bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3621: Targeted hyaluronic acid nanoparticles improve treatment response in pancreatic cancer
Authors: Jajja Mohammad Raheel , Zhu Lei , Wang Dazhi , Staley Charles A. , El-Rayes Bassel , Kooby David A. , Yang Lily 
Published: August 2019

Abstract
Pancreatic cancer has poor response to chemotherapy with desmoplastic stroma identified as a delivery barrier. We have developed a nanoparticle (NP) drug system using an engineered ligand of receptor binding region of urokinase plasminogen activator (ATF) and the catalytic domain of metalloprotease (MMP14) carrying SN38 (CPT-11 analog). Hyaluronic acid (HA), a naturally occurring protein was chosen as the backbone to produce a biocompatible NP. HA can also bind to CD44, highly expressed in epithelial cancers. Dual uPAR, CD44 targeting allows for targeted delivery and facilitates receptor mediated endocytosis of NP-drug complex. MMP14 activity degrades extracellular matrix to deplete the stromal barrier. SN38 was encapsulated and recombinant ATFmmp14 conjugated to surface of self-assembled hyaluronic acid spheres (200nm) to form the complete particle (HANP). Cytotoxicity assays were conducted to determine IC50 in cell lines. Patient derived xenograft (PDX) model of a drug resistant pancreatic cancer was used for efficacy studies. Orthotopically implanted tumors were treated with HANP (10mg/kg SN38 dosage) weekly for 6 weeks via tail vein and overall survival compared to conventional therapy. HANP in-vitro cytotoxicity was greater than conventional Irinotecan (&gt;80x) and liposomal irinotecan (&gt;900x) in a PDX derived cell line (Table 1). In-vivo efficacy study demonstrated a significant improvement in survival of PDX bearing mice with HANP (n=9) (median survival 50 days), compared to FOLFIRINOX (n=9) and Gemcitabine-nab-Paclitaxel (n=9) (median survival 37 days each) and no treatment (n=13) (median survival 22 days). Combination of HANP with a modified-FOLFIRINOX regimen (n=9) led to median survival &gt;72 days (p&lt;0.001). HANP alone or in combination with a modified FOLFIRINOX led to significantly improved survival in a pancreatic cancer PDX model. Further studies are underway to evaluate preclinical PD/PK for eventual translation as targeted therapy for pancreatic cancer.
In-vitro cytoxicity assay for IC50 determinationDrugIC50 (uM)HANP0.01SN-380.012Irinotecan0.8Liposomal Irinotecan9
Citation Format: Mohammad Raheel Jajja, Lei Zhu, Dazhi Wang, Charles A. Staley, Bassel El-Rayes, David A. Kooby, Lily Yang. Targeted hyaluronic acid nanoparticles improve treatment response in pancreatic 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 3621.
Abstract 3626: Develop novel nanoparticle formulations of disulfiram copper for cancer therapy
Authors: Chen Wu , Yang Wen , Stewart Landon F. , Coombs David T. , Shen Jianzhong , Chen Pengyu , LI Feng 
Published: August 2019

Abstract
Despite remarkable progress in cancer treatment, drug resistance remains a significant issue for prostate cancer, breast cancer, and others. Disulfiram (DSF), an alcohol-aversion drug, has been repurposed for cancer treatment and overcome drug resistance. DSF and copper ions form a copper diethyldithiocarbamate (Cu-DSF) complex which has a potent anticancer activity. However, the poor aqueous solubility of Cu-DSF creates a significant formulation challenge, and there is no formulation available for clinical use. We developed a Stabilized Metal Ion Ligand Nanocomplex (SMILE) technology to prepare Cu-DSF nanoparticle (NP) formulations where in situ formed DSF-Cu NPs were stabilized by an optimal amount of stabilizers (e.g. poly(ethylene glycol)-poly(lactide)). The SMILE technology involves a novel formulation design and an innovative preparation process using a 3D-printed microfluidic device. After optimizing the protocol, we can prepare Cu-DSF NPs with size in the sub-100 nm range which are suitable for intravenous injection and can target solid tumors through enhanced permeability and retention (EPR) effects. Cu-DSF NPs prepared with SMILE method showed high drug loading efficiency (above 90%) and high drug concentration (at least 2 mg/mL). The drug concentration of Cu-DSF NPs developed in our study was much higher than those in micelle NP formulations prepared with the classical film-dispersion method. Since we used generally recognized as safe (GRAS) excipients approved by the US Food and Drug Administration (FDA) or other excipients with well-recognized safety profiles, the developed NP formulations will have less regulatory hurdle for FDA approval. Because of the novel preparation process and unique formulation design, the SMILE technology can produce Cu-DSF NPs on a large scale and thus paved the way for its mass production and commercialization. We also determined the anticancer effects of Cu-DSF NPs with multiple assays including MTT assay, colony-forming assay, calcein-AM/propidium iodide staining, and others. Cu-DSF NPs showed excellent anticancer activity against various prostate cancer and breast cancer cells as well as drug-resistant cancer cells. In summary, we developed a novel SMILE method to prepare Cu-DSF NP formulations which could address drug delivery and formulation challenges of DSF-based chemotherapy and facilitate the clinical translation.
