bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2193: Characterization of the aggresome targeted Q141K ABCG2/BCRP variant.
Authors: Basseville Agnes , Shukla Suneet , Tamaki Akina , Robey Robert , Ambudkar Suresh V. , Bates Susan E. 
Published: August 2014

Abstract
ABCG2 is a member of the G subfamily of human ABC transporters. It is an ATP-dependent protein and is a half-transporter that must dimerize for function. In various tumor cell lines, ABCG2 was involved in resistance to chemotherapy, by transporting numerous anticancer agents including tyrosine kinase inhibitors. Studies show the transporter has an important role in normal tissue protection, including the blood-brain and maternal-fetal barriers. It has also been observed that ABCG2 may play a protective role with respect to exposure to smoke or dietary carcinogens. A common variant in human ABCG2, the polymorphism Q141K, impairs expression and function, thereby reducing drug clearance and increasing the toxicity of chemotherapy and other substrate drugs. Although the activity of the Q141K variant is regularly described, biochemical data remain rare. Q141K has an impaired trafficking to cell surface compared to the WT protein and is sequestered in the aggresome. Here we characterized the Q141K and WT protein in human cells, studying post-translational modification, biochemistry, dimerization status, half-life, and endocytosis. Glycosylation and phosphorylation are equivalent, as is ATP binding and hydrolysis, and substrate binding using IAAP competition assays. Cell treatment with romidepsin, an HDAC inhibitor approved by FDA as an anticancer agent, restored the impaired variant trafficking, leading to an increase in drug efflux. The restoration of ABCG2 Q141K function has potential applications in oncology and in medicine, in improving normal tissue protection and drug elimination, as well as in cancer prevention since several carcinogens are substrates for ABCG2.
Citation Format: Agnes Basseville, Suneet Shukla, Akina Tamaki, Robert Robey, Suresh V. Ambudkar, Susan E. Bates. Characterization of the aggresome targeted Q141K ABCG2/BCRP variant. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2193. doi:10.1158/1538-7445.AM2013-2193
Abstract 2194: Tyrosyl DNA phosphodiesterase I is a prognostic factor and its inhibition synergizes response to topoisomerase poisons in malignant glioma.
Authors: Al-Keilani Maha , Agarwal Supreet , Alqudah Mohammad , Sibenaller Zita , Ryken Timothy , Assem Mahfoud 
Published: August 2014

Abstract
Malignant Glioma is the most common type of primary brain tumors in adults accounting for about 80% of all gliomas. Despite the advances in treatment and diagnosis, the prognosis of malignant glioma is still poor with a median survival less than a year for glioblastoma patients. Targeting DNA-repair mechanisms is a clinically relevant option for enhancing response to DNA-damaging anticancer agents. TDP1 has been recently discovered to be responsible for the repair of the irreversible DNA-topoisomerase I covalent complexes produced by topoisomerase I poisons. Other studies have suggested its role in the repair of the DNA damage produced by ionizing radiation and temozolomide. However, TDP1 relevance has not yet been studied in glioma. Thus the aims of this project are to identify the role of TDP1 in glioma aggressiveness and resistance to therapies. We hypothesize that high-grade gliomas possess higher TDP1 levels which are associated with lower survival and resistance to therapy.
Quantitative real-time PCR analysis of TDP1 in glioma biopsies revealed a negative prognostic effect of TDP1, where the level of TDP1 mRNA was inversely correlated with patient survival. Moreover, western blot showed an overexpression of TDP1 in glioma biopsies compared to normal tissues and increased expression with higher grades. TDP1 overexpression in U87 cell lines did not induce resistance to temozolomide, topotecan, etoposide or doxorubicin. This may be related to other downstream DNA repair enzymes that need to be also modulated to fully induce drug resistance. However, TDP1 inhibition using small molecules synergizes the cytotoxicity of topotecan, etoposide, and doxorubicin, confirming thus its critical role in response to several therapeutic agents.
As a conclusion, TDP1 is a new and promising prognostic factor and a modulator of therapy response in malignant glioma that may help in stratification of patients. Additionally, targeting TDP1 is a novel strategy that will widen the therapeutic options for malignant glioma where topoisomerase I and II poisons can be part of the gold standard therapy when used in combination with TDP1 inhibitors.
Citation Format: Maha Al-Keilani, Supreet Agarwal, Mohammad Alqudah, Zita Sibenaller, Timothy Ryken, Mahfoud Assem. Tyrosyl DNA phosphodiesterase I is a prognostic factor and its inhibition synergizes response to topoisomerase poisons in malignant glioma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2194. doi:10.1158/1538-7445.AM2013-2194
Abstract 2197: p53-dependent expression of the fluorouracil (5-FU) catabolic enzyme dihydropyrimidine dehydrogenase (DPD) in mouse liver.
Authors: Gokare Prashanth R. , Finnberg Niklas , Allen Joshua , Dai Jenny , El-Deiry Wafik 
Published: August 2014

