bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 446: BAP1 mutation in mesothelioma and “BAP1 Cancer Syndrome”
Authors: Nasu Masaki , Napolitano Andrea , Pastorino Sandra , Tanji Mika , Flores Erin , Baumann Francine , Powers Amy , Gaudino Giovanni , Pass Harvey I. , Yang Haining , Carbone Michele 
Published: May 2015

Abstract
Malignant mesothelioma (MM) is a lethal cancer whose pathogenesis results from complex interactions between host genetics and environmental carcinogens, such as asbestos and erionite fibers. Recently, BAP1 (BRCA associated protein 1) has been identified as a novel MM tumor suppressor gene located at 3p21, a region frequently deleted in MM, which encodes for a deubiquitinase enzyme known to target histones and other proteins.
We discovered that germline BAP1 mutations cause a novel cancer syndrome characterized by a significant excess of both pleural and peritoneal MM, uveal and cutaneous melanoma and possibly other tumors. In the same study, we reported that 22% sporadic MM tumors, among the Caucasian population, harbored somatic BAP1 mutations. Several other studies supported a relevant role of BAP1 in MM. However, a significant variation in the frequency of BAP1 mutation was found across different studies and populations. In fact, one research group found BAP1 gene altered in 61% of tumor samples from a Japanese cohort, pointing out to a possible influence of ethnicity on the prevalence of BAP-1 alterations among MM patients. However, the limitations in tumor sample sizes and methodological differences across studies do not allow for conclusive associations. We are now further analyzing BAP1 status and possible clinicopathological associations using different and more sensitive methods, such as MPLA, DNA and RNA sequencing, DNA copy number and methylation. Our preliminary results indicate that, regardless of ethnicity, BAP1 plays a crucial role in MM pathogenesis. More experiments are urgently needed to see whether BAP1 expression could be used in diagnostic, prognostic, or therapeutic settings. The impact of this work will extend to other cancers with BAP1 mutations.
Citation Format: Masaki Nasu, Andrea Napolitano, Sandra Pastorino, Mika Tanji, Erin Flores, Francine Baumann, Amy Powers, Giovanni Gaudino, Harvey I. Pass, Haining Yang, Michele Carbone. BAP1 mutation in mesothelioma and “BAP1 Cancer Syndrome”. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 446. doi:10.1158/1538-7445.AM2014-446
Abstract 4462: Structure-activity relationship studies for PSMA-targeted tubulysin conjugates
Authors: Wang Kevin , Hahn Spencer , Santhapuram Hari , Qi Longwu , Kleindl Paul , Vaughn Jeremy , You Fei , Reddy Joe , Dorton Ryan , Leamon Christopher , Vlahov Iontcho 
Published: May 2015

Abstract
Prostate-specific membrane antigen (PSMA) is a cell-surface receptor expressed on prostate cancer cells. Recent findings suggest that PSMA is also abundant on newly formed blood vessels which supply most non-prostatic solid tumors; including lung, colon, breast, renal, liver, and pancreatic carcinomas. These reports have provided solid support for the concept of designing drug conjugates for PSMA-targeted cancer therapy. Here we describe our structure-activity relationship analyses resulting in the discovery of highly potent PSMA-targeted tubulysin conjugates. In our study, more than thirty ligand-drug constructs were designed and synthesized based on strategically placing a variety of chemical groups responsible for evoking a targeted biological effect in vitro and in vivo. The optimized molecular architecture is comprised of a high affinity PSMA-binding urea-type ligand, a water soluble peptide- or carbohydrate-based spacer unit, a cleavable disulfide-containing self-immolative linker system, and the highly potent chemotherapy drug tubulysin which inhibits microtubule activity . One of the conjugates possessed superior targeted activity and was selected for further preclinical development.
Citation Format: Kevin Wang, Spencer Hahn, Hari Santhapuram, Longwu Qi, Paul Kleindl, Jeremy Vaughn, Fei You, Joe Reddy, Ryan Dorton, Christopher Leamon, Iontcho Vlahov. Structure-activity relationship studies for PSMA-targeted tubulysin conjugates. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4462. doi:10.1158/1538-7445.AM2014-4462
Abstract 4477: pH-responsive PEG-HPAH micelles for drug delivery and their potential in cancer therapy
Authors: Xu Qin , Yu Jingshuang , Zhu Bangshang 
Published: May 2015