Citation Format: Wu Chen, Wen Yang, Landon F. Stewart, David T. Coombs, Jianzhong Shen, Pengyu Chen, Feng LI. Develop novel nanoparticle formulations of disulfiram copper for cancer therapy [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 3626.
Abstract 3629: Development of Combrestatin loaded vascular cell modified CLENS for targeting cellular models of tumor vascular endothelia in vitro
Authors: Sanghvi Kanchi S. , Campbell Robert , Yan Guang 
Published: August 2019

Abstract
Purpose: The American Cancer Society predicts that about 0.6 million people would die of cancer and about 1.7 million new cases will be diagnosed in the year 2018. One important goal of cancer treatment is to minimize uptake of the cytotoxic drug agent by normal tissues. CLENs (cell membrane lipid-extracted nanoliposomes) have been developed to enhance targeted delivery of drugs to cancer cells located in the tumor interstitial matrix environment. The purpose of this study was to evaluate the use of CLENs for tumor vascular targeting.
Methods: We expanded tumor endothelial cells derived from the pancreas followed by membrane extraction and the development of MS1-VEGF CLENs for vascular targeting. We evaluated the benefits of the additional inclusion of conventional liposome components (DOPC/Chol/DPPE-PEG5000) in various ratios, including the synthetic cationic lipid DOTAP (50 mol%), known for its vascular targeting characteristics when employed with conventional liposome components. We performed cellular uptake studies to determine relative level of selectivity in connection with the inclusion of LE (lipid extract) material. We determined also the effect of the additional inclusion of DOTAP in CLENs for targeting. We separated free drug from drug incorporated in CLENs using dialysis cassettes with MWCO of 10 kD. We evaluated the efficiency of Combrestatin A4 Phosphate (a microtubule-destabilizing agent) loading in CLENs by HPLC.
Results: The addition of (50 mol%) cationic lipid DOTAP content in CLENs increased the overall zeta potential of the preparation from -14.26 ± 3.65 mV to 10.24 ± 4.23 mV. The average particle size for MS1-VEGF CLENs was approximately 137 ± 7 nm. The cellular uptake studies revealed that CLENs consisting of 70 mol% LE demonstrated the greatest selectivity towards MS1 VEGF cells, when compared to minimal uptake observed for non-target human glioblastoma (U87-MG) cell control. However, the data suggest also an overwhelming cationic lipid effect when DOTAP was included in the CLENs. Where overall cellular uptake increased, the selectivity afforded by LE decreased. Preliminary drug loading studies (between 20 and 45%) suggested that LE inclusion in nanoliposomes influenced the capacity for drug loading.
Conclusion: The inclusion of MS1-VEGF lipid extract material in nanoliposomes improved vascular selectivity. The additional inclusion of DOTAP enhanced targeting, but the preference for target versus non-target cells had diminished. Additional studies are currently underway.
