bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5487: Functional analysis of rare dihydropyrimidine dehydrogenase variants relevant to 5-fluorouracil toxicity
Authors: Shrestha Shikshya , Offer Steve , Diasio Robert B. 
Published: August 2015

Abstract
5-Fluorouracil (5-FU) is a cornerstone drug for the treatment of several aggressive tumors; however, adverse 5-FU toxicity contributes to approximately 1,300 deaths annually in the U.S. While three genetic variations in dihydropyrimidine dehydrogenase (DPD; DPYD gene) are well-established predictors of toxicity (i.e., *2A, I560S, D949V), the contributions of additional reported missense DPYD variants (&gt;130) have not been adequately evaluated in clinical studies. Our lab has previously developed methods to study DPYD variants for potential clinical relevance to 5-FU toxicity using in vitro and cellular approaches (see Offer et al. Cancer Research 2013 & 2014). In the current study, we measured the in vitro enzyme activity of 47 uncharacterized missense variants that have been previously reported in dbSNP and NHLBI ESP databases. Additionally, we assessed the impact of these variants on 5-FU sensitivity in multiple transgenic human cellular models using real-time cellular analysis. Approximately one-third of the studied variants showed significantly reduced enzyme activity compared to wild type. Of the DPD-deficient variants identified in this study, 8 were profoundly deficient (&lt;12.5% of “wildtype” activity), with enzyme activities similar to *2A. Two deficient variants showed modest reductions in enzyme activity (12.5-25% activity), similar to I560S. The remaining 5 deleterious variants exhibited mild deficiency (&gt;25% activity, but significantly lower than “wildtype”), similar to D949V. Cellular sensitivity to 5-FU for cells expressing these variants paralleled the in vitro enzyme activity results, with deleterious variants showing reduced tolerance to 5-FU relative to cells transgenic for wildtype DPD. These trends were observed in multiple cell lines derived from various tissues and tumor types. Overall, our results add to the growing database of deleterious DPYD variations. Many of these variants have been observed primarily in non-Caucasian racial groups, consistent with our previous reports. These data suggest that the deleterious variants classified in this study may be important predictors of 5-FU toxicity, particularly in individuals of non-Caucasian ancestry. Additionally, these data suggest that genetic testing for rare variants may improve the success of predictive tests for 5-FU toxicity. Finally, this study suggests that in vitro and cellular models may be important pharmacogenomic methods to rapidly characterize variants of potential relevance in additional drug-gene pathways.
Citation Format: Shikshya Shrestha, Steve Offer, Robert B. Diasio. Functional analysis of rare dihydropyrimidine dehydrogenase variants relevant to 5-fluorouracil toxicity. [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 5487. doi:10.1158/1538-7445.AM2015-5487
Abstract 5496: Effect of BTK inhibitors on differentiation of human monocyte-derived dendritic cells
Authors: Sun Zhijian , Zhou Dongping , Luo Lusong 
Published: August 2015

Abstract
Dendritic cells (DCs) are primary antigen-presenting cells (APCs), which process tumor antigen and present it on the cell surface to the T cells of the adaptive immune system. However, immature DCs facilitate tolerance toward cancer cells. Bruton's tyrosine kinase (BTK) is highly expressed in B cells, monocytes, macrophages and dendritic cells and plays crucial roles in differentiation and activation of myeloid cells. Dendritic cells in Btk−/− mice were reported to have more mature phenotype and stronger in vitro and in vivo T cell stimulatory ability than wild-type DCs. However, the functions of BTK in human DC differencation and maturation were not well characterized. In this study, we revealed the effect of BTK inhibition with ibrutinib, an FDA approved drug for chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), in human monocyte derived dendritic cells (moDCs). We show that BTK was expressed in monocytes and moDCs. BTK activity was regulated during moDCs differencation and BTK inhibitors blocked GM-CSF/IL4 induced activation of BTK. LPS instead of CD40L treatment increased BTK phosphorylation. It was noted that the percentage of CD11c+ MHC IIlow subsets, which represented the immature DCs, was significantly reduced upon ibrutinib treatment during moDC differencation. Meanwhile, ibrutinib dose-dependently increased proportion of CD11c+ MHC IIhigh cells, which represent more mature DCs. We also tested BGB-3111, a more selective BTK inhibitor without ITK, TXK, EGFR, HER2 and JAK3 activity in the same assay. We observed increased MHC II level during differentiation of human moDCs with BGB-3111 treatment. These results support combination strategies for BTK inhibitors with other cancer immunotherapy agents.
Citation Format: Zhijian Sun, Dongping Zhou, Lusong Luo. Effect of BTK inhibitors on differentiation of human monocyte-derived dendritic cells. [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 5496. doi:10.1158/1538-7445.AM2015-5496
Abstract 55: Over-expression of FoxM1 in breast cancer can be therapeutically targeted using thiostrepton
Authors: Ahmed Maqbool , Hussain Azhar , Begum Rafiya , Thangavel Saravanan , Ajarim Dahish S. , Beg Shaham , Uddin Shahab , Al-Kuraya Khawla S. 
Published: August 2015

