bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3898: Structure-based optimization of small molecule inhibitors of the protein-protein interaction between menin and mixed lineage leukemia (MLL)
Authors: Pollock Jonathan , Borkin Dmitry , Kempinska Katarzyna , Purohit Trupta , Li Xiaoqin , Wen Bo , Zhao Ting , Miao Hongzhi , Shukla Shirish , He Miao , Sun Duxin , Cierpicki Tomasz , Grembecka Jolanta 
Published: July 2016

Abstract
Chromosomal translocations that affect the Mixed Lineage Leukemia (MLL) gene result in acute myeloid and lymphoid leukemias. Fusion of MLL with one of 60 different partner genes generates MLL fusion proteins which lead to enhanced cell proliferation, up-regulation of Hoxa9 and Meis1 genes and block hematopoietic differentiation, ultimately leading to acute leukemia. Importantly, the N-terminal region of MLL is retained in all MLL fusion proteins and represents the interaction site of menin, a critical oncogenic cofactor for MLL fusion proteins. As a result, inhibition of the menin-MLL interaction should abrogate the development and progression of MLL leukemia. Therefore, disruption of the menin-MLL interaction with small molecule inhibitors might represent a therapeutic strategy for patients harboring MLL-rearrangements.
The development of potent small molecule inhibitors of protein-protein interactions with optimized drug-like properties represents a challenging task in the lead optimization process. Here, we employed structure-based design with extensive medicinal chemistry efforts to optimize the thienopyrimidine class of menin-MLL inhibitors represented by the MI-136 compound. Our efforts resulted in development of MI-538, which represents the most potent small molecule inhibitor of the menin-MLL interaction developed to date. MI-538, which binds to menin with a Kd of 6.5 nM demonstrated superior cellular activity in MLL-AF9 transformed leukemic cells with a GI50 = 83 nM. In a mouse xenograft model utilizing MV4:11 human MLL leukemia cells, treatment with MI-538 significantly reduced tumor growth. Overall, systematic exploration of substituents on MI-136 led to the identification of MI-538 with improved activity, selectivity, polarity and pharmacokinetic profile, making it suitable for in vivo studies. Interestingly, we found that simultaneous incorporation of multiple substituents optimized for each site on the cyanoindole ring of MI-136 does not always positively affect the activity or drug-like properties of these compounds. This study demonstrates challenges in optimizing inhibitors of protein-protein interaction for potential therapeutic applications.
Citation Format: Jonathan Pollock, Dmitry Borkin, Katarzyna Kempinska, Trupta Purohit, Xiaoqin Li, Bo Wen, Ting Zhao, Hongzhi Miao, Shirish Shukla, Miao He, Duxin Sun, Tomasz Cierpicki, Jolanta Grembecka. Structure-based optimization of small molecule inhibitors of the protein-protein interaction between menin and mixed lineage leukemia (MLL). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3898.
Abstract 3899: Preclinical development of tetra-branched NT4 peptide theranostics
Authors: Brunetti Jlenia , Depau Lorenzo , Falciani Chiara , Riolo Giulia , Mandarini Elisabetta , Pini Alessandro , Bracci Luisa 
Published: July 2016

Abstract
The tetra-branched peptide NT4 is a potential cancer theranostic, which very selectively binds to human cancer tissues in different malignancies and can efficiently and selectively deliver drugs or liposomes for cancer cell imaging or therapy, in vitro and in vivo. By using NT4 conjugated to methotrexate or 5FdU we obtained significant reduction of tumor growth in xenografted nude mice. Very recently we reported that conjugation of paclitaxel to NT4 leads to increased therapeutic activity of the drug in an orthotopic model of breast cancer in mice and produces tumor regression which is not achieved with unconjugated paclitaxel in identical experimental conditions. We demonstrated that NT4 specifically binds to sulfated glycosaminoglycans and LRP receptors on cancer cells and tissues.