Citation Format: Kanchi S. Sanghvi, Robert Campbell, Guang Yan. Development of Combrestatin loaded vascular cell modified CLENS for targeting cellular models of tumor vascular endothelia in vitro [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 3629.
Abstract 365: Indotecan (LMP400), indimitecan (LMP776) and LMP744, a new class of non-camptothecin topoisomerase I inhibitors selective for schlafen11-positive and BRCA-deficient cells that synergize with olaparib
Authors: Marzi Laetitia , Szabova Ludmila , Ohler Zoe Weaver , Sharan Shyam , Beshiri Mike , Murai Junko , Kelly Kathy , Pommier Yves 
Published: August 2019

Abstract
To overcome the limitations of topoisomerase inhibitors, irinotecan and topotecan (chemical instability, drug efflux substrates, short half-life, dose-limiting bone marrow and gastrointestinal toxicity), we have developed the indenoisoquinolines (LMP400, LMP776 and LMP744). To rationally select patients for phase 2 clinical trials, we have taken two approaches. First, we mined the cancer cell lines genomic databases with CellMinerCDB and found that a dominant response determinant to the indenoisoquinolines is Schlafen 11 (SLFN11), a recently identified executor of cells undergoing replication stress. We validated this finding in isogenic cell lines. Second, because the major lesions generated by the trapping of TOP1 are replication-induced DNA double-strand breaks that are repaired by homologous recombination (HR), we determined whether the indenoisoquinolines exhibit a “synthetic lethality” in cells presenting BRCA1, BRCA2 or PALB2 deficiency. In addition, we tested wether this selectivity could be enhanced when combined with the PARP inhibitor, olaparib. Survival and cell cycle alterations were tested after treatment with the indenoisoquinolines as single agents in isogenic DT40, DLD1 and OVCAR cell lines, with BRCA1, BRCA2 or PALB2 deficiencies, and organoids cultured from patient-derived xenografts with BRCA2 loss, as well as in combination with olaparib. We found that BRCA1-, BRCA2- and PALB2-deficient cells are 3 to 5 times more sensitive to the indenoisoquinolines compared to isogenic cell lines. Moreover, combination treatments showed high synergy between all three indenoisoquinolines and olaparib. We also established the synergy between LMP400 (Indotecan) and olaparib in orthotopic allograft models derived from genetically engineered mouse models for serous epithelial ovarian cancer harboring BRCA1 loss. Better efficacy was observed with the combination over single agent treatments of LMP400 or olaparib. Our results provide a rationale for Phase 2 indenoisoquinoline clinical trials with the indenoisoquinolines in HR-deficient cancers as single agents and in combination with PARP inhibitors, and for measuring Schlafen 11 (SLFN11) as a clinical response determinant.
Citation Format: Laetitia Marzi, Ludmila Szabova, Zoe Weaver Ohler, Shyam Sharan, Mike Beshiri, Junko Murai, Kathy Kelly, Yves Pommier. Indotecan (LMP400), indimitecan (LMP776) and LMP744, a new class of non-camptothecin topoisomerase I inhibitors selective for schlafen11-positive and BRCA-deficient cells that synergize with olaparib [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 365.
Abstract 3653: Immunogenomic landscape of pediatric solid malignancies
Authors: Wei Jun S. , Brohl Andrew S. , Song Young K. , Najaraj Sushma , Gangalapudi Vineela , Walton Ashley , Wen Xinyu , Ladanyi Marc , Khan Javed 
Published: August 2019

Abstract
Malignancy remains the leading cause of disease-related death in children. To identify potential tumor-driving molecular targets and immunogenomic profiles in pediatric cancers, we performed RNA-seq analysis on a cohort of 792 pediatric solid malignant tumors across 14 different diagnoses in conjunction with additional 147 normal tissues for comparison. Sequencing data was analyzed for expressed mutations, fusion events, and expressional patterns, providing therapeutic targets and rich cancer biology for these childhood cancers. Furthermore, we describe immunogenomic features of the tumors including immune cell infiltrate, neoantigen expression, expression of immunomodulatory molecules, and T cell receptor repertoire. Across the cohort, we observed a striking correlation between the expressed neoantigen burden in tumors and enrichment of the effector immune signatures. Histology-specific immunogenomic patterns were also apparent. Several of the pediatric cancers such as alveolar soft part sarcoma and osteosarcoma exhibit rich immune cell infiltration and evidence for activated T cell activities, whereas others such as Ewing’s sarcoma and yolk sac tumors generally have a very low T cell infiltration. We demonstrate that RNA-seq is a powerful tool to identify clinically relevant and histology-specific recurrent mutations, novel oncogenic fusions, and translationally relevant immunogenomic patterns for pediatric cancers. This study also represents one of the largest of its type to date and provides a framework for future translational efforts in pediatric cancer.