Abstract
Fluorouracil (5-FU) a commonly used drug in the treatment of cancer is hampered by a short unpredictable plasma half-life, which complicates dose modulation to minimize toxicity and improve efficacy of 5-FU treatment. Strategies to improve on the unfavorable pharmacokinetic properties of 5-FU, currently under clinical trial, involve targeting of the catabolic enzyme dihydropyrmidine dehydrogenase (DPD).This requires understanding the mechanisms regulating the expression of DPD and the inducibility of 5-FU catabolism, which is inadequately investigated. By performing in silico analysis we were able to identify putative p53 binding sites in the proximity of the dihydropyrimidine dehydrogenase gene (DPYD) and confirm by chromatin immunoprecipitation (ChIP) that p53 increasingly locates to a binding site (about 1.8 ± 0.05 fold over untreated control) downstream of DPYD (P53DBS) following a single IV bolus of 5-FU (150 mg/kg bw) in mouse liver. Indeed, DPYD mRNA increased by 1.8 fold and protein by 1.8 fold (P&lt; 0.0005) respectively in a time- and p53-dependent manner in the liver of treated with 5-FU. Our ongoing studies are focused on assessing p53-dependent regulation of DPD-activity and the resulting change in 5-FU bioavailability We suggest that p53 can regulate an important step of pyrimidine-catabolism and targeting p53 in the context of 5-FU therapy of malignancies carrying p53 mutations may be another strategy to improve treatment efficacy.
Citation Format: Prashanth R. Gokare, Niklas Finnberg, Joshua Allen, Jenny Dai, Wafik El-Deiry. p53-dependent expression of the fluorouracil (5-FU) catabolic enzyme dihydropyrimidine dehydrogenase (DPD) in mouse liver. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2197. doi:10.1158/1538-7445.AM2013-2197
Abstract 2203: Characterization of raloxifene glucuronidation and the role of UGT genotypes on raloxifene metabolite profiles in vivo.
Authors: Sun Dongxiao , Jones Nathan R. , Andrea Manni , Lazarus Philip 
Published: August 2014

Abstract
Raloxifene is a 2nd-generation selective estrogen receptor modulator used for the prevention and treatment of osteoporosis and the prevention of breast cancer in postmenopausal women. Raloxifene is extensively metabolized by glucuronidation to form raloxifene-6-glucuronide (ral-6-Gluc) and raloxifene-4’-glucuronide (ral-4’-Gluc). The goal of the present study was to determine whether functional polymorphisms in active UGTs could play a role in altered raloxifene glucuronidation in vivo. Using homogenates from HEK293 UGT-overexpressing cell lines, raloxifene was shown to be glucuronidated primarily by the hepatic UGTs 1A1 and 1A9 and the extra-hepatic UGTs 1A8 and 1A10; no detectable raloxifene glucuronidation activity was found for UGT2B enzymes. Functional UGT1A1 transcriptional promoter genotypes were significantly (ptrend=0.005) associated with ral-6-Gluc formation in human liver microsomes, and, consistent with the decreased raloxifene glucuronidation activities observed in vitro with cell line over-expressing UGT1A8 variants, the UGT1A8*2 variant was significantly (p=0.023) correlated with total raloxifene glucuronide formation in human jejunum homogenates. While ral-4’-Gluc exhibited 1/100th the anti-estrogenic activity of raloxifene itself as measured by binding to the estrogen receptor, raloxifene glucuronides comprised ∼99% of the circulating raloxifene dose in raloxifene-treated subjects, with ral-4’-Gluc comprising ∼70% of raloxifene glucuronides. Plasma ral-6-Gluc (ptrend=0.0025), ral-4’-Gluc (ptrend=0.001), and total raloxifene glucuronides (ptrend=0.001) were increased in raloxifene-treated subjects who were predicted slow metabolizers [UGT1A8 (*1/*3)] vs intermediate metabolizers [UGT1A8 (*1/*1) or UGT1A8 (*1/*2)] vs fast metabolizers [UGT1A8 (*2/*2). These data suggest that raloxifene metabolism may be dependent on UGT1A8 genotype and that UGT1A8 genotype may play an important role in overall response to raloxifene.
Citation Format: Dongxiao Sun, Nathan R. Jones, Manni Andrea, Philip Lazarus. Characterization of raloxifene glucuronidation and the role of UGT genotypes on raloxifene metabolite profiles in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2203. doi:10.1158/1538-7445.AM2013-2203
Abstract 2209: Contribution of FKBP5 genetic variation to gemcitabine treatment and survival in pancreatic cancer.
Authors: Ellsworth Katarzyna A. , Eckloff Bruce W. , Li Liang , Moon Irene , Fridley Brooke L. , Jenkins Greg D. , Carlson Erin , Brisbin Abra , Abo Ryan , Bamlet William , Petersen Gloria , Wieben Eric D. , Wang Liewei 
Published: August 2014