Abstract
pH-responsive hyperbranched polymers have attracted much attention due to their unique properties for tumor-targeted drug delivery. In this study, we describe a pH-responsive drug carrier, poly (ethylene glycol) (PEG)-hyperbranched polyacylhydrazone (HPAH), which can form nanoscale micelles to be used as anti-cancer drug carriers with pH-controlled drug release. The molecular structure of PEG-HPAH was confirmed by nuclear magnetic resonance spectroscopy (NMR) and Fourier transform infrared spectroscopy (FTIR). The drug-loaded micelles with a diameter of approximately 190 nm, were prepared using a dialysis method against PBS with a pH of 8.0. The drug-loaded micelles showed the desired pH-dependent drug release properties. The drug release levels were low at neutral and alkaline pH, but increased significantly with a decrease in the pH of the medium. Intracellular uptake results indicated that the PEG-HPAH-drug micelles could efficiently deliver chemotherapeutic drugs into the cells. In addition, it was found that the subcellular localization of the drug-loaded micelles was different from that of free drugs, in which the drug-loaded micelles were mainly in the cytoplasm. The docetaxel (DTX)-loaded PEG-HPAH micelles presented a high cytotoxic activity against tumor cells in vitro. When combined with the administration of glucose, the PEG-HPAH-DTX micelles exhibited a superior anti-tumor efficacy and a lower systemic toxicity in vivo. The biodistribution profile showed increased accumulated drug levels in tumor tissue and plasma in micelles treated group. The results indicate that the nanoscale PEG-HPAH-DTX micelles may serve as a novel selective tumor-targeting drug delivery system.
Citation Format: Qin Xu, Jingshuang Yu, Bangshang Zhu. pH-responsive PEG-HPAH micelles for drug delivery and their potential in cancer therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4477. doi:10.1158/1538-7445.AM2014-4477
Abstract 4485: Synthesis of targeted docetaxel-polymer conjugate and its anti-tumor efficacy
Authors: Lee Young Bok , Kim Deog Joong , Yang Miyoung , Ahn Chang-Ho , Nan Anjan 
Published: May 2015

Abstract
Over the last decade, it has been shown that nanopolymer therapeutics can be engineered to target cancer cells specifically and can deliver the cancer agent in a time-release fashion, thereby leaving normal healthy cells unaffected by toxic drugs such as docetaxel. Docetaxel has been used to treat several types of cancers, but it has provided pharmaceutical challenges due to its poor solubility and toxicities associated with the co-solvents. Given that nanotechnology can enhance the specificity, efficacy and safety of cancer agents and with the need of a new alternative formulation for docetaxel delivery, we developed a poly N-(2-hydroxypropyl) methacrylamide (HPMA)-Docetaxel (Doc) conjugate with Folate (FA) targeting ligand and evaluated the effect of the product in both in vitro human cancer cell lines and in vivo mice xenograft tumor models. Analysis of the product displayed the incorporation of 7.9% of docetaxel and 2.1% of folate with 38.6kDa MW and 1.92 of polydispersity, and an improvement in water solubility. The product inhibited the proliferation of a variety of human cancer cells in nM ranges in in vitro study. The maximal tolerated dose (MTD) of the product in mice was more than 150 mg/kg (as a docetaxel amount), which is much higher than that of free docetaxel (∼25 mg/kg). In mice bearing tumor xenografts, treatment with the polymer-conjugate strongly inhibited the growth of various human tumors, extended survival, and enhanced tumor regression significantly without effects on body weight compared to control animals. The results clearly demonstrate that our new polyHPMA-docetaxel-folate conjugate compound is a promising candidate for anti-tumor chemotherapeutics with reduced toxicity and prolonged survival.
Citation Format: Young Bok Lee, Deog Joong Kim, Miyoung Yang, Chang-Ho Ahn, Anjan Nan. Synthesis of targeted docetaxel-polymer conjugate and its anti-tumor efficacy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4485. doi:10.1158/1538-7445.AM2014-4485
Abstract 4493: Medi-573 alone or in combination with mammalian target of rapamycin inhibitors, targets the insulin-like growth factor pathway in sarcomas
Authors: Zhong Haihong , Fazenbaker Christine , Breen Shannon , Chen Cui , Huang Jiaqi , Chris Morehouse , Yao Yihong , Hollingsworth Robert 
Published: May 2015

