bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3619: Nanoparticle formulation of VERU 111 for pancreatic cancer treatment
Authors: Kashyap Vivek K. , Hafeez Bilal B. , Wang Qinghui , Chauhan Neeraj , Nagesh Prashanth K. , Yallapu Murali M. , Miller Duane D. , Li Wei , Jaggi Meena , Chauhan Subhash C. 
Published: August 2019

Abstract
Background: Pancreatic cancer (PanCa) is one of the leading causes of cancer-related mortality in the United States due to very limited therapeutic options. Thus, developing novel therapeutic strategies will help for the management of this disease. We recently identified VERU-111, a novel synthetic molecule which showed potent anti-cancer effect against PanCa via targeting clinically important βIII and βIV tubulin isoforms. In this study, we synthesized and characterized its novel nanoformulation (MNP-VERU) and evaluated its therapeutic effects in vitro and xenograft mouse model.
Methods: MNPs were prepared by chemical precipitation method and loaded with VERU-111 using diffusion method. This formulation was characterized for particle size, chemical composition, and drug loading efficiency, using various physico-chemical methods (TEM, FT-IR, DSC, TGA, and HPLC). The internalization of MNP-VERU was achieved after 6 hours incubation with MNP-VERU in PanCa cells. To determine therapeutic efficacy of MNP-VERU, we performed various in vitro (MTS, wound healing, boyden chamber real-time xCELLigence, and apoptosis assays) and in vivo (mouse tumor xenograft) studies using PanCa. Effect of MNP-VERU on various key oncogenic signaling pathways, and miRNAs was evaluated by Western blot, immunohistochemistry (IHC), confocal microscopy, qRT-PCR and in situ hybridization (ISH) analyses respectively.
Result: Our novel MNP-VERU formulation provided average size of 110 nm in dynamic light scattering (DLS) and exhibited -8.23 to -11.65 mV zeta potential with an outstanding loading efficiency (94%). Cellular uptake and internalization studies demonstrate that MNP-VERU escape lysosomal degradation, providing efficient endosomal release to cytosol. MNP-VERU showed remarkable anti-cancer potential in various PanCa cells (Panc-1, AsPC-1, HPAF-II, BxPC-3, MiaPaca) and more effectively repressed βIII and βIV tubulin isoforms via restoring the expression of miR-200c. MNP-VERU more effectively suppressed AsPC-1 cells derived xenograft tumors in athymic nude mice.
Conclusions: Taken together, our results suggest that MNP-VERU has more anti-cancer potential than free VERU-111 against PanCa. MNP-VERU may reduce the toxicity and improve the bioavailability of free VERU-111 and could be used for the management of PanCa.
Citation Format: Vivek K. Kashyap, Bilal B. Hafeez, Qinghui Wang, Neeraj Chauhan, Prashanth K. Nagesh, Murali M. Yallapu, Duane D. Miller, Wei Li, Meena Jaggi, Subhash C. Chauhan. Nanoparticle formulation of VERU 111 for pancreatic cancer treatment [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 3619.
Abstract 362: Depolymerized fucosylated chondroitin sulfate in pancreatic cancer, metastasis and cancer-associated thrombosis
Authors: Yao Yiming , Godugu Kavitha , Jin Yongsheng , Jiang Yi , MOUSA SHAKER A. 
Published: August 2019

