bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3623: Mesenchymal stem cells engineered with TAT peptide functionalized nanoparticles improve therapeutic efficacy of paclitaxel in an orthotopic lung tumor model
Authors: Prabha Swayam , Moku Gopikrishna , Layek Buddhadev , Panyam Jayanth 
Published: August 2019

Abstract
Tumors are characterized by uneven vascular perfusion with near normal blood flow in the outer most regions, while the inner regions can be avascular. In addition, elevated interstitial fluid pressure and rigid extracellular matrix compromise intra-tumoral solute transport and hence limited drug efficacy. Mesenchymal stem cells (MSCs) have the unique advantage of being able to migrate specifically to both primary tumors and metastases following systemic administration. However, poor payload capacity of MSCs limits their use as drug delivery carriers. To address this issue, we investigated polymeric nanoparticles that were functionalized with transactivator of transcription (TAT) peptide. Paclitaxel loaded PLGA nanoparticles (15-16 % w/w paclitaxel; diameter of 225 ± 7 nm; and zeta potential of −15 ± 4 mV) were prepared by emulsion-solvent evaporation method, followed by TAT-conjugation to the surface of nanoparticles via maleimide-thiol chemistry. Nanoengineered MSCs were generated by incubating MSCs in suspension with 100 µg/mL paclitaxel loaded nanoparticles for 4 hours at 37°C. Our studies demonstrated that TAT functionalization improved the paclitaxel loading in MSCs. In addition, engineering MSCs with TAT functionalized nanoparticles did not affect the differentiation and migration properties of MSCs. Further, MSCs engineered with TAT peptide functionalized nanoparticles resulted in significant inhibition of tumor growth and overall improved survival in a mouse orthotopic model of lung cancer compared to that with free drug treatment. In summary, our results demonstrated that MSCs nanoengineered using TAT functionalized nanoparticles can serve as an efficient carrier for tumor specific delivery of anticancer drugs, resulting in greatly improved therapeutic efficacy.
Citation Format: Swayam Prabha, Gopikrishna Moku, Buddhadev Layek, Jayanth Panyam. Mesenchymal stem cells engineered with TAT peptide functionalized nanoparticles improve therapeutic efficacy of paclitaxel in an orthotopic lung tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3623.
Abstract 3628: Comparison of CD44 expression in pancreatic cancer, pancreatic stem and normal pancreatic cells: Development of CLENs for tumor targeting and therapy using cell models
Authors: Adegunle Dotun D. , Ansah Eugene Boakye , Nguyen Danny , Sanghvi Kanchi , Goodrich Drew , Campbell Robert 
Published: August 2019

Abstract
Purpose: The incidence of drug resistance in pancreatic cancer correlates with poor prognosis, increased disease progression and unfavorable treatment outcomes. CD44, a surface membrane proteoglycan has been identified to be directly involved in pancreatic cancer drug resistance and metastasis. As such, the aim of this research was to screen various pancreatic cells for their expression of CD44, and to begin the early design and development of cell membrane lipid-extracted nanoliposmes (CLENs) for enhanced targeting and therapy.
Methods: Three pancreatic cancer cells- Panc-1, MiaPaCa 2, MS1 VEGF and a normal cell line- hTERT- were employed for this study. Stem cell, Mia PaCa-2, served as a positive control for screening purposes. Four liposome compositions were prepared using various ratios of DOPC, Chol, DPPE-PEG5000, and cellular membrane lipid-extracted (LE) was derived from target cell, Panc 1. To evaluate CD44 glycoprotein expression, cells were seeded in 48-well plates and incubated overnight. Fluorescence measurements were determined at excitation wavelength of 485/25 and emission wavelength at 528/20 nm. G44-26 monoclonal antibody was used for CLENs antibody conjugation studies. A Sephadex G-25 column was used for separation of bound and unbound antibody material, and fluorescence detection was used for cell culture analysis. Fluorescence detection was performed at excitation and emission wavelengths of 530/25 and 590/25, respectively.
Results: The relative level of CD44 expression for each of the cell lines was as follows. Panc1&gt;Mia PaCa-2 = hTERT&gt;MS1-VEGF. There was a statistically significant difference between Panc-1 and Mia Paca 2 (P&lt;0.001), between hTERT and MS1 VEGF (P&lt;0.05), and between Panc-1 and hTERT (P&lt;0.0001). The inclusion of Panc1-LE in combination with additional liposome components did not increase cellular uptake significantly. The conjugation of G44-26 monoclonal antibody to the liposomes increased average size of all 4 preparations. Average size for CLENs and G44-26 monoclonal antibody -CLENs increased from 140.75 ± 3.22 nm to 250.23 ± 15.31 nm.
Conclusion: Future studies are required to demonstrate the effect of G44-26 monoclonal antibody liposome conjugates to further exploit the optimal expression of CD44 for pancreatic drug targeting.
Citation Format: Dotun D. Adegunle, Eugene Boakye Ansah, Danny Nguyen, Kanchi Sanghvi, Drew Goodrich, Robert Campbell. Comparison of CD44 expression in pancreatic cancer, pancreatic stem and normal pancreatic cells: Development of CLENs for tumor targeting and therapy using cell models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3628.
Abstract 3631: Development of targeted nanoformulation of talazoparib for combined chemoradiation therapy in lung cancer
Authors: Singh Bijay , Abdelhalim Mostafa , Warrington Stephanee , Sridhar Srinivas 
Published: August 2019

Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) therapy exploits a synthetic lethality strategy in cancers with inherent damage in DNA repair or transcription pathways. Talazoparib is a potent PARPi that is currently indicated for oral inhibitor therapy in several cancer clinical trials. Oral administration of these inhibitors typically results in poor bioavailability and tumor accumulation. In contrast, nanoparticle formulation provides a safe vehicle for parenteral administration of therapeutic drugs with sustainable release reducing systemic toxicity and also protect from surveillance of immune cells, thereby increasing the bioavailability of the drugs in vivo. Moreover, targeting strategy for the nanoparticles will improve the accumulation of drugs in the tumors. Here, we developed a targeted formulation of Talazoparib (NanoTLZ) which was decorated with anti-EGFR antibody as a ligand to ameliorate the cellular uptake of NanoTLZ via EGFR-mediated endocytosis. In vitro tests showed that NanoTLZ is more effective in cell growth inhibition than free Talazoparib. When combined with radiation with different doses from 2-10Gy, NanoTLZ showed a strong radiosensitization effect as evidenced with almost no colonies formation at 6 Gy of radiation dose. The high therapeutic efficacy of combined chemoradiation therapy in Calu 6 cell line can be attributed to the higher accumulation of NanoTLZ in the cancer cells as compared to the free Talazoparib which is also marred with efflux of the drug from the cells. The slow and sustained release of Talazoparib from nanoparticle formulation inside the cells lead enhanced inhibition of DNA repair pathways. These studies provide very encouraging results to evaluate the efficacy of these nanoparticles in lung cancer animal models.
Citation Format: Bijay Singh, Mostafa Abdelhalim, Stephanee Warrington, Srinivas Sridhar. Development of targeted nanoformulation of talazoparib for combined chemoradiation therapy in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3631.
Abstract 3639: EGCG-gold nanoparticles exhibit greater anti-tumor activity over conventional gold nanoparticles or EGCG due to potential synergistic interactions
Authors: Chavva Suhash Reddy , Deshmukh Sachin Kumar , Kanchanapally Rajashekhar , Tyagi Nikhil , Coym Jason W. , Singh Ajay P. , Singh Seema 
Published: August 2019

Abstract
Epigallocatechin gallate (EGCG) possesses significant anti-tumor activity and binds to laminin receptor over-expressed on cancer cells with high affinity. However, the use of EGCG in therapeutics is limited due to its poor bioavailability and limited stability. Gold nanoparticles (GNPs) serve as excellent drug carriers and protect the conjugated drug from enzymatic metabolization. Here, we investigated if EGCG-formulated GNPs (E-GNPs) would demonstrate superior anti-cancer activity compared to EGCG or conventionally-synthesized citrate-GNPs (C-GNPs) due to their synergistic interactions. Cell viability studies showed greater growth inhibition by E-GNPs, compared to EGCG, or C-GNPs. Cellular uptake studies revealed that, unlike C-GNPs, E-GNPs were taken-up more efficiently by cancerous cells than noncancerous cells. Furthermore, data showed that E-GNPs induced more apoptosis in cancer cells, compared to EGCG, and C-GNPs. From the mechanistic standpoint, we observed that E-GNPs inhibited the nuclear translocation and transcriptional activity of NF-κB with greater potency than EGCG, whereas C-GNPs were only minimally effective. Altogether, our data suggest that E-GNPs can serve as effective anti-cancer agents.
Citation Format: Suhash Reddy Chavva, Sachin Kumar Deshmukh, Rajashekhar Kanchanapally, Nikhil Tyagi, Jason W. Coym, Ajay P. Singh, Seema Singh. EGCG-gold nanoparticles exhibit greater anti-tumor activity over conventional gold nanoparticles or EGCG due to potential synergistic interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3639.
Abstract 3645: Cooperation between canonical Wnt and TGF-beta pathways promotes sarcoma angiogenesis
Authors: Hawkins Allegra G. , Pedersen Elisabeth A. , Jiang Wei , Treichel Sydney , Sperring Colin , Read Jay , Magnuson Brian , Patel Rajiv M. , Thomas Dafydd , Chugh Rashmi , Lawlor Elizabeth R. 
Published: August 2019