Considering the role of sulfated glycosaminoglycans in cancer cell interaction with the extracellular matrix, we have analyzed the effect of NT4 in cancer cell adhesion and migration on different supports. NT4 inhibits adhesion and migration of different human cancer cell lines, strongly affecting directionality of cell movement.
We have also constructed and validated a novel theranostics nanodevices, by conjugation of NT4 to quantum dots, for selective diagnosis and imaging of different human carcinomas.
Thanks to their high cancer selectivity and versatile chemical conformation, NT4 peptides can be exploited for constructing cancer theranostics, which may also reduce tumor aggressiveness and metastatic potential by inhibiting cancer cell migration.
References:
Falciani, C. et al. Cancer selectivity of tetrabranched neurotensin peptides is generated by simultaneous binding to sulfated glycosaminoglycans and protein receptors. J Med Chem. 2013, 56, 5009-18.
Brunetti, J. et al. Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug. Scientific Reports. DOI:10.1038/srep17736.
Citation Format: Jlenia Brunetti, Lorenzo Depau, Chiara Falciani, Giulia Riolo, Elisabetta Mandarini, Alessandro Pini, Luisa Bracci. Preclinical development of tetra-branched NT4 peptide theranostics. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3899.
Abstract 3905: Anti-tumor effect of combined irreversible electroporation and liposome-encapsulated NVP-BEZ235
Authors: Li Tian , Wang Lucas , Qiao Yang , Singhana Burapol , Melancon Marites P. 
Published: July 2016

Abstract
Introduction
Irreversible electroporation (IRE) is a technique that uses electrical pulses to cause disruption in the lipid bilayer integrity by creating nanopores. Regions that are close to the probe will have a permanent, irreversible damage to the cells, while farther away regions will subject the cell membranes to re-seal (reversible). This reversible region provides opportunity for enhanced nanoparticle uptake. In this study, we tested the efficacy of combined IRE and nanoparticle-mediated drug delivery in vitro and in vivo in a hepatocellular carcinoma model.
Methods
Liposome-encapsulated NVP-BEZ235 (L-BEZ) was made from hydration-sonication, followed by an optional extrusion step. Particle size was tested via dynamic light scattering. BEZ concentration was quantified by fluorescence. Cytotoxicity of IRE and its drug combinations was tested on Hep3B cells using ECM 830 (BTX Harvard Apparatus) at 1600 V/cm field strength. In vivo efficacy was studied on nude mice bearing Hep3B xenografts with single dose of IRE, or drug alone (L-BEZ or BEZ at 4 mg/kg, intratumoral injection), and its combinations.
Results and Discussion
Liposomes range from 100-500 nm in hydrodynamic volume. Highest loading efficiency achieved was 90% (1.8 mg/mL of BEZ). To test the release of BEZ from the liposome, solution of L-BEZ was treated with IRE and the supernatant was tested against Hep3B cells. The extract from L-BEZ had a significantly higher cytotoxicity (51%) as compared to the empty liposome (20%) with a p-value&lt;0.05. This suggests that IRE can release BEZ from the liposome. The LC50 values of L-BEZ and BEZ was determined to be the same (47 ng/mL). In vitro combination treatment of L-BEZ + IRE showed higher cytotoxicity than the controls (BEZ + IRE, BEZ alone, and IRE alone). In vivo, IRE and its combinations significantly suppressed tumor growth more than non-IRE treated groups. Histology showed a median percent necrosis for L-BEZ + IRE (37%) doubled compared to IRE treatment alone (17%).
Conclusion
The use of minimally invasive IRE in combination with nanoparticle-mediated drug delivery treatment is a promising technique to achieve local disease control in hepatocellular carcinoma.
Citation Format: Tian Li, Lucas Wang, Yang Qiao, Burapol Singhana, Marites P. Melancon. Anti-tumor effect of combined irreversible electroporation and liposome-encapsulated NVP-BEZ235. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3905.