Abstract
Breast cancer incidence is increasing worldwide and is one of the most common cancers among women in Saudi Arabia. In spite of conventional treatment regimes in breast cancer, the prognosis is still poor. However, over the last decade, outcome of breast cancer has improved due to increased awareness among the population leading to early detection. Forkhead box protein 1 (FoxM1), is an important member of Forkhead family protein, plays an important role in the pathogenesis of various cancer including basal cell carcinoma. In addition, FoxM1 has also been shown to be involved in the pathogenesis of breast cancer from other regions. However, the role of FoxM1 in Saudi Arabia breast cancer has not been fully elucidated. Therefore in this study, we first evaluated the expression of FoxM1 in a panel of patients with breast cancer samples in Saudi Arabia by immuno histo chemistry. Our data showed that FoxM1 is over expressed in 79% (770/975) of breast cancer and directly associated with clinical parameters such as younger age (&lt;30yrs)(p = 0.00172),high Grade(p&lt;0.0001), mucinous histology (p&lt;0.0001), and triple negative phenotype (p&lt;0.0001). In addition, FoxM1over-expession was also significantly associated with activated AKT (p = 0.0001), as well as high Ki67 expression(p&lt;0.0001),matrix metalloproteinase-9 (MMP-9) (p &lt;0.0001), and XIAP (p &lt;0.0001). In vitro, using breast cancer cell lines, we found that treatment with thiostrepton resulted in inhibition of cell viability and induction of apoptosis in a dose dependent manner. In addition, in these cell lines, thiostrepton treatment caused down regulation of FoxM1, in activation of AKT and decreased the expression of XIAP, and MMP-9. Furthermore pharmacological inhibition of FoxM1 triggered Caspase dependent apoptosis in breast cancer cell lines. Altogether, our results suggest that FoxM1 and its associated signaling pathway may be a potential target for therapeutic intervention in the treatment of breast cancer.
Citation Format: Maqbool Ahmed, Azhar Hussain, Rafiya Begum, Saravanan Thangavel, Dahish S. Ajarim, Shaham Beg, Shahab Uddin, Khawla S. Al-Kuraya. Over-expression of FoxM1 in breast cancer can be therapeutically targeted using thiostrepton. [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 55. doi:10.1158/1538-7445.AM2015-55
Abstract 550: Evaluation of NQO1 as a potential diagnostic marker for bladder cancer
Authors: Cuff Simone , Lewis Ruth , Jaffar Mohammed , Knox Richard , Weeks Ian 
Published: August 2015

