bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5594: JNK1 and MERTK are markers of MEK inhibitor resistance and new targets for therapy.
Authors: Beech Jaymes , Kelly Kim 
Published: August 2014

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating human cancers, having a median survival of 6 months and a 5-year survival rate of 6%. It is the fourth leading cause of cancer deaths due to its resistance to conventional radiotherapy and chemotherapy and a lack of early detection. Alternatively, small molecule inhibitors have been emerging as a means of transitioning away from non-selective treatments towards a more personalized approach.
Pancreatic cancer, having mutant K-RAS and TP53 in upwards of 90% of cases, appears to be a great candidate for molecular therapy due to this high genetic homogeneity among patients. TP53 is an inactivation mutation and not a candidate for inhibition. K-RAS is an over-activating mutation but unfortunately cannot currently be treated by small molecule inhibitors. However, its downstream pathways, which signal both growth and survival, can. The most predominant of these is the MAP kinase pathway. Several small molecules have been developed to target members of this pathway such as MEK 1/2 including U0126, PD0325901 and AZD6244. Often, however, these therapies are still ineffective and it would be immensely beneficial to be able to predict when MEK inhibition will be effective or should conversely be avoided.
To discover such markers, we tested a panel of 18 pancreatic cancer cell lines for sensitivity to the MEK inhibitor AZD6244. After classifying each line's sensitivity, microarray and qPCR analysis found significantly different genes between the sensitive and resistant groups. Most notable were MERTK and MAPK8, which both were upregulated in resistant lines and showed some redundancy in the studies. These genes code for the Tyrosine-protein kinase Mer (MERTK) and c-Jun N-terminal kinase (JNK1) proteins respectively. Correlation studies showed both gene and protein expression levels to track with resistance to the small molecule inhibitor. To test whether these genes and the proteins they code for could serve as potential new therapy targets, shRNA studies were performed. Studies yielded a noticeable decrease in proliferation in both MAPK8 and MERTK knockdown, even being lethal in one case. While the results support the importance of these proteins for tumorgenecity, knockdown did not alter the cell lines’ sensitivity to MEK inhibition. Our findings suggest the use of MERTK and JNK1 as markers of MEK inhibition resistance and propose new target for future therapies.
Citation Format: Jaymes Beech, Kim Kelly. JNK1 and MERTK are markers of MEK inhibitor resistance and new targets for therapy. [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 5594. doi:10.1158/1538-7445.AM2013-5594
Abstract 5600: Destruction of prostate cancer cell xenografts by FSH-Lytic peptide conjugates.
Authors: Aggarwal Sita , Gauthier Ted , Alila Hector , Leuschner Carola , Karki Namrata , Solipuram Rajasree , Hansel William 
Published: August 2014

Abstract
Background: In previous studies (Hansel, et al., Mol. and Cell. Endocrinol. 269:26-33, 2007),we showed that conjugates of membrane destroying lytic peptides with either LHRH or with a 15-amino acid segment of the β chain of human chorionic gonadotropin (hCG) target and destroy human prostate, breast and ovarian cancer cells in tumor bearing nude mice. Recently (Radu et al., N. England J. Med. 363:1621-1630, 2012) reported that endothelial cells in blood vessels supplying cancers express follicle-stimulating hormone (FSH) receptors.
Objectives:The objectives of this study were to synthesize a bioconjugate of a lyticpeptide (Phor18) to each of three segments of the β chain of FSH that are known to bind to the FSH receptor, and test these conjugates (FSH90-95-Phor18, FSH81-95-Phor18 and FSH33-53-Phor18) for their ability to target and lyse prostate cancer cells in vitro and in vivo.
Results: In in vivo experiments, administration of FSH90-95-Phor18 and FSH81-95-Phor18 significantly (p &lt; 0.05) inhibited prostate cancer cell (PC-3) growth, as measured by tumor volumes and tumor weights at necropsy. FSH33-53-Phor18 also caused a significant reduction in tumor volume at necropsy at a dose of 1 mg/kg, but the reduction in tumor weight was not statistically significant (p &gt; 0.05). The average tumor volume was maintained at significantly lower levels in the mice treated with FSH90-95-Phor18 (p=0.027), FSH81-95-Phor18 (p=0.029) when compared with vehicle and free peptide treatment groups during the study (p &lt; 0.05). Immunohistochemical analyses for FSHR were performed on the tumor samples. FSHR-positive endothelial cells were found in many vessels supplying the tumors of control mice, but few FSHR-positive endothelial cells were present in tumors of mice treated with FSH90-95-Phor18, FSH81-95-Phor 18 or FSH33-53-Phor 18. FSH81-95-Phor 18 was the most effective of the three conjugates tested in destroying the FSHR-bearing endothelial cells and in inhibiting tumor growth of the PC-3 xenografts in nude mice.
Conclusion: These data show that Phor18 conjugates of FSH β chain segments that bind to FSHR expressed by the endothelial cells of the blood vessels supplying the tumors are capable of inhibiting prostate cancer cell tumor growth by inhibiting angiogenesis. These FSH β chain-lytic peptide conjugates may be useful in treating prostate and other FSHR expressing cancers.
Citation Format: Sita Aggarwal, Ted Gauthier, Hector Alila, Carola Leuschner, Namrata Karki, Rajasree Solipuram, William Hansel. Destruction of prostate cancer cell xenografts by FSH-Lytic peptide conjugates. [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 5600. doi:10.1158/1538-7445.AM2013-5600
Abstract 5638: Preclinical evidence supporting cotargeting insulin-like growth factor receptor (IGF-1R) and Src in non-small cell lung cancer.
Authors: Kim Jin-Soo , Min Hye-Young , Yun Hye Jeong , Jang Hyun-Ji , Kim Edward S. , Liu Diane , Lee J. Jack , Behrens Carmen , Lippman Scott M. , Hong Waun Ki , Wistuba Ignacio I. , Lee Ho-Young 
Published: August 2014