Abstract
The FKBP5 gene encodes the FKBP51 immunophilin, a negative regulator of AKT. Variability in level of FKBP5 expression is a major factor contributing to variation in response to several classes of chemotherapeutic agents including gemcitabine, first line treatment for pancreatic cancer. Genetic variation of FKBP5 could influence its expression, function, and, ultimately, treatment response of pancreatic cancer. We set out to comprehensively study the role of genetic variation in FKBP5 identified by Next Generation DNA resequencing in response to gemcitabine treatment of pancreatic cancer by utilizing both tumor and germline DNA samples from 43 pancreatic cancer patients, including 19 paired tumor-normal samples. Genotype-phenotype association studies with overall survival (in tumor only) as well as with FKBP5 gene expression were performed using the same samples in which Next Generation DNA resequencing had been performed, followed by functional genomic studies of top selected single nucleotide polymorphisms (SNPs). In-depth resequencing identified 404 FKBP5 SNPs in both normal and tumor DNA patient samples. SNPs with the smallest p-values for association with FKBP5 survival or expression were subjected to functional genomic studies. Electromobility shift assay (EMSA) showed that the rs73748206 “T” allele altered DNA-protein binding patterns, consistent with a significantly increased reporter gene activity. The effect of rs73748206 was also confirmed by mRNA expression studies using lymphoblastoid cell lines (LCL) derived from the same patients from whom DNA used for resequencing had been obtained. This comprehensive FKBP5 resequencing study provides insight into the role of inheritance in variation in response to gemcitabine therapy of pancreatic cancer.
Citation Format: Katarzyna A. Ellsworth, Bruce W. Eckloff, Liang Li, Irene Moon, Brooke L. Fridley, Greg D. Jenkins, Erin Carlson, Abra Brisbin, Ryan Abo, William Bamlet, Gloria Petersen, Eric D. Wieben, Liewei Wang. Contribution of FKBP5 genetic variation to gemcitabine treatment and survival in pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2209. doi:10.1158/1538-7445.AM2013-2209
Abstract 221: Cancer stem cell-selected patient-derived xenograft models with sensitivity to FAK and Pan-PI3K/mTOR inhibitors .
Authors: Weaver David T. , Paterson Daniel , Padval Mahesh , Pachter Jonathan , Lewis Michael 
Published: August 2014

