bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A80: Cancer-specific targeting nanomicelles for diagnosis and treatment of bladder cancer.
Authors: Pan Amy Wang , Lin Tzu-yin , Zhang Hongyong , Goodwin Neal , Pan Chong-xian , Li Yuanpei , Lam Kit 
Published: August 2014

Abstract
Background: We previously developed a bladder cancer-specific targeting ligand named PLZ4 (amino acid sequence: cQDGRMGFc) that can specifically bind to both human and dog bladder cancer cells in vitro and in vivo. We have also developed a nanoscale micellular drug delivery platform. To minimize premature drug release during circulation, disulfide crosslinks are introduced to the micelles, which are cleaved under the intracellular reducing environment, where the drugs are released. Here, we assess the antitumor activity and toxicity of the PLZ4-coated and paclitaxel (PTX)-loaded micelles, with or without disulfide crosslinks.
Materials and Methods: Micelle-building monomers (ie, telodendrimers) are synthesized through conjugation of polyethylene glycol with cysteine (for disulfide crosslink) and a cholic acid cluster at one end and PLZ4 at the other. Such monomers self-assemble under aqueous condition to form micelles. Human bladder cancer cell line 5637 and patient-derived xenografts (PDX) are used for in vitro and in vivo drug delivery studies.
Results: PLZ4-coated micelles are about 20 nm in diameter. The PTX loading capacity is approximately 5 mg/ml in 20 mg of telodendrimers. PLZ4 confers cancer-specific drug delivery both in vitro and in vivo. Formulation of PTX in micelles significantly decreases the toxicity and allows intravenous administration of three times the maximum tolerated dose without increasing the toxicity, and improves the overall survival of mice carrying patient-derived bladder cancer xenografts to 64 days (without PLZ4 on micelle surface) and 76 days (PLZ4 targeting micelles) when compared to free parental PTX at 27 days (p&lt;0.0001). In contrast to free paclitaxel in Cremophor (Taxol®), the micelle formulation of PTX does not induce mast cell degranulation. To determine the minimal requirement of PLZ4 for targeted drug delivery, we compared and found that micelles with 2% and 50% of PLZ4 on surface exhibited similar antitumor activity in mice carrying patient-derived xenografts.
Conclusion: Micellular formation of PTX coated with PLZ4 shows promising antitumor activity with decreased toxicity in the treatment of bladder cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A80.
Citation Format: Amy Wang Pan, Tzu-yin Lin, Hongyong Zhang, Neal Goodwin, Chong-xian Pan, Yuanpei Li, Kit Lam. Cancer-specific targeting nanomicelles for diagnosis and treatment of bladder cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A80.
Abstract A84: Nanoparticles-TRAIL demonstrated superior anti-tumor activity in champions and START tumor graft models.
Authors: Friedman Jay A. , Wick Michael , Gamez Lizette , Chaves Rodger , Bruckheimer Elizabeth , Kleinman Shifra , Perlstein Benny 
Published: August 2014

Abstract
Glioblastoma (GBM) is characterized by recurrence and resistance to conventional treatments such as chemotherapy and radiation. Therefore alternative therapeutic approaches are needed. TRAIL, a promising anti-tumor agent, induces apoptosis in cancer cells but not in normal cells. However, its short half-life and lack of efficient administration modes are serious impediments to its therapeutic efficacy. Nanoparticles (NP) have been used as effective delivery tools for various anticancer drugs. In the current study, TRAIL was covalently conjugated to the surface of iron oxide NP via its primary amine groups. The efficacy of TRAIL conjugated NP (NP-TRAIL), temozolomide (TMZ), and NP-TRAIL + TMZ was evaluated in vivo in three human TumorGraft models representing human GBM from Champions Oncology or START, ST108, CTG-0667 and ST146. Champions Oncology has developed an innovative platform that utilizes the implantation of primary human tumors in immune-deficient mice in a manner that preserves the biological properties of the original human tumor and results in more rigorous and clinically relevant models for drug discovery. Previous reports have shown the correlation between responsiveness observed in Champions TumorGraft™ models and clinical responses of the patients from which the models were derived. Results demonstrated significant tumor growth inhibition (TGI) following treatment with either TMZ alone or the combination of NP-TRAIL + TMZ. In TumorGraft model ST108 the combination demonstrated superior anti-tumor activity, 109% TGI, compared to TMZ alone, 53% TGI. Interestingly, in addition to tumor growth inhibition, the combination also demonstrated 2 partial responses whereas TMZ alone demonstrated none. The MGMT methylation status of the specimens, which is known to be correlated to the degree of response to TMZ, was evaluated and results were found to be low indicative of an unmethylated status.
In conclusion, our innovative compound NP-TRAIL was tested in vivo on three different TumorGraft models, each representing a GBM patient with unmethylated MGMT. The combination treatment of NPT+TMZ was found to be effective and superior to treatment with either NPT or TMZ as single agents and suggests that NP-TRAIL, in combination with TMZ, may be an effective treatment of GBM.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A84.
Citation Format: Jay A. Friedman, Michael Wick, Lizette Gamez, Rodger Chaves, Elizabeth Bruckheimer, Shifra Kleinman, Benny Perlstein. Nanoparticles-TRAIL demonstrated superior anti-tumor activity in champions and START tumor graft models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A84.
Abstract A91: Activating EGFR mutation, G719A, was selected in the c-MET amplified NSCLC-PDX-LU1901 during the treatments by c-MET inhibitors and the resistance development.
Authors: Yang Mengmeng , Cai Jie , Guo Sheng , Yu Shijun , Qian Wubin , Song Xiaoming , Wang Youzhu , Wery Jean-Pierre , Li Henry 
Published: August 2014