Abstract 3907: Enhanced chemotherapeutic effect with matrix metalloproteinase sensitive liposomes
Authors: Brogaard Rikke Y. , Eliasen Rasmus , Melander Fredrik , Hansen Anders E. , Kjær Andreas , Andresen Thomas Lars 
Published: July 2016

Abstract
Introduction: Drug bioavailability following intra-tumoral accumulation is a major challenge in existing drug delivery systems. A site-specific trigger for obtaining drug release specifically in tumor tissue would overcome this problem and enhance the antitumor effect of the carried drug. Our aim was to develop a new drug delivery platform based on liposomes that are sensitive to matrix metalloproteinases (MMPs).
Methods: In the present work, we have designed a matrix metalloproteinase (MMP)-sensitive liposomal drug delivery system encapsulating oxaliplatin, which by tumor-specific enzymatic dePEGylation allows for controlling the precision of drug release. The dePEGylation is provided by a cholesterol-anchored PEGylated lipopeptide containing a short peptide sequence cleavable by MMP-2 and MMP-9. These MMP-sensitive liposomes are designed to make a charge-reversal transformation upon encountering MMPs in the tumor environment. The surface charge of the liposome turns from slightly negative to positive, resulting in cationic liposomes. In vitro cellular uptake of the liposomes was assessed using flow cytometry and ICP-MS, and further confirmed by confocal microscopy in CT26 and HT1080 cell lines. In vivo studies was evaluated in a syngeneic murine model of MMP-positive CT26 colon cancer.
Results: We successfully formulated MMP-sensitive, oxaliplatin encapsulated liposomes and characterized their zeta potential, size, stability and encapsulation efficiency. The results showed uniformly dispersed particles, and the charge-reversal properties were confirmed as the surface charge changed from slightly negative to distinct positive upon enzymatic cleavage generating cationic liposomes. These MMP-sensitive liposomes were evaluated in vitro and in vivo with a high correlation. In vivo studies showed a prolonged circulation profile with minimal leakage, and similar accumulation in tumors as conventional Stealth liposomes. Efficacy experiment in the same model demonstrated significantly improved antitumor activity relative to free oxaliplatin, and with a superior effect compared to the conventional Stealth liposomes.
Conclusion: With this study, we establish a promising liposomal drug delivery platform for the carriage and release of numerous anticancer drugs into the microenvironment of an MMP-positive tumor.
Citation Format: Rikke Y. Brogaard, Rasmus Eliasen, Fredrik Melander, Anders E. Hansen, Andreas Kjær, Thomas Lars Andresen. Enhanced chemotherapeutic effect with matrix metalloproteinase sensitive liposomes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3907.
Abstract 3908: A multifunctional peptide for targeted imaging, localization of transformed cell and chemotherapy for nasopharyngeal carcinoma and other cancers
Authors: Lin Chin-Tarng , Hsiao Jong-Kai , Liu Hon-Man , Wu Hang-Chung , Yu Alice 
Published: July 2016

Abstract
Introduction: In treating cancer with chemotherapy, the ultimate goal is to deliver sufficient amounts of the drug to tumor cells while minimizing the damage of normal tissue. To achieve this purpose, using a phage-displayed random peptide library to screen the nasopharyngeal carcinoma (NPC)-TW01 cell line, we identified a specific peptide (L-peptide), which binds specifically to NPC tumor cells but not normal cells. To investigate whether this L- peptide can also bind to other cancer cell lines, be used for cancer tissue binding, targeted imaging and chemotherapy, we have performed this experiment. Methods: A fluorescein-labelled L-peptide was used to perform FACScan for 7 cancer cell lines. The L-peptide was linked to dextran coated iron oxide (L-P-Fe3O4) nanoparticles and a biotin labeled modified L-peptide (biotin-mL-P) were also used to localize L-peptide targeted protein (X-protein) in NPC and breast cancer surgical specimens. This conjugate was also injected intravenously to SCID mice bearing NPC and breast cancer xenografts for magnetic resonance imaging (MRI) analysis. Furthermore, L-peptide-linked liposomal doxorubicin (L-P-Lipo-Dox) was used to observe the efficacy of peptide-targeted chemotherapy in both cancers. Results and Conclusions: FACscan revealed specific binding of L-peptide to NPC, breast cancer, lung cancer, and neuroblastoma. The X-protein in both cancer specimens localized by biotin-mL-P was seen in many NPC and breast cancer tumor cells with some unstained tumor cells, but not or very weak in normal tissue; the X-protein in formalin-fixed paraffin-embedded section could be localized by L-P-Fe3O4 histochemistry in both cancer specimens. MRI analysis of both cancer xenograft bearing mice after injection of L-P-Fe3O4 revealed significant change in the MR signal intensity. A high efficacy of L-P-Lipo-Dox treatment for both cancers with minimal adverse effect was obtained. This multifunctional L-peptide seems able to be used for localization of its binding protein in each cancer cell type, molecular MRI analysis and targeted chemotherapy with minimal adverse effect in different cancer types.