Abstract
The Depolymerized fucosylated chondroitin sulfate (dHG) prepared from natural fucosylated chondroitin sulfate, which was isolated from sea cucumber, showed remarkable anti-cancer efficacy in suppressing primary tumor growth, tumor angiogensis and metastasis. The anti-metastasis properties were demonstrated in multiple mouse cancer models, including B16F10 melanoma-induced lung metastasis model, 4T1 breast cancer induced lung metastasis model, Luciferase transfected SUIT-2 pancreatic cancer induced lung metastasis model as well as surgical removal SUIT-2 pancreatic tumor induced metastasis. Additionally, dHG demonstrated potent anti-angiogenesis efficacy against various growth factors-mediated angiogenesis. Cancer metastasis is a multiple process and regulated by a complex signaling network. Our In vitro studies demonstrated that dHG is a multiple targets agent. dHG inhibits angiogenesis and P-selectin, both are involved in cancer metastasis. dHG also induces TFPI release, especially TFPI-2 release. TFPI-2 has been recognized as a potent tumor suppressor. It inhibits the migration and invasion of human cancer cells. Low expression of TFPI-2 results in enhanced growth and metastasis of a variety of human tumors. Thrombelastography (TEG) showed that mixing of dHG and 1-10 picogram of TFPI-1 or TFPI-2 generated significant anti-thrombotic effect while dHG itself has very low anticoagulant activity. Thrombosis is a significant problem for cancer patient. dHG potentially inhibits thrombosis and normalizes hemostasis. Our studies demonstrated that dHG is a promising therapeutic agent for metastatic cancer and cancer-associated thrombosis management.
Citation Format: Yiming Yao, Kavitha Godugu, Yongsheng Jin, Yi Jiang, SHAKER A. MOUSA. Depolymerized fucosylated chondroitin sulfate in pancreatic cancer, metastasis and cancer-associated thrombosis [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 362.
Abstract 3627: Development of CLENs for future treatment & diagnostic detection using cell models of drug-resistant ovarian cancer
Authors: Amini Negar , Emerson Joshua , Clement Jenel 
Published: August 2019

Abstract
Current guidelines suggest the use of a platinum agent and a taxane as first line therapy for ovarian cancer where total surgical resection is limited. Liposomal preparations of these drugs have demonstrated therapeutic value by increasing drug uptake and reducing toxicity. The following research aims to improve target specificity by employing a multi-strategic approach to drug targeting and treatment in vitro. Cellular membrane lipid-extracted nanoliposomes (CLENs) were constructed in part from lipid extracts (LE) derived from the membrane of multidrug resistant ovarian cancer (SKOV-3-MDR) cell lines, and more conventional components of liposomes. Formulations of greatest interest were selected after comparing cellular uptake studies of conventional liposomes to various types of CLENs composed of mixed ratios of DOPC, cholesterol, and LE. Cellular uptake was measured by rhodamine fluorescence (RF) following 24 hours incubation in 48 well plates, where RF was used as an indicator of cellular uptake. To determine effectiveness of LE, formulations with and without synthetic cationic lipid DOTAP were compared. Flow cytometry was used to evaluate liposome binding. Additional studies include drug loading efficiency and SRB cytotoxicity studies involving cisplatin, and the effect of additional inclusion of MAG-C (magnetic material) in the SKOV-3 lipid extract-containing liposomes. CLENs containing 15% LE demonstrated greater uptake compared to CLENs prepared with 0% and 5% LE content. Minimal uptake was observed in non-target cancer cell lines (prostate cancer-CRL-1740 and gliobastoma-U87MG), as well as with normal pancreas, non-malignant (hTERT) cell line. The fluorescence intensity values reported for SKOV-3-MDR, CRL-1740, U87-MG and hTERT, were 437 ± 153, 295 ± 67, 57 ± 6, and 29 ± 6, respectively. The additional inclusion of DOTAP showed significant cellular uptake with and without LE. Flow cytometry showed greater initial binding of CLENs to target cells when LE was included in preparations. Incorporation efficiency of cisplatin into SKOV-3 CLENS was 67%. Chemotherapy drug-loaded CLENs is an appealing vehicle as it addresses many parameters. Early findings suggest that CLENS is a suitable vehicle for targeting and treatment using a drug-resistant ovarian cancer cell line. CLENS allows for faster initial nanoparticle binding, cell-type specific uptake, and enhances cytotoxicity. Our encouraging results corroborate this theorem, showing greater targeting with reduced uptake by non-target cells. Additional studies involving MAG-C are currently underway.
Citation Format: Negar Amini, Joshua Emerson, Jenel Clement. Development of CLENs for future treatment & diagnostic detection using cell models of drug-resistant ovarian 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 3627.
Abstract 363: CYT01B, a novel RAD51 inhibitor, acts synergistically with PARP inhibitors
Authors: Maclay Tyler , Day Melinda , Mills Kevin 
Published: August 2019