Abstract
MEDI-573 is a human antibody that neutralizes the insulin-like growth factors, IGF-1 and IGF-2. IGFs are over-expressed in multiple types of cancer; their over-expression is a potential mechanism for resistance to IGF-1 receptor (IGF-1R)-targeting therapy. Effects of IGFs on cell proliferation, differentiation, and survival are mediated through their binding to and activation of IGF-1R or insulin receptor A (IR-A). In this study, we studied the anti-tumor activity and mechanism of action of MEDI-573 in models of sarcoma. MEDI-573 potently inhibited in vitro proliferation of several sarcoma cell lines, with Ewing's sarcoma cell lines being the most sensitive. This inhibition also occurred after growth stimulation with added IGF-1- and IGF-2. The effect of MEDI-573 on IGF signaling was also examined. Treatment with MEDI-573 markedly reduced levels of pIGF-1R, pIR, and pAKT, and significantly blocked IGF-1- and IGF-2-induced activation of the IGF-1R and AKT pathways. MEDI-573 inhibited the growth of sarcoma xenografts in vivo, and inhibition correlated with neutralization of IGF-1 and IGF-2. Combination of MEDI-573 with either rapamycin or another mTOR inhibitor, AZD2014, significantly enhanced the anti-tumor activity of MEDI-573, and this response correlated with modulation of AKT and mTOR signaling. In summary, sarcoma cells respond to autocrine or paracrine growth stimulation by secreted IGF-1 and IGF-2, and inhibition of IGF-1 and IGF-2 by MEDI-573 results in potent anti-tumor activity in several sarcoma models. Our data provide evidence for evaluation of MEDI-573 and mTORi combinations in clinical studies of sarcoma patients.
Note: This abstract was not presented at the meeting.
Citation Format: Haihong Zhong, Christine Fazenbaker, Shannon Breen, Cui Chen, Jiaqi Huang, Morehouse Chris, Yihong Yao, Robert Hollingsworth. Medi-573 alone or in combination with mammalian target of rapamycin inhibitors, targets the insulin-like growth factor pathway in sarcomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4493. doi:10.1158/1538-7445.AM2014-4493
Abstract 4495: Sym013, novel pan-HER monoclonal antibody mixture, augments radiation response in human lung and head and neck tumors
Authors: Francis David , Huang Shyhmin , Werner Lauryn , Lantto Johan , Horak Ivan D. , Kragh Michael , Harari Paul M. 
Published: May 2015