Abstract
The antitumor efficacy of IGF-1R targeting agents (TKIs or antibodies) has been evaluated in recent clinical trials, but the effect has been found to be marginal and limited. Since it has been suggested that IGF-1R and Src signaling pathways cooperate with each other in the proliferation and survival of cancer cells, we investigated the role of Src in the resistance to the IGF-1R TKI and further suggested the rationale of co-targeting of IGF-1R and Src in the treatment of NSCLC. We examined Src-mediated regulation of IGF-1R activation and assessed the effect of the combined treatment with an IGF-1R TKI and a Src inhibitor on the proliferation, survival, and signaling changes in human NSCLC cells and NSCLC xenografts in nude mice. In addition, expressions of the IGF-1R signaling axis were evaluated in tissue microarrays of NSCLC from two independent databases (N=352, and 353, respectively) and correlated with clinicopathologic characteristics and patient survival. We found co-activation of IGF-1R and Src in various NSCLC cells and modulation of IGF-1R signaling by overexpression or knockdown of Src. Combined blockade of IGF-1R and Src resulted in the suppression of cell proliferation, induction of apoptosis, inhibition of signaling responsible for cell survival and proliferation, and tumor growth in vivo. In human tissue samples, p-IGF-1R/IR, IGF-1R, and pSrc expressions were significantly associated with squamous cell carcinoma (SCC) in both TMAs. pIGF-1R/IR and pSrc had strong positive correlation with each other (P&lt;.0001 and P&lt;.0001, respectively). The expression of pSrc serves as a predictor of poor survival in these patients by multivariate analysis in patients with adenocarcinoma. Our data suggest that Src may play an important role in the resistance of a small molecule inhibitor targeting IGF-1R, and IGF-1R and Src are activated in NSCLC patients and thus should be investigated as therapeutic targets in NSCLC patients. Further studies would be necessary to examine the efficacy of combined treatment targeting IGF-1R and Src in NSCLC patients.
Citation Format: Jin-Soo Kim, Hye-Young Min, Hye Jeong Yun, Hyun-Ji Jang, Edward S. Kim, Diane Liu, J. Jack Lee, Carmen Behrens, Scott M. Lippman, Waun Ki Hong, Ignacio I. Wistuba, Ho-Young Lee. Preclinical evidence supporting cotargeting insulin-like growth factor receptor (IGF-1R) and Src in non-small cell lung 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 5638. doi:10.1158/1538-7445.AM2013-5638
Abstract 5667: Cytotoxicity of two-component drug delivery systems targeting HER2(+) cancer cells.
Authors: Hapuarachchige Sudath , Kato Yoshinori , Artemov Dmitri 
Published: August 2014