Abstract
The present method for detection of bladder cancer involves ultrasonography followed by cystoscopy. This process is time intensive, requires skilled personnel and is unpleasant for the patient as a result of its invasive nature. This results in patient drop-out and patients that have recovered from bladder cancer are lost to follow-up due to the necessity for hospital visits for monitoring. We have used a novel test in order to monitor NAD(P)H quinone oxidoreductase 1 (NQO1) activity in cells recovered from routine urine samples since expression of NQO1 has previously been reported to be increased in several tumour types including transitional cell carcinoma of the bladder.
Informed consent and urine samples were obtained from 73 bladder cancer patients and 42 age-matched bladder cancer-negative outpatients at the University Hospital of Wales, Cardiff. Live exfoliated cells were collected from the urine and assessed for their ability to metabolise an NQO1-specific substrate into a highly fluorescent product. Fluorescence intensity was then measured in a simple, inexpensive instrument. Results were checked against clinical correlates, bladder cancer stage, age, medication, and smoking status. Initial tests in cell lines showed excellent correlation with NQO1 levels detected by other methods. We found that in patient samples, while cell numbers in urine and expression of NQO1 per cell were not in themselves significant, NQO1 per ml of urine was highly significantly increased in bladder cancer patients (p = 0.009). Further, NQO1 was higher in patients that had high grade tumours as described in the WHO 2004 guidelines (p = 0.003).
The sensitive fluorescence-based method to detect NQO1 activity in exfoliated urothelial cells shows exceptional promise in the development of rapid, non-invasive bladder cancer diagnostics. The method will be used on larger numbers of samples in order to be able to verify these initial findings.
Note: This abstract was not presented at the meeting.
Citation Format: Simone Cuff, Ruth Lewis, Mohammed Jaffar, Richard Knox, Ian Weeks. Evaluation of NQO1 as a potential diagnostic marker for bladder cancer. [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 550. doi:10.1158/1538-7445.AM2015-550
Abstract 5506: Anti-angiogenic effects of zoledronic acid on osteotropic breast cancer cells
Authors: Jackson Cynthia , Whalen William , Morshedian Shana , Bush Jason A. 
Published: August 2015

Abstract
Emerging data suggest the bisphosphonate, zoledronic acid (ZOL), exerts both indirect and direct anti-tumor effects by decreasing tumor cell proliferation, increasing apoptosis, and inhibiting angiogenesis. Recent data indicate that antiangiogenic factors exert cellular effects via suppression of mitochondrial oxidative phosphorylation/respiration and elevation of intracellular ROS levels. This project intended to define proteins involved in response to ZOL-treatment of an osteotropic breast cancer cell line, MDA-231BO. Results demonstrate that MDA-231BO cells are more sensitive to ZOL cytotoxicity and salutary effects are both media- and calcium-dependent. This cytotoxicity was more pronounced in spheroid cultures. To investigate pro-apoptotic mechanisms of ZOL, total RNA, whole cell protein lysates, or mitochondrial-enriched fractions were isolated from MDA-231BO cells and using a combination of RT-PCR, 1D/2D-PAGE separation and MALDI-MS/MS, we identified several angiogenesis inhibitors that were upregulated and pro-angiogenic factors that were downregulated after ZOL treatment. Functional studies demonstrate the improved efficacy of ZOL on MDA-231BO compared to MDA-MB-231 controls. However, when the cells were challenged in a hypoxic environment, these effects were mitigated. Taken together, these results further support a model that ZOL tips the ‘angiogenic switch’ in favor of anti-angiogenic factors in cancer cells with a propensity for bone metastases.
Citation Format: Cynthia Jackson, William Whalen, Shana Morshedian, Jason A. Bush. Anti-angiogenic effects of zoledronic acid on osteotropic breast cancer cells. [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 5506. doi:10.1158/1538-7445.AM2015-5506
Abstract 5518: Development of bio-affinity nanoparticles: Applications for cancer imaging and therapeutics
Authors: Dotan Idit , Roche Philip J.R. , Mitmaker Elliot , Trifiro Mark A. , Paliouras Miltiadis 
Published: August 2015