Citation Format: Chin-Tarng Lin, Jong-Kai Hsiao, Hon-Man Liu, Hang-Chung Wu, Alice Yu. A multifunctional peptide for targeted imaging, localization of transformed cell and chemotherapy for nasopharyngeal carcinoma and other cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3908.
Abstract 3932: Values of single nucleotide polymorphisms identified from genome-wide association studies on risk prediction, risk reclassification, and population-based screening of breast-cancer
Authors: Huang Yubei , Song Fengju , Chen Kexin 
Published: July 2016

Abstract
Background: With an increasing number of single nucleotide polymorphisms (SNPs) being identified from genome-wide association studies (GWAS), it's important to examine whether these SNPs have values in public health. And it's also unclear how to select the targeted SNPs valuable for population-based screening from numerous GWAS-identified SNPs.
Methods: Based on the fraction of the genetic risk explained by a SNP, the area under the receiver operating characteristic curve (AUC), integrated discrimination improvement, and net reclassification improvement were used to select targeted SNPs and to evaluate the values of genetic risk score (GRS) with targeted SNPs on risk prediction, risk reclassification, and effects of population-based screening among 2 million simulated Chinese women aged 35-69 years.
Results: A total of 11 targeted SNPs from 23 GWAS-identified SNPs would be valuable for population-based screening of breast cancer among Chinese women. After incorporating GRS with targeted SNPs into traditional risk predication based on established risk factors (ERF) of breast cancer, the AUC significantly improved from 65.5% to 67.5% (P&lt;0.001). Additional 25.5% (P&lt;0.001) population would be correctly reclassified into cases or controls. If screening targeted at top 25% high-risk women, screening-detected cancer would significantly increase 4.2% (49.2% vs 45.0%, P&lt;0.001) for screening strategy included GRS and ERF in risk assessment before screening compared with that only included ERF in risk assessment.
Conclusion: GRS based on targeted GWAS-identified SNPs could significantly improve the risk prediction, risk reclassification, and the effects of population-based screening. Further real-world studies are needed to validate this method and these results.
Citation Format: Yubei Huang, Fengju Song, Kexin Chen. Values of single nucleotide polymorphisms identified from genome-wide association studies on risk prediction, risk reclassification, and population-based screening of breast-cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3932.
Abstract 3934: Analysis of PKC-ζ protein and mRNA levels in normal and malignant breast tissue
Authors: Apostolatos Christopher , Smalley Tracess , Duncan Mildred A. 