Citation Format: Jun S. Wei, Andrew S. Brohl, Young K. Song, Sushma Najaraj, Vineela Gangalapudi, Ashley Walton, Xinyu Wen, Marc Ladanyi, Javed Khan. Immunogenomic landscape of pediatric solid malignancies [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 3653.
Abstract 3654: Recurrent deletions of 3q13.31 in human osteosarcoma commonly affect TUSC7 and LINC00901
Authors: Ameline Baptiste , Kovac Michal , Saba Karim H. , Barenboim Maxim , Nathrath Michaela , Nord Karolin H. , Baumhoer Daniel 
Published: August 2019

Abstract
Background: Osteosarcoma, the most common primary tumor of bone, generally harbors complex structural rearrangements. In this study, we identified frequent mono- and bi-allelic deletions of the two long non-coding RNAs TUSC7 and LINC00901, both located on the long arm of chromosome 3 (3q13.31). Their precise biological function remain largely unknown, although it was suggested that TUSC7 may participate in micro-RNA trapping and thereby could be involved in tumor suppressor gene regulation. Moreover, the presence of a TP53 responsive element upstream of their coding region suggests an involvement in the convoluted TP53 signaling pathway. Methods: Whole genome sequencing data (n=104) and Affymetrix Cytoscan arrays (n=52) were used to derive copy-number profiles of each tumor and interrogated for LINC00901 and TUSC7 deletions. These findings were validated in an independent set of 102 formalin-fixed and paraffin-embedded tissue samples using RNA in situ hybridization techniques. Results: Mono- and bi-allelic deletions were detected in 68 (43.5%) sequenced and array-profiled osteosarcomas. Of these, 34 tumors (50%) acquired deletions in both genes whilst additional focal deletions of TUSC7 and LINC00901 were acquired in 11 (16%) and 19 (28%), respectively. The four remaining cases (6%) revealed copy number losses within the intergenic region between TUSC7 and LINC00901. In addition, reduced amounts or complete losses of hybridisation signals were detected in similar proportions in the independent set of FFPE samples. Conclusions: We identified recurrent 3q13.31 deletions in 68/156 (43,5%) human osteosarcomas which seems remarkable in a tumor well known for its high amount of genomic complexity and intertumoral heterogeneity. TUSC7 and LINC00901 might act as downstream effectors of the TP53 pathway and could be functionally equivalent to TP53 inactivation in case of copy number loss. To further elucidate the consequences of 3q13.31 aberrations we aim to correlate our findings with transcriptome data which is currently ongoing.
Citation Format: Baptiste Ameline, Michal Kovac, Karim H. Saba, Maxim Barenboim, Michaela Nathrath, Karolin H. Nord, Daniel Baumhoer. Recurrent deletions of 3q13.31 in human osteosarcoma commonly affect TUSC7 and LINC00901 [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 3654.
Abstract 3658: Characterization of the role of L3MBTL3 in medulloblastoma tumorigenesis
Authors: Zhang Honglai , Fernandez Ester Calvo , Peabody Claire , Kuick Rork , Park Sung-Soo , Saunders Thomas , Camelo-Piragua Sandra , Rual Jean-Francois M. 