Abstract
Treatment of advanced cancer, is an extremely challenging proposition. Surgery is curative at early stages, but with substantial complications. Molecular treatments in early disease are of questionable benefit, coupled with the lack of therapeutic options in advanced disease, make treatment extremely challenging. Early cancers evolve through many somatic mutations involving many selective processes, induced in part by classical drug therapies themselves initiating drug resistance. Genetic cancers studies show extensive single missense mutations, copy number variations, splicing variants, genetic rearrangements and short DNA alterations in a large number of genes. However, physical agent therapies are immune to genetic alterations, a targeting the cancer cell and adjacent cells. By investigating cell surface markers that are correlated with disease progression, we have coupled bio-affinity agents (antibody, ligand, aptamer) to functionalized carbon nanoparticles and developed a platform of delivering highly-localized “energy” in the immediate proximity to the cells causing significant cellular damage. Similarly, these agents can be simultaneously used as imaging agents, creates a theranostic treatment agent. We have used papillary thyroid (PTC) and prostate cancer (CaP) cancer cells and selectively targeted THSR and PSMA, respectively in our models. Using a 2W laser light for 30 seconds, we are able to achieve near 100% cell killing of targeted cells, whereas receptor-null cells remain unharmed. Electron microscopy was used as a direct analysis to answer the mechanistic question of cell necrosis and cell death that cannot be approached via light microscopy. Altogether these results suggest that significant and specific cell killing can be achieved with small amounts of power over short periods of time. In conclusion, whereas in the past, simultaneous multiple drugs therapies have been limited by systemic toxicities, this approach represents a single delivery platform that can carry several small molecule drugs, in conjunction with new genetic modalities, in a targeted fashion with the added benefit of self-imaging so as to document successful targeting.
Citation Format: Idit Dotan, Philip J.R. Roche, Elliot Mitmaker, Mark A. Trifiro, Miltiadis Paliouras. Development of bio-affinity nanoparticles: Applications for cancer imaging and therapeutics. [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 5518. doi:10.1158/1538-7445.AM2015-5518
Abstract 5519: Engineered protein nanocage for targeted delivery of siRNA to cancer cells
Authors: Lee Eun Jung , Yang Yoosoo , Kim In-san , Kim Kwangmeyung , Lee Jeewon 
Published: August 2015

Abstract
Considering the problems of small interfering RNA (siRNA) delivery using traditional viral and non-viral vehicles, a new siRNA delivery system to enhance efficiency and safety needs to be developed. Here we genetically engineered human ferritin based protein nanocage to simultaneously display various functional peptides on the surface of protein nanocage: cationic peptide to capture siRNA, tumor cell targeting and penetrating peptides, and enzymatically cleaved peptide to release siRNA inside tumor cell. In particular, we easily changed the tumor cell targeting peptide depending on target moiety [epidermal growth factor receptor or vimentin in this case] on the tumor cell surface. The polymerized siRNA (poly siRNA) tightly bound to the engineered protein nanocage and formed stable and condensed structure (poly siRNA-protein nanocage complex) without cytotoxicity problem. Furthermore, siRNAs in the condensed complex were effectively protected from endonuclease due to a shielding effect of protein nanocage. In the in vitro treatment of poly siRNA-protein nanocage complex, both of the tumor cell targeting and penetrating peptides were important for efficient delivery of siRNA, and the red fluorescent protein (RFP) expression in RFP-expressing tumor cells was notably suppressed by the delivered siRNA with the complementary sequence to RFP mRNA. It seems that the human ferritin-based protein nanocage is an efficient, stable, and safe tool for siRNA delivery, having a great potential for application to in vivo cancer treatment. The unique feature of protein nanocage is that multiple and functional peptides can be simultaneously and evenly placed and also easily switched on the protein nanocage surface through a simple genetic modification, which is likely to make protein nanocage appropriate for targeted delivery of siRNA to a wide range of cancer cells.
Citation Format: Eun Jung Lee, Yoosoo Yang, In-san Kim, Kwangmeyung Kim, Jeewon Lee. Engineered protein nanocage for targeted delivery of siRNA to cancer cells. [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 5519. doi:10.1158/1538-7445.AM2015-5519
Abstract 5523: A novel aptamer targeting agent for prostate cancer
Authors: Powell Gray Bethany , Kelly Linsley , Levy Matthew , Sullenger Bruce A. 
Published: August 2015