Abstract
Local and metastatic progression of solid tumors depends on crosstalk between tumor cells and the tumor microenvironment (TME), including both stromal cells and the extracellular matrix (ECM). We recently showed that high Wnt/beta-catenin activity in Ewing sarcoma correlates with diminished patient survival and that canonical Wnt signaling alters the tumor secretome, influencing ECM protein composition. In light of this, we investigated the hypothesis that Wnt/beta-catenin supports tumor progression by modulating tumor: TME crosstalk. Our results reveal that, in discrete tumor cell sub-populations, beta-catenin activation sensitizes cells to TGF-beta ligands through derepression of the TGF-beta receptor, TGFBR2, resulting in canonical Wnt-induced, TGF-beta-dependent upregulation of TGF-beta targets. Significantly, these Wnt/TGF-beta responsive targets include multiple AngioMatrix genes that are known to alter the TME to promote angiogenesis, including tenascin-C and collagens. Studies of Ewing sarcoma models, in vitro and in vivo, as well as in two independent patient cohorts, confirm that a direct relationship exists between beta-catenin and TGF-beta activation in tumor cells and angiogenesis in the local TME. Mechanistically, this is due, in part, to tenascin C-mediated promotion of endothelial cell proliferation. Thus, functional cooperation between canonical Wnt and TGF-beta signaling in Ewing cells induces secretion of pro-angiogenic factors. This study reveals a novel link between Wnt and TGF-beta signaling in Ewing sarcoma and illustrates the critical contribution of tumor cell heterogeneity and tumor: TME crosstalk to sarcoma progression.
Citation Format: Allegra G. Hawkins, Elisabeth A. Pedersen, Wei Jiang, Sydney Treichel, Colin Sperring, Jay Read, Brian Magnuson, Rajiv M. Patel, Dafydd Thomas, Rashmi Chugh, Elizabeth R. Lawlor. Cooperation between canonical Wnt and TGF-beta pathways promotes sarcoma angiogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3645.
Abstract 3657: Defining the role of the RNA-binding protein MSI2 in neuroblastoma
Authors: Pilgrim Adeiye , Cuya Selma , Chen Dongdong , Schnepp Robert 
Published: August 2019

Abstract
Neuroblastoma (NB) is the most common extracranial solid tumor of childhood with a 5-year survival rate approaching 50% in high-risk patients and like other pediatric cancers, lacks many targetable mutations. Thus, novel therapeutic approaches are needed. Previous research has shown that the RNA-binding protein (RBP), LIN28B, enhances MYCN expression and induces NB formation. Additionally, we previously demonstrated that LIN28B-RAN-AURKA signaling drives NB oncogenesis. These results highlight the role of RBPs in modulating NB tumorigenesis.
The Musashi family includes RBPs that have been previously shown to be associated with worse prognosis in adult malignancies, including colon cancer and pancreatic cancer, among others. Thus, we speculated that the Musashi family might influence aggressive phenotypes in pediatric tumors, such as neuroblastoma. MSI2 is robustly expressed in neuroblastoma tumors, and, indeed, increased levels of Musashi-2 (MSI2) correlate with worse NB prognosis. In order to begin to elucidate its role in NB tumorigenesis, we knocked-down MSI2 in human NB cell lines using multiple independent short hairpin RNAs (shRNA) and small interfering RNAs (siRNA) and examined the impact on proliferation, survival, and downstream target genes relative to scrambled control RNA-treated cells. From these experiments, we observed decreased colony formation in clonogenic assays, increased apoptosis and decreased proliferation. To gain an initial understanding of the downstream targets that MSI2 influences, we performed Nanostring analysis in 2 human NB cell lines, Kelly and SK-N-DZ and found that knocking down MSI2 led to a downregulation of many cancer-related genes including IDH2 and other metabolic targets. IDH2 is a mitochondrial enzyme and its mutant is known to be involved in gliomagenesis. Changes in IDH2 expression have also been linked to epigenetic alterations. Finally, wild-type IDH2is upregulated in lung cancer and contributes to tumor growth. Therefore, we are currently examining the functional relationship between MSI2 and IDH2 in NB.
Citation Format: Adeiye Pilgrim, Selma Cuya, Dongdong Chen, Robert Schnepp. Defining the role of the RNA-binding protein MSI2 in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3657.
Abstract 3659: Alyref is a novel binding partner and co-factor for MYCN-driven oncogenesis in neuroblastoma
Authors: Nagy Zsuzsanna , Kanikevich Maxwell , Koach Jessica , Mayoh Chelsea , Carter Daniel , Liu Tao , Du Yanhua , Jiang Cizhong , Haber Michelle , Norris Murray , Cheung Belamy , Marshall Glenn 
Published: August 2019