Abstract
Genomic instability is recognized as a driver of tumorigenesis and cancer progression. Loss of tumor suppressors or activation of oncogenes can induce DNA damage stress, promoting genomic instability and creating dependencies upon key DNA repair pathways. These dependencies can be targeted therapeutically to induce synthetic lethality. We have developed a novel RAD51 inhibitor, CYT01B, which we have previously shown to be preferentially active in Activation Induced Cytidine Deaminase (AID) expressing cells, and in other tumor derived cell lines with elevated levels of DNA damage and/or reduced DNA repair capabilities. CYT01B acts by reducing RAD51 focus formation, and depleting the nuclear pool of RAD51. We have observed anti-tumor effects with CYT01B in preclinical models, but have yet to determine if RAD51 could act as a sensitizer to current therapeutics. A main resistance mechanism to PARP inhibitors is the overexpression of RAD51, making it an attractive potential combination for our RAD51 inhibitor. To determine potential drug synergy, a matrix study was performed with CYT01B (concentration range of 20nM to 5µM) and 5 different PARP inhibitors including olaparib (78nM to 5µM), niraparib (78nM to 5µM), veliparib (780nM to 50µM), rucaparib (156nM to 10µM), and talazoparib (39nM to 2.5µM). The combination matrix was tested in cell lines of varying AID expression and PARP inhibitor sensitivity: ARPE19/HPV16 (HPV immortalized epithelial cell line), KYSE-70 (head and neck cancer cell line), Daudi (Burkitt’s Lymphoma cell line), HCC1143 (TNBC), and BT20 (TNBC). We used both the Loewe Additivity model and the Bliss Independence model to determine drug interaction (synergistic, independent, or antagonistic). In general, we observed synergy with all the combinations in the tumor derived cell lines. In the transformed epithelial cell line, synergy was observed only in the olaparib combination. The strength of the synergistic effect differed amongst the PARP inhibitors, with olaparib giving the strongest synergy scores. From this data we hypothesize that the synergistic activity with CYT01B is related to the PARP trapping efficiency of the PARP inhibitors; greater trapping efficiency the greater the synergy. These data suggest that CYT01B may be active as a combinatorial therapy with PARP inhibitors. Overall, we conclude that there is significant potential for combining RAD51 and PARP inhibition in future cancer treatment strategies, and warrants future exploration in vivo.
Citation Format: Tyler Maclay, Melinda Day, Kevin Mills. CYT01B, a novel RAD51 inhibitor, acts synergistically with PARP inhibitors [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 363.
Abstract 3632: Enhanced efficacy of optimized phenethyl isothiocyanate and cisplatin co-encapsulated liposome nanoparticle for treatment of non-small cell lung cancer
Authors: Sun Mengwei , Shi Yi , Pasqua Anthony Di 
Published: August 2019

Abstract
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, which is the leading cause of cancer-related death in the United States. Accounting for about 85% of all lung cancers, NSCLC is difficult to treat and its survival rates are low. After decades of basic and clinical research, the most effective treatments still involve the first-generation anticancer agent cisplatin (CDDP) in combination with other drugs. Naturally-occurring compound, phenethyl isothiocyanate (PEITC), can be used to sensitize NSCLC cells to CDDP. We have previously proved that co-encapsulation of PEITC and CDDP in liposomes enhances the cytoxicity toward NSCLC cells, compared to free PEITC or CDDP. In this study, liposomal-PEITC-CDDP is optimized and the release of PEITC and CDDP from the nanoparticle is characterized. In vitro studies show that liposomal-PEITC-CDDP has a higher cytotoxicity toward both A549 and H596 human NSCLC cell lines than toward WI-38 and BEAS-2B human normal lung cell lines. Therfore, we have prepared an efficacious therapy with a potential for fewer side-effects due to low off-target toxicity.
Citation Format: Mengwei Sun, Yi Shi, Anthony Di Pasqua. Enhanced efficacy of optimized phenethyl isothiocyanate and cisplatin co-encapsulated liposome nanoparticle for treatment of non-small cell 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 3632.
Abstract 3637: Development of a polyethylenimine conjugated liner multiblock polymer to deliver VEGF siRNA for triple negative breast cancer
Authors: Li Yuanke , Zhao Zhen , Cheng Kun 
Published: August 2019

