTEN mutation, which is the lowest among different strategies tested. At a cost-effectiveness threshold of $100,000/Quality Adjusted Life Year (QALY), CC15 is the optimal strategy for female patients older than 50 years while CC10 is the optimal strategy for female patients younger than 50 years old and male patients of all ages. These results are robust in one-way sensitivity analyses. In probabilistic sensitivity analysis, CC10 and CC15 are the optimal strategies in 73% and 21% of the simulations respectively at a willingness to pay $100,000/QALY.
Conclusion:
CC score as a clinical risk calculator is a cost-effective pre-screening method to identify CS-like patients for PTEN germline testing.
Citation Format: Joanne Ngeow, Chang Liu, Ke Zhou, Kevin Frick, David B. Matchar, Charis Eng. Detecting germline PTEN mutations among at-risk cancer patients: An age and gender-specific cost effectiveness analysis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3732. doi:10.1158/1538-7445.AM2015-3732
Abstract 3736: Assessment of tobacco use within 30 days increases referral for cessation support
Authors: Cooper Samuel Lewis , Hoover Katherine , Garrett-Mayer Elizabeth , Cummings Kenneth Michael , Carpenter Matthew J. , Crowley Kelly , Marshall David T. , Warren Graham W. 
Published: August 2015

Abstract
Background: Cancer patients who self-report tobacco use within the past 30 days are at high risk for relapse and benefit from cessation support. However, there is little data on whether assessment of tobacco use within the past 30 days increases referral rates to a cessation program across cancer disease sites.
Methods: Structured tobacco assessments were administered to 426 new adult patients in a Radiation Oncology clinic at a single institution. Multiple logistic regression was used to assess if clinical aspects of cancer diagnosis (age, gender, race, disease site [head/neck or thoracic {HNT} vs. other], stage [advanced vs. early], and purpose [curative vs. palliative]) affected cessation service referral rates identified using assessment of tobacco use within the past 30 days.
Results: Complete medical and tobacco use data were compiled for 387 adult cancer patients (91%). Of these, 147 (38%) were women, 259 (67%) were Caucasian, 115 (30%) were black, 177 (46%) were diagnosed with HNT cancer, and 289 (74%) were being considered for curative cancer treatment. Ever smoking was reported in 273 patients (71%), and 83 (21%) reported current smoking everyday or some days. In 180 former smokers who reported time since last cigarette, 21 (12%) reported smoking within with past 30 days and 9 (7%) of these reported smoking within the past day or week. In 21 patients who were identified for cessation support through evaluation of smoking within the past 30 days, 6 (29%) were women, 7 (33%) were black, 15 (71%) were being considered for curative treatment, and 15 (71%) were diagnosed with a HNT cancer. Multiple logistic regression identified that younger age (10 yr OR 2.41, 95% CI 1.47 - 3.98) and HNT cancer (OR 8.13, 95% CI 2.2-30.3) but not gender, race, stage, and purpose were significantly associated with referral based on assessment of tobacco use within the past 30 days. Identification of smoking within the past 30 days increased cessation referrals by 25% from 83 to 114 patients.
Conclusions: Assessment of tobacco use within the past 30 days increased referrals to a smoking cessation program from a Radiation Oncology clinic using a standardized tobacco assessment. In clinical trials and practice, including this question has particular benefit for younger patients and patients with head/neck or thoracic tumors.
Citation Format: Samuel Lewis Cooper, Katherine Hoover, Elizabeth Garrett-Mayer, Kenneth Michael Cummings, Matthew J. Carpenter, Kelly Crowley, David T. Marshall, Graham W. Warren. Assessment of tobacco use within 30 days increases referral for cessation support. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3736. doi:10.1158/1538-7445.AM2015-3736
Abstract 3747: Identification of NSCLC biomarkers underlying quantifiable drug-induced clonal fitness
Authors: Jameson Katherine L. , Frick Peter L. , Tyson Darren R. , Yankeelov Thomas E. , Quaranta Vito 
Published: August 2015