Abstract
The HER2 (ErbB-2) is a class of epidermal growth factor receptors, which is overexpressed in 20-30% breast cancer cases that consequently show poor prognosis, cancer growth, and progression. Trastuzumab is a humanized, monoclonal antibody widely used as a first line therapeutic against HER2(+) breast cancers. However, recent clinical observations reveal that approximately half of patients with HER2(+) disease do not benefit from trastuzumab or have disease that becomes refractory to it. The combination therapy based on antibody-drug conjugates is a promising strategy to overcome the immunotherapeutic resistance of tumors. Since single delivery components face the barriers of extravasation from vessels and diffusion to the target site, we have developed a sequential two-component delivery system where components are assembled on the target cell surface and internalized delivering high dose of therapeutics. In this study, trastuzumab was functionalized with PEGylated azide groups and labeled with rhodamine or NIR CF-680 dyes, to obtained T(PEG4-Az)8(Rhod/CF-680)2 as a first delivery component. Albumin (BSA) was functionalized with strain-promoted alkyne (DIBO), substituted with paclitaxel, and labeled with Alexa Fluor 488 or CF-750 to obtained A(DIBO)10(Pac)2(Alexa 488/CF-750)2 as the second delivery component. Substitution of paclitaxel was carried out with sulfo-NHS-paclitaxel which increases the solubility of the drug in reaction medium. While reduced solubility of paclitaxel modified BSA was observed for the substitution of &gt;5 paclitaxel molecules, one to four paclitaxel substitutions on BSA shows no precipitations in PBS. The in vivo cytotoxicity of the two-component delivery system was assessed using HER2(+) overexperssing BT-474 breast cancer cells and a standard WST-8 assay. For in vitro therapeutic study, we used T(PEG4-Az)8(CF-680)2 and A(DIBO)10(Pac)2(CF-750)2 (with non-functionalized trastuzumab as the first component in controls). We observed an increased cytotoxicity of the two-component delivery system with IC50 of 0.101 μM, comparing to IC50 of 0.247 μM for the control.
Citation Format: Sudath Hapuarachchige, Yoshinori Kato, Dmitri Artemov. Cytotoxicity of two-component drug delivery systems targeting HER2(+) cancer cells. [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 5667. doi:10.1158/1538-7445.AM2013-5667
Abstract 579: The interaction of ZSCAN4 with TRF1: effects on regulation of telomere elongation in cancer cells.
Authors: lee kyungwoo 
Published: August 2014

Abstract
Telomeres are repetitive sequences at the ends of chromosomes protected by DNA binding proteins of shelterin complex that form capping structures. One of these proteins, TRF1, plays a role in the regulation of telomere length through its interaction with other proteins in the shelterin complex. High levels of TRF1 expression have been shown to accelerate telomere shortening, whereas dominant-negative inhibition of TRF1 leads to telomere elongation. Recently, the newly identified Zinc finger and SCAN domain containing4 gene (ZSCAN4) plays a key role in genomic stability by regulating telomere elongation and was shown to co-localize with TRF1 foci in mouse embryonic stem cell. Here, we show that ZSCAN4 is a TRF1 association protein in breast cancer cells. We hypothesized that ZSCAN4 would affect levels of TRF1expression and correspondingly control the function of TRF1 through negative regulation and dominant-negative inhibition. Using Co-immunoprecipitation and TNT Pull-down assay, we demonstrate that ZSCAN4 binds with TRF1 in vitro. Localization and visualization of interacting protein-protein interactions in living cells are crucial to elucidate between TRF1 and ZSCAN4. Using a bimolecular fluorescence complementation (BiFC) assay, we show the directly visualize TRF1 and ZSCAN4 interactions in living cells. Using telomere length assays, we demonstrate that ZSCAN4 is an association protein of TRF1 to regulate telomere and affect in the telomere elongation of cancer. The ZSCAN4 mediated cooperative binding of TRF1 to telomeric DNA has important implications for understanding the mechanism of telomere extension.
Citation Format: kyungwoo lee. The interaction of ZSCAN4 with TRF1: effects on regulation of telomere elongation in cancer cells. [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 579. doi:10.1158/1538-7445.AM2013-579
Abstract 600: Liposomal C6 ceramide appears to potentiate enhanced chemotoxicity of pancreatic cancer.
Authors: Wanebo Harold J. , Cong Cao , Shu Li , Shrayer David , Wan Yeushung , Bowen Wayne 
Published: August 2014