Abstract
Vascular endothelial growth factor (VEGF) plays important roles in the angiogenesis process and is correlated with high proliferation and metastasis of breast cancer, particularly in triple negative breast cancer (TNBC). Downregulation of VEGF expression with siRNA in cancer cells is therefore a potential strategy for TNBC treatment. A polyethylene glycol based bio-degradable, linear multiblock polymer was synthesized and conjugated with branched low-molecular-weight poly(ethyleneimine) (PEI) to form nanocomplexes with a VEGF siRNA. The nanocomplex can protect siRNA from serum degradation and deliver the VEGF siRNA into TNBC cells with 72% silencing activity and low cytotoxicity. In vitro activity studies showed that the siRNA nanocomplexes significantly inhibit 64% migration and 67% invasion of TNBC cells. Moreover, the nanocomplex exhibited efficient tumor penetration in a 3D tumor spheroid model, suggesting a good penetration capability of the nanocomplex in tumor microenvironment in vivo. More importantly, the VEGF siRNA nanocomplex efficiently inhibit tumor growth in vivo and successfully downregulate VEGF expression in the tumor. These results suggested that VEGF siRNA is a promising anti-tumor agent for TNBC therapy, and the PEI 1800 conjugated bio-degradable multiblock polymer is a promising system to deliver siRNAs to TNBC cells.
Note: This abstract was not presented at the meeting.
Citation Format: Yuanke Li, Zhen Zhao, Kun Cheng. Development of a polyethylenimine conjugated liner multiblock polymer to deliver VEGF siRNA for triple negative breast 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 3637.
Abstract 3649: Allelic imbalance in KMT2A-rearranged infant acute lymphoblastic leukemia
Authors: Yoo Byunggil , Farooqi Midhat S. , Kostadinov Rumen , Cheung Warren , Farrow Emily , Kelley Shannon , Miller Neil , Ge Bing , Gibson Margaret , Brown Patrick , Guest Erin M. , Pastinen Tomi 
Published: August 2019

Abstract
Background
Infant acute lymphoblastic leukemia (ALL) is a malignant disorder with poor clinical outcome. It is well-known that infant ALL cases with rearrangement of the KMT2A gene (KMT2A-r) have an even poorer prognosis than non-KMT2A-r cases. Interestingly, KMT2A-r infant ALL cases have remarkably few other genetic alterations. We hypothesized that non-coding events in cancer genomes (e.g. loss of expression or methylation) may play a role in this disease. Such events can be captured using genomic analyses in haploid genomes using analytical approaches for allelic imbalance quantification. Here, we examine whether allelic imbalance is a feature of infant ALL.
Methods
We performed whole genome sequencing (WGS) and RNA sequencing on peripheral blood or bone marrow specimens from 29 KMT2A-r cases and 14 non-KMT2A-r cases at diagnosis (DX), remission (MD), and relapse (RL) as applicable. WGS data from MD samples was phased using a 1000 Genomes reference panel. Biallelic expression was measured on the phased genome for transcripts with at least 2 SNPs and at least 15 aligned reads. Lesser allele fraction (LAF; allele fraction for the less prevalent allele) for DX/RL versus MD samples was compared for transcripts that had LAFs available in at least 3 cases using t-test. Transcript-level p-values were aggregated at the gene level using the Sidak method.
Results
Allelic imbalance in expression (LAF &lt;= 0.2) was observed in an average of about 600 genes per sample in infant ALL regardless of timepoint. Disease-specific allelic imbalance (skewed in DX samples but not in paired MD samples) was detected in 431 genes for the KMT2A-r cohort and 77 genes for the non-KMT2A-r cohort. A total of 38 genes with allelic imbalance were shared between the two cohorts. Notably, KMT2A was observed to be imbalanced in KMT2A-r samples. Genes of known significance that were found to be skewed included HOXA9 and PARP8.
Discussion
Our study suggests that allelic imbalance quantification may help uncover novel molecular mechanisms in infant ALL, especially KMT2A-r cases. However, similar to gene expression, the patterns of allelic imbalance in KMT2A-r cases at DX do not allow efficient prediction of which patients go on to relapse.
Citation Format: Byunggil Yoo, Midhat S. Farooqi, Rumen Kostadinov, Warren Cheung, Emily Farrow, Shannon Kelley, Neil Miller, Bing Ge, Margaret Gibson, Patrick Brown, Erin M. Guest, Tomi Pastinen. Allelic imbalance in KMT2A-rearranged infant acute lymphoblastic leukemia [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 3649.
Abstract 3676: Novel tumor suppressive role of Peptidylarginine deiminase IV involving cancer stem cell regulation in breast cancer models
Authors: Ochoa Humberto J. , Moshkovich Nellie , Tang Binwu , Yang Howard H. , Lee Maxwell P. , Wakefield Lalage M. 
Published: August 2019