Abstract
Sym013 represents a novel HER family targeting approach consisting of a mixture of six monoclonal antibodies against EGFR, HER2, and HER3. Sym013 effectively induces rapid, simultaneous down-regulation of all HER members. Compared with single receptor or dual receptor targeting of the HER family, Sym013 provides broader inhibition and greater down-regulation efficacy. In this current study, we examined the capacity of Sym013 in combination with ionizing radiation to augment tumor response in lung (NSCLC) and head and neck (HNSCC) cancer model systems.
The anti-proliferative effects of Sym013 were confirmed showing 30-60% growth inhibition across a variety of NSCLC and H&N cancer cell lines that express EGFR, HER2, and/or HER3. Furthermore, Sym013 inhibited the growth of tumor cells that exhibit resistance to cetuximab. Western blot analysis showed a dose-dependent down-regulation of HER family members and downstream MAPK and AKT signaling pathways following 24-hour treatment with Sym013. Clonogenic survival analysis revealed that Sym013 enhanced radiosensitivity in tumor cells following radiation exposure. We characterized the DNA damage profile following radiation via flow cytometric analysis of phosphorylated histone 2AX (γH2AX) foci. This revealed a significant increase of γH2AX following treatment with Sym013 and 2 Gy radiation when compared with Sym013 or radiation alone. Furthermore, combined treatment of Sym013 and radiation induced a significant G1 and G2 arrest. Using Annexin V/PI staining, we also found a significant increase in the apoptotic cell population following treatment of Sym013 and 6 Gy radiation. These results suggest that Sym013 augments radiation response via the induction of cell cycle arrest followed by the induction of apoptosis and cell death, likely reflecting inhibitory effects on DNA damage repair. Additional studies to examine the impact of Sym013 to augment radiation response as well as overcome acquired resistance to cetuximab in xenograft models are in progress. Overall, these data suggest the significant capacity of Sym013 to augment radiation response in lung and head and neck cancers. This unique antibody mixture warrants additional investigation as a promising novel HER family targeting strategy in cancer therapy.
Citation Format: David Francis, Shyhmin Huang, Lauryn Werner, Johan Lantto, Ivan D. Horak, Michael Kragh, Paul M. Harari. Sym013, novel pan-HER monoclonal antibody mixture, augments radiation response in human lung and head and neck tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4495. doi:10.1158/1538-7445.AM2014-4495
Abstract 4497: Therapeutic benefit of targeting ERK in mutant KRAS pancreatic ductal adenocarcinoma
Authors: Hayes Tikvah K. 
Published: May 2015

Abstract
The limited success of anti-MEK and anti-RAF therapies with KRAS mutant cancers has been attributed, in part, to de novo or acquired resistance mechanisms that arise after prolonged treatment. A majority of resistance mechanisms involve kinome reprograming to reactivate ERK downstream of inhibitor activity. Therefore, we hypothesized that directly targeting ERK would be an effective method for overcoming these resistance mechanisms. To address this possibility, we evaluated the sensitivity of a panel of mutant KRAS pancreatic ductal adenocarcinoma (PDAC) cell lines to the highly selective SCH772984 ERK1/2 protein kinase inhibitor. First, we found that the anchorage-dependent growth of 6 of 12 cell lines were sensitive to SCH772984 treatment (IC50&lt;2 uM). Some sensitive PDAC lines were resistant to the AZD6244 MEK1/2-selective inhibitor, indicating different mechanisms of action of these two inhibitors. Second, we identified phospho-AKT as a potential biomarker for PDAC SCH772984 sensitivity. Third, we assessed the molecular basis for anchorage-dependent growth inhibition. After 72 h treatment, flow cytometry analyses indicated impaired cell cycle progression through G1. Additionally, we found increased apoptosis as measured by formation of cleaved caspase-3. Together these observations suggest that sensitivity is a result of both impaired cell cycle progression and induction of apoptosis. Surprisingly prolonged SCH772984 treatment (2 weeks) resulted in senescence, as sensitive lines stained positive for senescence-associated beta-galactocidase. Furthermore, we found that senescent cells induced p16 and lost phospho-RB two common markers associated with induction of senescence. Onset of senescence was dependent on the loss of total MYC protein expression. Finally, we found that treatment with SCH772984 reduced tumorigenic growth in an in vivo xenograft mouse model. Our ongoing studies include determining the mechanisms of inhibitor resistance. In summary, our findings suggest that targeting ERK will be therapeutically beneficial for the treatment of KRAS mutant PDAC.
Citation Format: Tikvah K. Hayes. Therapeutic benefit of targeting ERK in mutant KRAS pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4497. doi:10.1158/1538-7445.AM2014-4497
Abstract 4543: Identification of downstream targets of polo-like kinase 1 in melanoma by large-scale label-free comparative proteomics profiling
Authors: Cholewa Brian D. , Hahn Molly P. , Scarlett Cameron O. , Ahmad Nihal 
Published: May 2015