Abstract
MYCN amplification is a poor prognostic indicator in neuroblastoma associated with high-risk disease. Therapies that directly repress the MYCN oncogenic signal in neuroblastoma are limited. We and others have shown that MYCN requires multiple cofactors to increase its protein stability in neuroblastoma cells, so that the very high MYCN levels required to drive tumourigenesis can be achieved. Here, we have identified ALYREF, a nuclear molecular chaperone protein, as a novel regulator of MYCN function in neuroblastoma. High expression of ALYREF predicted poor neuroblastoma patient survival and substantially correlated with MYCN levels in a large dataset (n=649) of human neuroblastoma tumour samples. ALYREF mRNA expression was also significantly increased in ganglia cells from the homozygous TH-MYCN neuroblastoma mouse in comparison to ganglia from wild-type littermates. Using co-immunoprecipitation and mass spectrometry, we identified ALYREF, as a direct binding partner of nuclear MYCN protein. Chromatin immunoprecipitation showed that MYCN bound the ALYREF gene promoter, and knockdown MYCN by MYCN siRNAs decreased ALYREF expression. A set of overexpression and knockdown experiments in MYCN-amplified neuroblastoma cells revealed that MYCN and ALYREF form a positive forward feedback expression loop. Overexpression of ALYREF further increased MYCN expression and protein stability in MYCN-amplified neuroblastoma cells. We found that ALYREF had a critical function in regulating the turnover of MYCN protein through transcriptional repression of the E3 protein ubiquitin ligase, NEDD4. The stabilized N-Myc oncoprotein enhanced ALYREF expression and stimulated cell growth of neuroblastoma. Additionally, we demonstrated that ALYREF plays a significant role in maintaining cell viability and proliferation of MYCN-amplified neuroblastoma cells. Taken together, our findings demonstrate a crucial role for ALYREF in regulating MYCN function and suggest that ALYREF-mediated stabilization of MYCN protein contributes to the development and progression of the disease. Thus inhibition of ALYREF activity using small molecules is a potential therapy for MYCN-amplified tumours.
Citation Format: Zsuzsanna Nagy, Maxwell Kanikevich, Jessica Koach, Chelsea Mayoh, Daniel Carter, Tao Liu, Yanhua Du, Cizhong Jiang, Michelle Haber, Murray Norris, Belamy Cheung, Glenn Marshall. Alyref is a novel binding partner and co-factor for MYCN-driven oncogenesis in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3659.
Abstract 3661: GLI1 contributes to proliferation, survival and drug-resistance of Ewing sarcoma (EWS) cells
Authors: Yoon Joon Won , Lamm Marilyn , Iannaccone Philip , Walterhouse David 
Published: August 2019