Abstract
We previously described the establishment of an Asian NSCLC patient derived xenograft (PDX), LU1901 (large cell carcinoma, or LCC), from a surgically removed patient tumor tissue, along with large panel of other NSCLC-PDX (1). LU1901 was found to have amplified c-MET gene and responded to multiple c-MET inhibitors, including crizotinib (near-complete regression) (1). Interestingly, we recently also observed that the TKI treatments, including crizotinib, induced rapid development of resistance against the TKIs (LU1902, LU1903) (2). However, efforts so far have yet to demonstrate mechanism causing the induced resistance (2). We are currently investigating many aspects of the resistant tumors, including histopathology and molecular features, e.g., further c-MET mutation, c-MET activation status, and inhibition by c-MET-TKI, etc. By hotspot sequencing of EGFR gene of LU1901 and LU1903 recently (Sanger Method), we found a known activating mutation, G719A in exon 18, was selected during the treatment that was also accompanied by the c-MET TKI resistance development. G719A has been found in small subset of patients (∼3%) (3), and has been associated with increased sensitivity to EGFR-TKIs (4), suggesting it could be a new driver mutation gained in resistant LU1903. At present, our working hypothesis is that the selection of G719A mutation of EGFR rendered LU1903 resistant to c-MET-TKI. We have planned further experiments to verify this hypothesis. As a first step, we performed RNAseq of the TKI-sensitive parental LU1901, and found that G719A seemed to already exist, although at much lower frequency as compared to wild type allele at this location. This preliminary results suggests that G719A is a pre-exist mutation in a small subset of LU1901 tumor cells which was rapidly selected out during c-MET TKI treatment. Our current working hypothesis is that this selection could be responsible for the resistance development. If our working hypothesis is eventually proven, it will provide a new important mechanism for the development of c-MET TKI resistancy that can occur in the clinic during MET based therapy.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A91.
Citation Format: Mengmeng Yang, Jie Cai, Sheng Guo, Shijun Yu, Wubin Qian, Xiaoming Song, Youzhu Wang, Jean-Pierre Wery, Henry Li. Activating EGFR mutation, G719A, was selected in the c-MET amplified NSCLC-PDX-LU1901 during the treatments by c-MET inhibitors and the resistance development. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A91.
Abstract B10: Modeling the complexity of colorectal tumors in Drosophila.
Authors: Bangi Erdem , Murgia Claudio , Teague Alexander , Sansom Owen , Cagan Ross 
Published: August 2014