Abstract
Polo-like kinase 1 (Plk1) is a serine-threonine kinase that plays a critical role in the cell cycle by regulating mitotic entry, progression and exit. In recent years, Plk1 has gained considerable attention as a promising mechanism-based therapeutic target in a variety of cancers. Pre-clinical studies have suggested that Plk1 inhibition is capable of reducing cancer cell growth both in vitro and in vivo with tremendous efficacy and with minimal detriment to normal cells. This evidence has spurred the development of many Plk1-specific inhibitors that has culminated in over 30 clinical trials, either completed or ongoing. However, the remarkable pre-clinical success of Plk1 inhibitors has yet to be validated at the clinical level, thus stressing on an urgent need for a better understanding of Plk1 signaling. In an effort to further elucidate the molecular function of Plk1 inhibitors, we performed a comparative quantitative proteomics strategy to compare the proteome of human melanoma cells (A375) following treatment with the Plk1-specific ATP competitive inhibitor BI 6727 (25 nM, 24 h). We employed label-free nano-LC/MS/MS technology on a Q-exactive followed by SIEVE processing to identify more than 1800 proteins, ≤ 1% false discover rate, 343 of which had significantly altered expression. Using ingenuity pathway analysis (IPA) to select for proteins with more than two unique peptides and greater than a two-fold change, our proteomic analysis resulted in the identification of more than twenty proteins that were significantly dysregulated following Plk1-inhibition, many of which have not been previously shown to be associated with Plk1 signaling. Interestingly, the metabolic and proteasome pathways harbor the greatest portion of differentially expressed proteins, including five subunits of the 20S proteasome core particle and five members of the glycolysis pathway. Given the importance of these two pathways in cancer cell survival, this study provides two potential mechanisms of Plk1 inhibition that have yet to be explored. Further studies are currently ongoing in our laboratory to validate our findings in additional experiments.
Citation Format: Brian D. Cholewa, Molly P. Hahn, Cameron O. Scarlett, Nihal Ahmad. Identification of downstream targets of polo-like kinase 1 in melanoma by large-scale label-free comparative proteomics profiling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4543. doi:10.1158/1538-7445.AM2014-4543
Abstract 4548: The anti-proliferative activity of TAS-108 (a steroid anti-estrogen) is augmented by high ERβ levels in breast cancer cells
Authors: Cheong Ye-Hwang , Choi Young J. 
Published: May 2015

Abstract
Background: TAS-108 is an anti-estrogen that binds to both ERα and ERβ and has potent anti-proliferative activity in vitro and in vivo assay. Recently, the phase II clinical study of TAS-108 demonstrated competitive clinical benefits with decreased adverse effects. However, the molecular mechanism TAS-108 remains uncharacterized.
Methods: Plasmids containing ERα or ERβ fused with N- and C-terminal fragments of firefly luciferase were constructed for split luciferase complementation assays. The resulting plasmids were transfected in HEK293 cells for 24 hr and TAS-108 was added to the media for 6 hr. For RT-qPCR of AREG and TFF1 and proliferation assay, ERβ was transfected in MCF7 cells for 24hr. The proliferation level was determined by measuring the fluorescent level induced by Prestoblue® reagent.
Results: The split luciferase complementation assay demonstrates that TAS-108 increases ERα/β heterodimerization by ≈100-fold than ERα/α homodimerization. The potency of TAS-108 in MCF7 cells was increased significantly by the enforced expression of ERβ via transfection (MCF7-ERβ); 30nM TAS-108 was suitable to block the E2 mediated increases of AREG and TFF1 expression and significantly decreased proliferation of MCF7-ERβ.
Conclusions: TAS-108 has a higher affinity for ERα/β heterodimerization than ERα/α homodimerization, and TAS-108 anti-proliferative activity is augmented by blocking the expression of E2-induced proliferative genes when coupled with increased levels of ERβ. Our findings underscore the molecular role of ERβ in the biology and suggest that promoting ERα/β heterodimerization may be an effective strategy to increase anti-tumor activity in breast cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Ye-Hwang Cheong, Young J. Choi. The anti-proliferative activity of TAS-108 (a steroid anti-estrogen) is augmented by high ERβ levels in breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4548. doi:10.1158/1538-7445.AM2014-4548