Abstract
Lung cancer accounts for nearly 20% of all cancer-related deaths worldwide. Subsets of non-small-cell lung cancer (NSCLC; &gt;80% of all lung cancers) harboring activating epidermal growth factor receptor (EGFR) mutations are highly sensitive to erlotinib, a small-molecule EGFR tyrosine kinase inhibitor. However, clinical responses to erlotinib are variable and limited in duration as all tumors eventually relapse. Clonal heterogeneity is thought to be a major cause of relapse, but it has been difficult to quantify in drug-sensitive cancer cell populations. To overcome this obstacle, we quantify clonal fitness via live-cell imaging as a drug-induced proliferation (DIP) rate that incorporates cell division, death, and quiescence into a single metric. This fitness rate varies across cell types from positive (division prevails) to negative (death prevails) and, unlike traditional IC50 measurements, can effectively discriminate intricate degrees of drug sensitivity. Moreover, in monoclonal sublines isolated naïve-to-drug from NSCLC parental cell lines, erlotinib-treated DIP rates calculated in vitro predict the long-term growth rates (250+ days) of in vivo tumor xenografts. Using global proteomics across a panel of monoclonal sublines, we have characterized networks of biomarkers that act as molecular determinants of phenotypic drug fitness. We have identified unsuspected molecular correlates in the EGFR and AKT pathways and are currently investigating whether they can act as lead targets for small molecule inhibition in combination therapies. Our data indicate that a multi-scale systems approach integrating molecular subtyping with quantifiable clonal fitness can yield insights into clonal heterogeneity and lead to novel strategies to overcome tumor relapse.
Note: This abstract was not presented at the meeting.
Citation Format: Katherine L. Jameson, Peter L. Frick, Darren R. Tyson, Thomas E. Yankeelov, Vito Quaranta. Identification of NSCLC biomarkers underlying quantifiable drug-induced clonal fitness. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3747. doi:10.1158/1538-7445.AM2015-3747
Abstract 3762: The landscape of therapeutic targetable fusions
Authors: Yoshihara Kosuke , Wang Qianghu , Torres-Garcia Wandaliz , Zheng Siyuan , Vegesna Rahulsimham , Kim Hoon , Verhaak Roel GW 
Published: August 2015

Abstract
Gene fusions are an important class of cancer-contributing somatic alteration, and have an important significance as a tumor-initiating event and as a molecular therapeutic target for specific tumors. We analyzed RNA sequencing, DNA copy number and gene mutation data from 4,366 primary tumor samples to comprehensively detect fusion events in 13 tumor types. To reduce the number of false-positive predictions, we developed strict quality criteria on the basis of gene homology, transcript allele fraction (TAF), and partner gene variety. In addition, we used fusions detected in RNAseq data from 364 normal tissue samples to extract tumor-specific fusions. In total, 7,887 fusion transcripts with high confidence were detected across 13 tumor types. Our fusion prediction was validated by supporting evidence for a genomic rearrangement for 78 of 79 fusions in 48 glioma samples where whole genome sequencing data was available. Fusion transcript frequency was positively correlated with the levels of genomic instability in cancers, whereas tumor samples harboring fusions contained statistically significantly fewer driver gene mutations. We identified 221 fusion transcripts involving a tumor suppressor gene and these were wildtype in majority (98.2%), suggesting the fusion has a disruptive effect and a role in tumorigenesis. We identified at least one in-frame protein kinase fusion in 324 of 4,366 samples (7.4%). Potentially therapeutic targetable kinase fusions such as ALK, ROS, RET, NTRK, and FGFR gene families were detected in thyroid carcinoma (8.7%), glioblastoma (4.4%), bladder carcinoma (3.3%), lung squamous cell carcinoma (2.3%), lung adenocarcinoma (1.6%), lower grade glioma (1.5%), and head and neck cancer (1.0%), suggesting a potential for application of kinase inhibitors for multiple tumor types. In-frame fusion transcripts involving histone methyltransferase or histone demethylase genes, which may also be considered as therapeutic targets, were detected in 111 samples (2.5%). In summary, the landscape of transcript fusions detected across a large number of tumor samples revealed fusion events with clinical relevance that have not been previously recognized. Our findings support the concept of basket clinical trials where patients are matched with experimental therapies based on their genomic profile rather than the tissue where the tumor originated.
Citation Format: Kosuke Yoshihara, Qianghu Wang, Wandaliz Torres-Garcia, Siyuan Zheng, Rahulsimham Vegesna, Hoon Kim, Roel GW Verhaak. The landscape of therapeutic targetable fusions. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3762. doi:10.1158/1538-7445.AM2015-3762