Abstract
In this study, Tumor-initiating (Creighton et al, 2009) and EMT gene expression signatures (Gupta et al., 2009, Taube et al, 2009) were used as classifiers. Tumors from 25 human triple negative breast cancer Patient-Derived Xenografts (PDX) were examined with Affymetrix U133Plus2 RNA arrays. Datasets were RMA normalized, and samples scored with the TI or EMT signature based on the Pearson Correlation Coefficient of a vector of mean-centered expression values of signature genes and a vector of indicators for signature genes such that 1 (up-regulated, correlated) genes and -1 (down-regulated, anti-correlated) genes formed a TI or EMT score. A high EMT score is also representative of mesenchymal tumors. Several of the triple negative breast cancer PDX models had both high TI and high EMT scores, indicated by p&lt;0.05 of a one-sided Pearson Correlation Coefficient test. Two of the PDX models with high positive TI and EMT scores, 4664 and 3887, were evaluated for sensitivity to a FAK inhibitor (VS-4718), a pan-PI3K/mTOR inhibitor (VS-5584), and chemotherapy (docetaxel). FAK and PI3K/mTOR are implicated in tumorigenesis, including tumor initiation, growth, angiogenesis and metastasis. Both 4664 and 3887 tumors were N-cadherin-positive (mesenchymal), and strongly positive for CD44 (TI marker) by immunohistochemistry. These tumors were also weakly positive for E-cadherin and highly heterogeneous for pan-cytokeratin, two epithelial marker patterns suggesting a mesenchymal phenotype. Whereas 3887 was Notch3-positive, 4664 was Notch3-negative. VS-4718-treated 4664 and 3887 models showed diminished tumor growth over 21 days compared with vehicle-treated animals. VS-4718-treated animal tumors showed decreased FAK autophosphorylation (pY397) by immunohistochemistry. Likewise, the VS-5584-treated 4664 and 3887 animals blocked tumor growth over 21 days. In these models, the PI3K/mTOR pathways activate downstream signaling phosphorylation of pS6 pSer240/244, p4EBP1 pThr70, and pPRAS40 pThr246. In the VS-5584-treated 3887 tumors, pS6 pSer240/244 levels were significantly diminished relative to vehicle- and docetaxel-treated tumors. As predicted by TI and EMT gene expression indicators, both models were docetaxel-resistant.
These findings and our previous work on these agents for the inhibition of CSCs support the clinical development of the FAK and the pan-PI3K/mTOR inhibitors to target CSCs for treatment of breast, mesothelioma, ovarian and other cancers.
Citation Format: David T. Weaver, Daniel Paterson, Mahesh Padval, Jonathan Pachter, Michael Lewis. Cancer stem cell-selected patient-derived xenograft models with sensitivity to FAK and Pan-PI3K/mTOR inhibitors . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 221. doi:10.1158/1538-7445.AM2013-221
Abstract 2218: Systematic identification of combinatorial markers of drug sensitivity in cancer cell lines.
Authors: Tabchy Adel , Eltonsy Nevine , Mills Gordon B. 
Published: August 2014

Abstract
Purpose: Translating the cancer genome into highly efficacious targets to guide rational therapeutic combinations is a major emerging challenge.
Methods: We established an in silico bioinformatic platform in parallel with a high throughput screening platform evaluating the pharmacological activity of 37 novel targeted agents across 669 highly characterized cell lines representing the genetic and tumor-type heterogeneity of human cancers. Analysis of large scale pharmacological data coupled to massive sequencing data on cell lines was performed to systematically identify combinatorial biomarkers of sensitivity and resistance to cancer therapeutics. Genomic predictors discovered in a 141 cell line training set were validated in an independent non-overlapping test set of 359 cell lines screened on 14 of the compounds.
Results: We demonstrate combinations of genomic events that are co-occurring or mutually exclusive and act as co-drivers in various tumors, representing potential targets for combinatorial intervention in cancer. We find that multiple cooperating genomic events predict response to drug intervention independent of tumor lineage.
Conclusions: The coupling of scalable in silico and functional high throughput cancer cell line platforms for the identification of co-events in cancer delivers rational combinatorial targets for synthetic lethal approaches with a high potential to prevent the emergence of resistance.
Citation Format: Adel Tabchy, Nevine Eltonsy, Gordon B. Mills. Systematic identification of combinatorial markers of drug sensitivity in cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2218. doi:10.1158/1538-7445.AM2013-2218
Abstract 2220: Toxicities and antitumor efficacy of tumor-targeted AuNRs in mouse model.
Authors: Peng Xianghong , Mackey Megan , Austin Lauren , Oyelere Adegboyega , Chen Georgia , Huang Xiaohua , El-Sayed Mostafa A. , Shin Dong M. 
Published: August 2014