Published: August 2019

Abstract
Medulloblastoma is the most common malignant brain tumor of childhood. Therapeutic approaches to medulloblastoma have led to significant improvements but are achieved at a high cost to quality of life. The Notch pathway governs cell proliferation in many biological contexts, including medulloblastoma tumorigenesis. Using our proteomic platform, we discovered an interaction between RBPJ, a key co-factor of Notch for the mediation of Notch signals, and L3MBTL3, a methyllysine reader for which deletions are observed in medulloblastoma. We demonstrated that L3MBTL3 is part of a molecular mechanism linking the KDM1A demethylase to Notch signal modulation. We hypothesize that malfunction of this molecular mechanism may contribute to the previously suggested tumor suppressor role of L3MBTL3 in medulloblastoma. In a survival analysis using our L3mbtl3 KO mouse in combination with a genetically engineered mouse model of medulloblastoma, we validated our hypothesis that L3mbtl3 is a tumor suppressor in this disease context. Our discovery provides insights into the role of the L3MBTL3 in medulloblastoma that could be harnessed in the future for the therapeutic benefit of medulloblastoma patients.
Citation Format: Honglai Zhang, Ester Calvo Fernandez, Claire Peabody, Rork Kuick, Sung-Soo Park, Thomas Saunders, Sandra Camelo-Piragua, Jean-Francois M. Rual. Characterization of the role of L3MBTL3 in medulloblastoma 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 3658.
Abstract 3674: Protein levels of Piwi-like 1 and -2 protein are prognostic factors for muscle invasive urothelial bladder cancer patients
Authors: Eckstein Markus , Jung Rudolf , Weigelt Katrin , Sikic Danijel , Stöhr Robert , Geppert Carol , Agaimy Abbas , Lieb Verena , Hartmann Arndt , Wullich Bernd , Wach Sven , Taubert Helge W. 
Published: August 2019

Abstract
The Piwi-like proteins are essential for stem-cell maintenance and self-renewal in all multicellular organisms. We analyzed the expression of Piwi-like 1 and Piwi-like 2 by immunohistochemistry (IHC) in 95 muscle invasive bladder cancer (MIBC) samples using tissue microarray. Application of an immunoreactive score (IRS) revealed 37 and 45 patients who were Piwi-like 1 and -2 positive (IRS&gt;2). IHC results were correlated with clinico-pathological and survival data. The expression of both proteins was positively correlated with each other, lymph node metastasis and expression of CK20 and GATA 3. A negative correlation for both proteins was detected for disease-specific survival (DSS), recurrence, Ki67/MIB1 proliferation index, and CK5 expression. Detection of Piwi-like 1 protein positivity was associated with poor DSS (P=0.019; log rank test, Kaplan-Meier analysis), and in multivariate Cox’s analysis (adjusted to tumor stage and tumor grade), it was an independent prognostic factor for DSS (RR=2.16; P=0.011). Piwi-like 2 positivity was associated with DSS (P=0.008) and relapse-free survival (RFS; P=0.040), and in multivariate Cox’s analysis, Piwi-like 2 positivity was an independent prognostic factor for DSS (RR=2.46; P=0.004) and RFS (RR=3.0; P=0.003). Most interestingly, in the basal type patient subgroup (CK5+/CK20−), Piwi-like 2 positivity was associated with poorer DSS, OS and RFS (P&lt;0.001, P&lt;0.001 and P=0.006; log rank test). In multivariate analysis, Piwi-like 2 positivity was an independent prognostic factor for DSS (RR=10.49; P=0.001), OS (RR=5.71; P=0.001) and RFS (RR=6.35; P=0.016). In summary, Piwi-like 1 and -2 positivity are associated with clinico-pathological factors and survival. Therefore, both Piwi-like proteins are suggested as biomarkers for MIBC patients.
Citation Format: Markus Eckstein, Rudolf Jung, Katrin Weigelt, Danijel Sikic, Robert Stöhr, Carol Geppert, Abbas Agaimy, Verena Lieb, Arndt Hartmann, Bernd Wullich, Sven Wach, Helge W. Taubert. Protein levels of Piwi-like 1 and -2 protein are prognostic factors for muscle invasive urothelial bladder cancer patients [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 3674.