Abstract
Ewing sarcoma (EWS) is characterized by TET-ETS fusions, most commonly the EWSR1-FLI1 fusion. GLI1, a transcription factor in the Hedgehog (HH) signal transduction pathway and target of canonical HH signaling, is a direct transcriptional target of EWSR1-FLI1. A role for the HH signaling pathway and GLI1 in acquisition of a multidrug resistance phenotype has been previously observed in several human cancers. The role of the HH signal transduction pathway and GLI1 in the biology of EWS remains incompletely understood. We hypothesize that the majority of EWS cell lines express GLI1 based on non-canonical up-regulation by EWSR1-FLI1 and that further up-regulation of GLI1 may be associated with the development of drug resistance. Here, we show that EWS cell lines (CHLA-9, CHLA-10, CHLA-258, TC-32 and TC-71) express canonical HH pathway components (PTCH1, SMO, GLI1 and GLI3) and that cells lines established at the time of recurrence have higher GLI1 expression (CHLA-258 and TC-71) than those established at the time of diagnosis (CHLA-9, CHLA-10 and TC-32). Exposure to Sonic HH ligand in order to activate canonical HH signaling did not affect cell viability (MTT assay), proliferation (BrdU assay), or apoptosis (caspase 3/7 assay). However, inhibition of GLI1 activity with GANT61 reduced GLI1 expression (qRT PCR), cell viability (MTT assay) and cell proliferation (BrdU assay) but increased apoptosis (caspase 3/7 assay) and sensitivity of the cells to vincristine (VCR) (MTT assay), suggesting GLI1 plays roles in each of these processes. We then established VCR-resistant EWS cell lines (TC-71 [45-fold increase in the IC-50] and TC-32 [27-fold increase in the IC-50]) by exposing cells to serially increasing concentrations of VCR. We used an 86-gene cancer drug resistance PCR array (Qiagen) to characterize gene expression differences between untreated vs. recurrent EWS cell lines and between parental vs. VCR-resistant EWS cell lines. Among the changes in gene expression, we showed higher GLI1 expression in the recurrent EWS cell lines (CHLA-258 cells [4.8-fold] and TC-71 [3.4-fold]) vs. untreated CHLA-9 cells, and in VCR-resistant TC-71 cells (2.2-fold) vs. parental TC-71 cells. Down-regulation of GLI1 by GANT61 or GLI1 siRNA enhanced sensitivity of the cells to VCR. Our results suggest that GLI1 expression contributes to proliferation, survival and drug-resistance of EWS cell lines. Strategies to inhibit GLI1 may have therapeutic benefit in EWS.
Citation Format: Joon Won Yoon, Marilyn Lamm, Philip Iannaccone, David Walterhouse. GLI1 contributes to proliferation, survival and drug-resistance of Ewing sarcoma (EWS) cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3661.
Abstract 3669: Defining an ELAVL1-Musashi 2 signaling cascade in neuroblastoma tumorigenesis
Authors: Cuya Selma M. , Pilgrim Adeiye , Rathi Komal , Chen DongDong , Schnepp Robert 
Published: August 2019

Abstract
Background: Patients with high-risk neuroblastoma endure an extremely intense, multidrug treatment regimen and yet, approximately half of them die, thus mandating a better approach to this cancer. Our laboratory is investigating the overarching hypothesis that RNA binding proteins (RBPs), which play key roles in balancing self-renewal, differentiation, and cell proliferation, are deregulated in neuroblastoma, and drive oncogenic signaling networks. Therefore, RBPs may constitute novel targets for therapeutic development. In this work, we focus on Musashi 2 (MSI2), an RBP that has been shown to play a critical role in the maintenance of stem cell populations and in the formation of aggressive tumors, notably in acute myeloid leukemia and in colon cancer. The role of MSI2 in neuroblastoma, however, has not been assessed and is the focus of this investigation.
Methods: To test this hypothesis, we used in silico analysis of neuroblastoma gene expression datasets annotated with clinical parameters. Additionally, we used shRNAs to manipulate transcripts of interest in neuroblastoma cells and measured effects on cell proliferation, cell cycle status, and apoptosis.
Results: Gene expression profiling revealed that MSI2 is robustly expressed in neuroblastoma cell lines, tumors, and patient derived xenografts, within both the MYCN and non-MYCN amplified context. Immunoblotting in a representative panel of lines confirmed the expression of MSI2 at the level of protein. High MSI2 expression was associated with more advanced stages of neuroblastoma across multiple independent datasets and was correlated with worse survival. Depletion of MSI2 using four independent shRNAs led to 2 to 3-fold decreased proliferation across four cell lines that was due in part to increased apoptosis. Another RBP, ELAVL1, is also expressed within neural lineages, and has been shown to regulate MSI1 expression. We hypothesized that ELAVL1 might similarly promote MSI2 expression and we demonstrated that, ELAVL1 depletion led to decreased MSI2 expression.
Conclusions: MSI2 is robustly expressed in multiple models of neuroblastoma and appears to drive increased proliferation and survival. Currently, we are investigating the functional interplay between ELAVL1 and MSI2 providing a foundation for designing strategies to target the ELAVL1-MSI2 interaction for therapeutic effect.
Citation Format: Selma M. Cuya, Adeiye Pilgrim, Komal Rathi, DongDong Chen, Robert Schnepp. Defining an ELAVL1-Musashi 2 signaling cascade in neuroblastoma tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3669.