Abstract
Near infrared (NIR)-absorbing gold nanorods (AuNRs) can be systemically or locally delivered into tumors and subsequent irradiated by nonionizing NIR laser light, and creates heat to destroy cancer cells, this technique has been demonstrated to dramatically improve the efficacy of conventional plasmonic photothermal therapy (PPTT) without contrast agents or with molecular agents of dye molecules. In the present study, we have synthesized new HNSCP-1-conjugated AuNRs for targeting the squamous cell carcinoma of the head and neck (SCCHN), and studied the biodistribution and associated toxicity of such SCCHN-targeted AuNRs in a BALB/c mouse model and SCCHN xenograft models. Our results showed that the conjugation of HNSCP peptide to AuNRs decreased the blood circulation time compared with that of the PEG-coated AuNRs (22nm). The PEG coated-AuNRs (10,000/AuNR, 22nm) were mainly found in the liver(57%) and spleen (38%), while about 92% of the injected HNSCP-1 peptide conjugated-AuNRs (10,000/AuNR) accumulated in the liver (72 hours after AuNRs injection). The tumor-targeted AuNRs increased the accumulation of AuNRs in the tumor mass compared with that of non-targeted AuNRs. The long-term uptake fate of the AuNRs in a mouse model (15 months after injection of 3.6 μg AuNRs) has been studied, and no remarkable toxicities have been observed. Our results showed that the PPTT treatments (single dose of intratumoral injection of 0.5ug HNSCP-1-AuNRs, followed by 2 min of 0.9-1.1 W/cm2 NIR laser exposure) could inhibit the tumor growth in nude mice bearing human SCCHN Tu212 xenograft tumor model. Conclusions: HNSCP-1-AuNRs may selectively accumulate in the tumor mass and inhibit the tumor growth via the PPTT without observed toxicities.
This research was supported by NCI U01 CA 151802.
Citation Format: Xianghong Peng, Megan Mackey, Lauren Austin, Adegboyega Oyelere, Georgia Chen, Xiaohua Huang, Mostafa A. El-Sayed, Dong M. Shin. Toxicities and antitumor efficacy of tumor-targeted AuNRs in mouse model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2220. doi:10.1158/1538-7445.AM2013-2220
Abstract 2221: Enhanced SH3:linker interaction allosterically sensitizes Abl kinases to small molecule inhibitors.
Authors: Panjarian Shoghag B. , Iacob Roxana , Shugui Chen , Wales Thomas , Engen John R. , Smithgall Thomas E. 
Published: August 2014

Abstract
Bcr-Abl is the oncogenic protein-tyrosine kinase responsible for the pathogenesis of chronic myelogenous leukemia (CML). Clinical management of CML has been revolutionized by imatinib, a selective ATP-competitive inhibitor of Bcr-Abl kinase activity. Imatinib selectivity is due in part to its ability to recognize and stabilize the inactive conformation of the kinase domain. This conformation is stabilized by intramolecular binding of the SH3 domain to the
SH2-kinase linker, which in turn packs against the back of the kinase domain. Imatinib resistance can be caused by point mutations that either affect drug binding directly (e.g., through mutation of the gatekeeper position, Thr315) or that allosterically disturb the downregulated kinase domain conformation (e.g., through mutation or phosphorylation of the SH3 domain). These observations suggest that strengthening the regulatory SH3:linker interaction present in
Bcr-Abl may stabilize a downregulated kinase domain conformation, thus sensitizing the kinase domain to inhibitor action. To explore this possibility, we created a series of modified c-Abl and Bcr-Abl proteins with enhanced
SH3-linker interactions. By systematically increasing the proline content of the linker, we identified high-affinity linkers that stabilized intramolecular
SH3 binding without disturbing the overall regulation of the kinase core.
Enhanced SH3:linker interaction completely reversed c-Abl core activation by a
C-lobe myristate binding pocket mutation, and substantially reduced activation by mutations in the ATP binding site (T315I) as well as the SH2:C-lobe interface (Y158D). Remarkably, enhanced SH3:linker interaction dramatically sensitized Bcr-Abl not only to imatinib but also to the myristic acid binding pocket inhibitor, GNF-2. These effects were observed in the context of both wild-type and imatinib-resistant forms of Bcr-Abl. Hydrogen exchange mass spectrometry of recombinant Abl core proteins with high-affinity linkers revealed dynamic coupling between the SH3:linker interface, the GNF-2 binding site in the C-lobe myristate binding pocket, and the active site.
Taken together, these studies provide strong evidence that regulatory
SH3:linker interaction is retained in the context of Bcr-Abl, and supports the idea that small molecules enhancing natural regulatory interaction at the
SH3:linker interface may have utility as chemical sensitizers of Bcr-Abl drug action in the kinase domain.
Citation Format: Shoghag B. Panjarian, Roxana Iacob, Chen Shugui, Thomas Wales, John R. Engen, Thomas E. Smithgall. Enhanced SH3:linker interaction allosterically sensitizes Abl kinases to small molecule inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2221. doi:10.1158/1538-7445.AM2013-2221