Abstract
Breast cancer accounts for &gt;500,000 deaths annually worldwide. Despite therapeutic advances, treated patients often relapse with metastases. Emerging research indicates that relapse may be driven by a subpopulation of tumor cells termed cancer stem cells (CSCs), that are uniquely capable of self-renewal and have enhanced drug resistance. Understanding the properties of these CSCs is critical for development of more effective therapies. Peptidyl arginine deiminase 4 (PADI4) is an enzyme that catalyzes deimination of arginine to citrulline. Citrullination of histones modulates expression of key stem cell transcription factors in embryonic stem cells (Christophorou, et al., 2014, Nature 507:104), so we hypothesized that PADI4 could be involved in CSC regulation. We showed that PADI4 mRNA and protein are expressed at varying levels across a panel of breast cancer cell lines, and we knocked down PADI4 in two high expressing lines, MCF10Ca1h and MDAMB231-LM2. PADI4 knockdown did not alter tumor cell proliferation in vitro, but it enhanced migration and invasion and increased cell survival. Importantly, PADI4 knockdown increased clonogenicity and enhanced tumorsphere formation, suggesting that it specifically increases the CSC population. In vivo studies showed higher tumor initiation efficiency following PADI4 knockdown, and increased lung metastasis. PADI4 is predicted to have multiple isoforms with unknown biological activity that complicate PADI4 expression-based analysis in patient data sets. We circumvented this issue by pharmacologically inhibiting PADI4 in MCF10Ca1h to generate a transcriptomic signature reflecting PADI4 gene activity. This PADI4 gene activity signature was shown to correlate with lower tumor grade and better disease outcome in transcriptomic datasets from human ER+ breast cancers. In conclusion, our findings suggest that PADI4 functions as a tumor suppressor in breast cancer, in part through effects on the CSC.
Citation Format: Humberto J. Ochoa, Nellie Moshkovich, Binwu Tang, Howard H. Yang, Maxwell P. Lee, Lalage M. Wakefield. Novel tumor suppressive role of Peptidylarginine deiminase IV involving cancer stem cell regulation in breast cancer 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 3676.
Abstract 3684: The TGFβ2-Snail1-miRNATGFβ2 circuitry is critical for the development of aggressive functions in breast cancer
Authors: He Zhimin , Zheng Guopei , Zhang Zhijie , Liu Hao , Zhou Binhua Peter 
Published: August 2019

Abstract
There have been contradictory reports on the biological role of transforming growth factor-βs (TGFβs) in breast cancer, especially with regard to their ability to promote epithelial-mesenchymal transition. Here, we show that TGFβ2 is preferentially expressed in mesenchymal-like breast cancers and maintains the epithelial-mesenchymal transition phenotype, correlating with cancer stem cell -like characteristic, growth, metastasis and chemo-resistance and predicting worse clinical outcome. However, this is only true in ERα- breast cancer. In ERα+ luminal-type breast cancer, estrogen receptor interacts with p-Smads to block TGFβ signaling. Furthermore, we also identify a microRNAs (miRNAs) signature (miRNAsTGFβ2) that is weakened in TGFβ2-overexpressing breast cancer cells. We discover that TGFβ2-Snail1 recruits EZH2 and BMI1 to convert miRNAsTGFβ2 promoters from an active to repressive chromatin configuration and then repress miRNAsTGFβ2 transcription, forming a negative feedback loop. On the other hand, miRNAsTGFβ2 overexpression reverses the mesenchymal-like traits in agreement with inhibition of TGFβ2-Snail1 signaling in breast cancer cells. These findings clarify the roles of TGFβ2 in breast cancer and suggest novel therapeutic strategies based on the TGFβ2-Snail1-miRNATGFβ2loop for a subset type of human breast cancers.
Keywords: TGFβ, EMT, miRNA, Snail1, feedback loop This study was supported by grants from the National Natural Science Foundation of China (No.81672616, 81872197, 81402196, 81272450 and 81772825); Guangdong Natural Science Funds for Distinguished Young Scholars (2016A030306003); Guangdong Special Support Program (2017TQ04R809).
Note: This abstract was not presented at the meeting.
Citation Format: Zhimin He, Guopei Zheng, Zhijie Zhang, Hao Liu, Binhua Peter Zhou. The TGFβ2-Snail1-miRNATGFβ2 circuitry is critical for the development of aggressive functions in breast 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 3684.