Abstract
Introduction: Pancreatic adenocarcinoma a highly lethal malignancy (5 yr survival ∼ 5%) is poorly responsive to all chemotherapy, in part related to presence of chemo resistant pathways: prosurvival (AKT/PI3K/mTOR and mutant KRAS. We previously demonstrated reversal of these resistant pathways by C6 Ceramide and now pursue optimum intracellular delivery using selected liposomal preparations of C6 Ceramide.
Methods: C6 Ceramide(C6Cer) in 4 different liposomal vesicle formulations were tested by MTT assay against pancreatic cell lines L3.6, PANC1 and MIA, combined with chemotherapy: Gemcitabine, Paclitaxel and Cetuximab.Liposomal preparations included : (#1)18:1 PC (1,2-dioleoyl-sn-glycero-3-phosphocholine; (#3),18:0 PC (1,2-distearoyl-sn-glycero-3-phosphocholine;(#5) DPGG (1,2-dipalmitoyl-sn-glycero-3-galloyl); and (#7) 18:0 PEG2 PE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N[methoxy(polyethylene glycol)-2000. (#1)18:1 PC- has low transition temp.(T*) and is fluid at body T*(# 3). 18:0 PC-is rigid with high transition (T*) . #5 DPGG- avoids RE System (is fluid at body T*, induces long circulations)#7. 18:0 PEG 2 PE - industry standard (also avoids RE system).Biologic effects of the 4 lipid formulations with/without C6 Ceramide were initially assessed invitro.
Results: Dose response MTT assay demonstrated no distinctive response of C6 combined liposomes vesicles # 1 & 3, but confirmed high activity in preparations #5 & 7.
MTT ResponseFractionControlTaxolGemcitabineCetuximab100%87%70%90%#5(C6)90%42%40%33%# 6 PPS control108%76%36%77%# 7 C6101%31%45%59%# 8 PBS control110%60%58%62%*Control-cell survival 72 hours ∼ 90%-100%(Drug Dose - C6 1 ug/ml, Pac. 1ug/ml,Gem 5ug/ml, Cetux 25ug/ml)
Conclude: Liposomal C6 preparations show high activity in potentiating chemo toxicity by Gemcitabine, Paclitaxel and Cetuximab against Pancreatic Cancer. Confirmatory in vivo studies are in process.
Citation Format: Harold J. Wanebo, Cao Cong, Li Shu, David Shrayer, Yeushung Wan, Wayne Bowen. Liposomal C6 ceramide appears to potentiate enhanced chemotoxicity of 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 600. doi:10.1158/1538-7445.AM2013-600
Abstract 604: Styrene compounds induce apoptosis in triple negative breast cancer cell lines.
Authors: Rorie Checo J. , Richardson Shaina L. , Lucas Agape C. , Thomas Phillip A. , Gurley Kashenya M. , Franks Marion A. 
Published: August 2014

Abstract
Triple negative breast cancer (TNBC) is a rare basal-like subtype of breast cancer that is highly aggressive due to its invasiveness and metastatic properties. TNBC is characterized by the loss or low expression of estrogen receptor, progesterone receptor, and HER2 proteins which have been targeted and established as somewhat effective therapy regiments in other breast cancer subtypes including luminal breast cancer. Since triple negative tumors are missing these established drug targets, there has been little advancement in the establishment of drug therapies to specifically target this breast cancer subtype and therefore the need for novel therapeutics in treating TNBC still remains. Previous reports have suggested that PARP inhibitors show promise in potentiating the effectiveness of other known chemotherapeutics. Styrene compounds are volatile organic compounds that have a similar structural composition to some known PARP inhibitors. Our group has developed styrene compounds composed of a 3-nitro group on the A ring and varying aryl groups in the B ring of the styrene, and then tested their biological effects on luminal and TNBC cell lines. In this study, four different styrene compounds were used to treat the luminal breast cancer cell line HCC70 and the triple negative breast cancer cell line HCC1806. The breast cancer cells were exposed to a 10, 100, and 1000 μM titration over a 24hr time period. The apoptotic effect on these cell lines were analyzed and measured via qualitative and quantitative methods. We show here that light microscopy revealed a classic apoptotic dose-response to all of the styrene compounds in the cell lines. We also used the cell viability and MTT assays to reveal a dose-response decrease in cell viability and increase in cell death to the titration of the styrene compounds. This preliminary data show that these compounds have the ability to induce apoptosis in luminal and triple negative breast cancer cell lines. Our preliminary results lead us to believe that these styrenes could represent a new chemotherapeutic treatment for Triple Negative Breast Cancer and potentially other breast cancer subtypes.
Citation Format: Checo J. Rorie, Shaina L. Richardson, Agape C. Lucas, Phillip A. Thomas, Kashenya M. Gurley, Marion A. Franks. Styrene compounds induce apoptosis in triple negative breast 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 604. doi:10.1158/1538-7445.AM2013-604
Abstract 609: Novel techniques for identifying apoptosis with pSIVA-IANBD in live and fixed cells.
Authors: Heiden Lisa S. , Krajewski Stan , Quintel Payton D. , Singh Sujay K. 
Published: August 2014