Abstract
The multigenic nature of human tumors presents a fundamental challenge for cancer research. To capture this genetic complexity we generated multigenic models of colon cancer in Drosophila—double, triple and quadruple combinations of transgenes representing mutations found together in sequenced human colon tumors. We then investigated the tumorigenic and metastatic potential of each of these combinations by targeting them specifically to the adult Drosophila colon as it shows important similarities to the human colon in terms of the signaling pathways that regulate its maintenance. We focused our initial analysis on three quadruple combinations: 1) rasG12V p53RNAi apcRNAi ptenRNAi, 2) rasG12V p53RNAi apcRNAi Smad4RNAi and 3) egfr p53RNAi apcRNAi Smad4RNAi. These models recapitulated key features of human cancer, including proliferation and multilayering of the colon epithelium, evasion of apoptosis and a senescence-like process, epithelial-mesenchymal-transition (EMT), migration and dissemination to distant sites within the body. Many tumor phenotypes arose as emergent properties of multigenic combinations. Using the dissemination phenotype of quadruple combination rasG12V p53RNAi apcRNAi ptenRNAi, as a quantitative read-out to monitor compound effects, we showed that multigenic models exhibit emergent resistance to a panel of clinically relevant compounds. We identified a mechanism of resistance for the PI3K/mTOR inhibitor BEZ235 and a combinatorial therapy that circumvents this resistance through a novel two-step process of emergent pathway dependence and suppression we term ‘induced dependence’. This approach proved effective in cultured human cancer cell lines, xenografts and a mouse model of colorectal cancer. Developing multigenic animal models that reference cancer genomes provides an effective approach for developing novel targeted therapies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B10.
Citation Format: Erdem Bangi, Claudio Murgia, Alexander Teague, Owen Sansom, Ross Cagan. Modeling the complexity of colorectal tumors in Drosophila. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B10.
Abstract B104: Liposomal C6 Ceramide appears to potentiate chemotoxicity of paclitaxel, gemcitabine and cetuximab against aggressive pancreatic cancer.
Authors: Wanebo Harold J. , Cao Cong , Lu Shaun , Shrayer David , Wan Yinsheng , Bowen Wayne , 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 have previously demonstrated reversal of these resistant pathways by C6 Ceramide and now are pursuing optimum intracellular delivery using selected liposomal preparations ofC6Ceramide.
Methods: C6 Ceramide housed in 4 different liposomal vesicle formulations were tested against pancreatic cell lines L3.6, PANC1 and MIA, using combination therapy with chemotherapy agents Gemcitabine, Paclitaxel and Cetuximab with determination of the MTT anti tumor response. 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 and is fluid at bodyT*(# 3). 18:0 PC- has high transition Temperature(T*) is rigid at body T*;#5 DPGG- avoids RE System (is fluid at bodyT*, 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.

Conclusion: 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 Information: Mol Cancer Ther 2013;12(11 Suppl):B104.
Citation Format: Harold J. Wanebo, Cong Cao, Shaun Lu, David Shrayer, Yinsheng Wan, Wayne Bowen, Wayne Bowen. Liposomal C6 Ceramide appears to potentiate chemotoxicity of paclitaxel, gemcitabine and cetuximab against aggressive pancreatic cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B104.
Abstract B106: mTORC1 inhibition is required for sensitivity to PI3K p110α inhibitors in PIK3CA-mutant breast cancer.
Authors: Elkabets Moshe , Vora Sadhna , Juric Dejan , Morse Natasha , Mino-Kenudson Mari , Muranen Taru , Tao Jessica , Bosch Campos Ana , Rodon Jordi , Ibrahim Yasir H. , Serra Violeta , Rodrik-Outmezguine Vanessa , Hazra Saswati , Singh Sharat , Kim Phillip , Quadt Cornelia , Manway Liu , Huang Alan , Rosen Neal , Engelman Jeffrey A. , Scaltriti Maurizio , Baselga José 
Published: August 2014

Abstract
Activating mutations of the PIK3CA gene occur frequently in breast cancer and inhibitors that are specific for PI3K p110α, such as BYL719, are being investigated in clinical trials. In a search for correlates of sensitivity to p110α inhibition among PIK3CA-mutant breast cancer cell lines, we observed that sensitivity to BYL719 (as assessed by cell proliferation) was associated with full inhibition of signaling through the TORC1 pathway. Conversely, cancer cells that were resistant to BYL719 had persistently active mTORC1 signaling, although Akt phosphorylation was inhibited. Similarly in patients, pS6 (residues 240/4) expression (a marker of mTORC1 signaling) was associated with tumor response to BYL719, and mTORC1 was found to be reactivated in tumors from patients whose disease progressed after treatment. In PIK3CA-mutant cancer cell lines with persistent mTORC1 signaling despite PI3K p110α blockade (that is, resistance), the addition of the allosteric mTORC1 inhibitor RAD001 to the cells along with BYL719 resulted in reversal of resistance in vitro and in vivo. Finally, we found that growth factors such as IGF1 and neuregulin1 can activate mTOR and mediate resistance to BYL719. Our findings suggest that simultaneous administration of mTORC1 inhibitors may enhance the clinical activity of p110α targeted drugs and delay the appearance of resistance.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B106.
Citation Format: Moshe Elkabets, Sadhna Vora, Dejan Juric, Natasha Morse, Mari Mino-Kenudson, Taru Muranen, Jessica Tao, Ana Bosch Campos, Jordi Rodon, Yasir H. Ibrahim, Violeta Serra, Vanessa Rodrik-Outmezguine, Saswati Hazra, Sharat Singh, Phillip Kim, Cornelia Quadt, Liu Manway, Alan Huang, Neal Rosen, Jeffrey A. Engelman, Maurizio Scaltriti, José Baselga. mTORC1 inhibition is required for sensitivity to PI3K p110α inhibitors in PIK3CA-mutant breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B106.
Abstract B110: Heterogeneous genetic alterations emerge during acquired resistance to anti-EGFR therapy in colorectal cancer.
Authors: Arena Sabrina , Misale Sandra , Lamba Simona , Siravegna Giulia , Lallo Alice , Hobor Sebastijan , Russo Mariangela , Buscarino Michela , Sartore-Bianchi Andrea , Bencardino Katia , Amatu Alessio , Siena Salvatore , Di Nicolantonio Federica , Bardelli Alberto 
Published: August 2014