Abstract
Background: Prostate cancer is both the most common cancer diagnosis and the second most common cause of cancer-related death for men in the United States. An ideal new therapy would selectively deliver the drug to the tumor while also preventing toxicity in normal tissue.
Methods and Results: Recent exciting clinical advances with antibody drug conjugates have resulted in FDA approval of such tumor-targeting therapies. However, antibodies are difficult to chemically modify, require humanization, and their large size hinders tumor penetration. Aptamers - small nucleic acid ligands - have many advantages over traditional antibody targeting agents, including ease of synthesis, amenability to chemical modification, and reversibility. Moreover, they exhibit antibody-like target affinities and specificities at a fraction of the size, allowing more efficient tumor penetration.
We have identified an aptamer, termed E3, which selectively internalizes into prostate cancer cells, but does not target normal cells. Additionally, E3 targets and internalizes into a variety of other cancer types, including breast, ovarian, lung, colon, melanoma, glioblastoma, liver, and leukemia cancers. Linking the E3 aptamer to a deimmunized version of the Pseudomonas exotoxin (PE38) kills prostate cancer cells in vitro with an IC50 of 0.4-1.1 nM while displaying no measured toxicity towards normal cells, and linking E3 to the highly toxic auristatin drugs, MMAE or MMAF, kills prostate cancer cells in vitro with an IC50 of 5-12 nM. Significantly, E3 maintains its tumor-targeting abilities in vivo, targeting both prostate tumors and patient-derived colon cancer tumors in mice as evidenced by near-infrared in vivo imaging.
Conclusions: Together, these studies show the potential therapeutic benefit of E3 drug targeting for the treatment of prostate cancer.
Citation Format: Bethany Powell Gray, Linsley Kelly, Matthew Levy, Bruce A. Sullenger. A novel aptamer targeting agent for prostate cancer. [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 5523. doi:10.1158/1538-7445.AM2015-5523
Abstract 5525: Antibody/drug-conjugated micelle as a versatile platform technology for targeted tumor delivery
Authors: Harada Mitsunori 
Published: August 2015

Abstract
Background:
Antibody-drug conjugates (ADCs) have been recognized as a promising anticancer agent, despite their stringent requirements of antibody affinity, internalization, payload potency, and linker stability. To drive the next generation of ADCs and improve versatility of the component combination, we have designed, prepared and recently developed Antibody/Drug-Conjugated Micelle (ADCM) system. ADCM is composed of polyethylene glycol-poly (amino acid derivative) polymers, which can form a micellar nanoparticle spontaneously in aqueous media with a diameter of 20-100 nm. Antibodies are attached to the surface of the nanoparticle, while payloads are incorporated in the inner core at a payload-to-antibody molecular ratio of 100-200. In this study, monoclonal antibody, trastuzumab or cetuximab, and anticancer drug, anthracycline antibiotic epirubicin or novel hemiasterlin analogue E7974, were used as a targeting sensor and a payload of the ADCM, respectively. Here we report the results of in vitro and in vivo studies.
Methods:
The ADCMs were prepared as described previously (Japan Patent No.4538666) with slight modification. To examine the cell binding behavior, flow cytometry analysis was performed using an Accuri C6 system. The antigen affinity was evaluated using a Biacore system. The cellular uptake was examined fluorescently using ADCMs employing Alexa 488-labeled antibodies. To compare the in vivo antitumor effects, ADCM, untargeted micelle and the payload were administered intravenously 3 times weekly at the same payload-equivalent dose to nude mice bearing human tumor xenografts with HER2 (NCI-N87 gastric or trastuzumab-resistant JIMT-1 breast tumor) or EGFR (BxPC-3 pancreatic or LS174T colon tumor) expression. Tumor volumes and animal body weights were monitored 2 or 3 times a week.
Results:
The ADCMs showed similar cell-binding behavior and antigen affinity to the original antibodies. They were found to be internalized more efficiently than the original antibodies. In vivo efficacy studies demonstrated that the ADCMs inhibited tumor growth most effectively compared to control formulations. The therapeutic indexes were significantly improved in terms of the maximum tolerated dose/ED50 (50% effective dose) compared to untargeted micelles and native payloads. These results suggest the potential clinical application of the ADCMs.
Conclusion:
These data showed improved versatility of the component combination and increased therapeutic indexes of ADCM system, indicating a promising next generation of ADCs.
Citation Format: Mitsunori Harada. Antibody/drug-conjugated micelle as a versatile platform technology for targeted tumor delivery. [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 5525. doi:10.1158/1538-7445.AM2015-5525