Published: July 2016

Abstract
It is estimated that in 2015 breast cancer will be the second leading cause of cancer death in women. For this purpose, biochemical markers for breast cancer have been investigated, to assist in early detection and more accurate diagnoses. In breast cancer tissue, the atypical isozyme of protein kinase C zeta, PKC-ζ, has been a topic in research; It has been shown that an overexpression of this protein may be indicative of developing carcinogenesis and contributes to proliferation through the NF kappa B pathway, which is a stress-regulated switch for cell survival. In this investigation, the expression of PKC-ζ was analyzed in normal and malignant female human breast tissue samples by Western blot, immunoprecipitation and PCR. In the preliminary results, the malignant breast tissue samples illustrated a significant expression of PKC ζ when compared to the expression of PKC-ζ in normal breast tissue samples. The same tissues were also processed for total RNA isolation which was followed by cDNA synthesis and Real Time PCR. The level of PKC-ζ mRNA was tested and no overexpression was observed in either malignant or normal breast tissue samples. While protein studies may suggest that PKC-ζ could be considered a biomarker for breast cancer, the same cannot be said about mRNA levels. The overexpression of PKC-ζ protein level and the normal PKC-ζ mRNA level are indicators of possible miRNA activity that may regulate translation in malignant tissues but not the normal.
Citation Format: Christopher Apostolatos, Tracess Smalley, Mildred A. Duncan. Analysis of PKC-ζ protein and mRNA levels in normal and malignant breast tissue. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3934.
Abstract 3944: Combining tumor glypican-3 expression and CD16 Expression on NK cells from peripheral blood to identify patients responding to codrituzumab/GC33/RO5137382
Authors: Chen Gong , Chen Ya-Chi , Reis Bernhard , Belousov Anton , Jukofsky Lori , Rossin Christine , Muehlig Axel , Xu Chao , Essioux Laurent , Ohtomo Toshihiko , Di Laurenzio Laura , Puig Oscar , Lee Ray 
Published: July 2016

Abstract
Background & Aims: Codrituzumab (GC33 or RO5137382), a monoclonal antibody targeting an oncofetal protein glypican-3 (GPC3) expressed on the cell surface of hepatocellular carcinoma (HCC), induces antibody-dependent cellular cytotoxicity (ADCC) and inhibits tumor growth in preclinical studies. Based on this mechanism of codrituzumab, two biomarkers GPC3 and CD16 of the NK cells, which are the effector cells of ADCC, were investigated to correlate with clinical efficacy of codrituzumab in patients with advanced HCC.
Methods: Data from a phase II clinical trial of codrituzumab were used for this analysis. GPC3 expression was determined by immunohistochemistry (IHC) analysis of tumor biopsies, and CD16 expression on NK cells were quantified by a flow cytometry analysis of peripheral blood mononuclear cells. Overall survival of patients with high exposure of codrituzumab or placebo (n = 113) was used to compare different patient subgroups stratified by high or low expression of GPC3 and CD16.
Results: In individual-biomarker analyses, longer survival after codrituzumab treatment correlates with either high expression level of GPC3 in tumors (n = 97, HR = 0.39, 95%CI = 0.21 - 0.70, p = 0.00081) or a relatively high level of CD16 expressed on NK cells (n = 80, HR = 0.44, 95%CI = 0.23 - 0.83, p = 0.0056) at baseline. Furthermore, joint analyses of the two biomarkers reveal that both high levels of GPC3 and CD16 are required for patients to benefit from codrituzumab treatment (n = 67, HR = 0.29, 95%CI = 0.13 - 0.62, p = 0.00074), and lack of either one of them leads to a loss of codrituzumab therapeutic effect.
Conclusions: The retrospective analysis supports the mechanism of ADCC, in which the combination of high GPC3 expression in tumors and high CD16 expression in NK cells from peripheral blood is associated with prolonged overall survival given treatment of codrituzumab. This result supports the usage of both GPC3 and CD16 as potential biomarkers to select HCC patients for codrituzumab treatment.
Citation Format: Gong Chen, Ya-Chi Chen, Bernhard Reis, Anton Belousov, Lori Jukofsky, Christine Rossin, Axel Muehlig, Chao Xu, Laurent Essioux, Toshihiko Ohtomo, Laura Di Laurenzio, Oscar Puig, Ray Lee. Combining tumor glypican-3 expression and CD16 Expression on NK cells from peripheral blood to identify patients responding to codrituzumab/GC33/RO5137382. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3944.