Abstract
Occurence of acquired resistance constitutes one of the major limitations to tumor treatment. In colorectal cancer, the use of anti-EGFR antibodies such as cetuximab and panitumumab is effective in only 15-20% of patients, till secondary resistance to targeted treatment develops. Shedding light on the molecular basis of resistance represents then a mandatory effort in order to foster new lines of therapy. We recently showed that KRAS mutations are responsible for the emergence of secondary resistance to EGFR therapy in a subset of CRC patients (Misale et al., Nature 2012). Here we investigated the role of additional genetic alterations in the development of resistance to EGFR blockade in CRCs. We initially exploited the “liquid biopsy” approach to measure tumor derived DNA mutations in the blood of patients who initially responded and then became refractory to either cetuximab or panitumumab. We found that multiple KRAS and NRAS alleles often emerge during treatment. To better characterize the role of these genetic alterations in CRC, we generated preclinical models, by chronic treatment of several CRC cell lines with cetuximab or panitumumab until resistant derivatives emerged. The resistant populations were a mixture of clones bearing an heterogeneous panel of genetic alterations in KRAS, NRAS and BRAF at various frequencies. Biochemical pathway analyses revealed that, regardless of the genetic alterations, resistant derivatives consistently displayed MEK and ERK activation, which persisted on EGFR inhibition. Collectively, these results identify genetically distinct mechanisms that mediate secondary resistance to anti-EGFR therapies, all of which converge on the reactivation of ERK signaling. With this work, we provide a rational strategy to overcome the multifaceted clonal heterogeneity that emerges when tumors are treated with anti-EGFR drugs; we propose that MEK inhibitors, in combination with cetuximab or panitumumab, should be considered for the treatment of CRC patients who become refractory to anti-EGFR therapies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B110.
Citation Format: Sabrina Arena, Sandra Misale, Simona Lamba, Giulia Siravegna, Alice Lallo, Sebastijan Hobor, Mariangela Russo, Michela Buscarino, Andrea Sartore-Bianchi, Katia Bencardino, Alessio Amatu, Salvatore Siena, Federica Di Nicolantonio, Alberto Bardelli. Heterogeneous genetic alterations emerge during acquired resistance to anti-EGFR therapy in colorectal cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B110.
Abstract B112: ARRY-334543 reverses multidrug resistance by antagonizing the activity of ATP-binding cassette subfamily G member 2.
Authors: Wang De-Shen , Patel Atish , Kumar Priyank , Xu Rui-Hua , Chen Zhe-Sheng 
Published: August 2014

Abstract
Background: ARRY-334543, an ATP-competitive, selective, reversible small molecule tyrosine kinases inhibitor of ErbB1 and ErbB2, has shown superior preclinical tumor inhibitory activity to that of lapatinib in a wide range of tumor cell lines and xenografts dependent on ErbB signaling pathway. We conducted this study to determine whether ARRY-334543 can enhance the efficacy of conventional anticancer drugs through interaction with ABC transporters, a major obstacle to successful cancer treatment.
Material and Methods: Lung cancer cell line NCI-H460 and its drug-selected derivative ABCG2-overexpressing NCI-H460/MX20, as well as the ABCG2-, ABCB1-, and ABCC10-overexpressing transfected cell lines were used for this study.
Results: Our results found that ARRY-334543 at 1.0 µmol/l significantly reversed ABCG2-mediated multidrug resistance (MDR) through directly inhibiting the drug efflux function of ABCG2, therefore resulting in the elevated intracellular accumulation of chemotherapeutic drugs in both the drug-selected derivative ABCG2-overexpressing NCI-H460/MX20 and ABCG2-overexpressing transfected cell lines, as well as the NCI-H460, which intrinsically expressed low level of ABCG2, whereas ARRY-334543 at 1.0 µmol/l only slightly reversed ABCB1- and partially reversed ABCC10-mediated MDR. However, ARRY-334543 at reversal concentration did not affect the expression levels of ABCG2 protein. Moreover, ARRY-334543 did not regulate the re-localization of ABCG2 from cell membrane to the cytoplasm.
Conclusion: We concluded that ARRY-334543 (1.0 μmol/l) significantly reversed drug resistance mediated by ABCG2.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B112.
Citation Format: De-Shen Wang, Atish Patel, Priyank Kumar, Rui-Hua Xu, Zhe-Sheng Chen. ARRY-334543 reverses multidrug resistance by antagonizing the activity of ATP-binding cassette subfamily G member 2. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B112.