Abstract
Historically, flow cytometry has been the primary technique for identifying individual cells undergoing apoptosis. However, imaging is becoming increasingly important for analyzing cell death and underlying mechanisms in living cell populations. In this study, we developed new techniques for using the polar sensitive pSIVA-IANBD Annexin XII probe to identify apoptosis in mixed populations of cells by multiple imaging of viable primary neuronal cultures over 0-72h. The pSIVA-IANBD probe was added to living cultures at time=0. pSIVA-IAND binds to exposed phosphatidylserine (PS) residues and fluoresces (in the FITC channel) only when bound to cells. Cultures were fixed and permeabilized at the end of their respective time courses and immunostained with MAP2 or NeuN neuronal markers to identify neurons, and counterstained with Hoeschst dye to visualize nuclei.
The results were imaged by an IFL multichannel inverted digital microscope (EVOS; AMG Inc, USA). They showed that bound pSIVA-IANBD was fixation resistant and the single (pSIVA-IANBD), double (pSIVA-IANBD + Hoescht) and as well as the triple (pSIVA-IANBD + Hoescht + antibody) stained cells were readily identifiable in the mixed cell population. They suggested that pSIVA-IANBD enables detection of PS, a hallmark of apoptosis by imaging of viable as well as post-fixed cells. Furthermore, since pSIVA-IANBD is not toxic to cells and does not require a washing step, it can be maintained in cultures with only a single application and no medium change for up to 72h. This allows continuous live monitoring of cells for apoptosis, cells can then be fixed and labeled with additional biomarkers of interest and imaged. These features render pSIVA-IANBD a particularly useful tool for toxicological studies of novel drugs in cell-based assays. pSIVA-IANBD is also suitable for flow cytometry and may supercede the widely used Annexin V-FITC PS probe which has has limited applications outside of flow cytometry.
Citation Format: Lisa S. Heiden, Stan Krajewski, Payton D. Quintel, Sujay K. Singh. Novel techniques for identifying apoptosis with pSIVA-IANBD in live and fixed cells. [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 609. doi:10.1158/1538-7445.AM2013-609
Abstract 613: The chromatin remodeling protein BRG1 modulates BRCA1’s response to UV irradiation.
Authors: Zhang Ling , Chen Hua , Gong Feng 
Published: August 2014

Abstract
The SWI/SNF chromatin remodeling complex plays a role in the repair of UV-induced DNA damage. It was proposed that chromatin remodeling activities are utilized to increase the accessibility of NER machinery and checkpoint factors to the damaged DNA. It was shown recently that BRCA1 contributes to UV damage response by promoting photoproduct excision, triggering post-UV checkpoint activation and post replicative repair. In this study, we show that BRCA1 rapidly binds to UV damage sites when cells are undergoing DNA synthesis. In contrast, two phosphorylated forms of BRCA1 do not accumulate at sites of UV damage. Depletion of BRG1, a core subunit of the human SWI/SNF-BAF complex, impairs the recruitment of BRCA1 to the damage sites and attenuates DNA damage induced BRCA1 phosphorylation. At UV lesions-stalled replication forks, BRG1 promotes RPA phosphorylation in response to UV irradiation, since UV-induced phosphorylation of chromatin bound RPA drops significantly when BRG1 is depleted in human cells. In addition, activation of ATR is attenuated when BRG1 is depleted. We propose that BRG1 functions upstream of BRCA1 and modulates its response to UV irradiation.
Citation Format: Ling Zhang, Hua Chen, Feng Gong. The chromatin remodeling protein BRG1 modulates BRCA1’s response to UV irradiation. [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 613. doi:10.1158/1538-7445.AM2013-613
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.