bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 281: Novel nucleic acid constructs and formulations for treatment of bladder cancer and malignant ascites
Authors: Liu Yan , Chen Yan , Fosnaugh Kathy , Seth Shaguna , Matsui Yoshiyuki , Harvie Pierrot , Johns Rachel , Takagi Akihide , Vaidyanathan Shobana , Severson Greg , Brown Tod , Zhu Tianying , Charmley Pat , So Alan , Houston Michael , Templin Mike 
Published: August 2012

Abstract
Nucleic acid-based therapeutics offer significant promise in treatment of difficult diseases by providing high sequence specificity against target genes including “non-druggable targets”. Different nucleic acid constructs, single-stranded antisense oligonucleotides, microRNA mimetics, miRNA-specific antagomirs (AntimiR), and double-stranded short-interfering RNAs (siRNAs), provide diverse therapeutic platforms to access targets in treatment of cancer and other diseases. Single-stranded oligonucleotides require additional modifications for increased serum stability, nuclease resistance, and to minimize immune response. Conformationally restricted nucleotide (CRN)-substituted AntimiRs targeting miR-21 and miR-122 demonstrated significant improvement in hybridization affinity with a concomitant increase in potency. A CRN-substituted AntimiR targeting microRNA-122 dosed at up to 50 mg/kg/day over three consecutive days led to a dose-dependent effect on de-repression of downstream liver-specific target genes, Aldolase A (AldoA), Glycogen Synthase I (GYS1) and Solute Carrier Family 7 member 1 (SLC7A1). This CRN-modified AntimiR produced up to a 5-fold increase in AldoA mRNA while demonstrating a good tolerability profile with no body weight changes and normal serum chemistry. Development of therapeutic siRNA constructs can be hampered by off-target effects and cytokine induction. Substitution of unlocked nucleobase analogs (UNAs) at specific positions in the passenger and guide strands of siRNA confers high specificity with minimal to no off-target activity. UsiRNAs were successfully delivered to bladder or abdominal tumors when encapsulated in DiLA2- or SMARTICLES®-derived liposomes. DiLA2−encapsulated polo-like kinase 1 (PLK1) UsiRNA demonstrated 95% mRNA reduction and up to 70-fold tumor growth inhibition in a bladder cancer orthotopic mouse model and 40-70% mRNA inhibition and ∼80% reduction in tumor-specific bioluminescence in a malignant ascites mouse model following intravesical or intraperitoneal dosing, respectively. In an orthotopic liver tumor animal model, liposomal encapsulated miRNA mimetics provided ∼80% reduction in tumors compared to buffer control. Combinations of formulations and construct capitalize on the advantages of nucleic acid-based therapeutics for precise targeting and flexible delivery to challenging drug targets in cancer and other indications.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 281. doi:1538-7445.AM2012-281
Abstract 2824: Therapeutic potential of multi-kinase inhibitor sorafenib in osteosarcoma cells
Authors: Ko Yunmi , Lee Jun Ah 
Published: August 2012

Abstract
Osteosarcoma (OS) is the most common primary malignant bone tumor in childhood and adolescence. The introduction of multiagent chemotherapy has greatly improved the survival of patients with osteosarcoma, however, the improvement in survival has reached a plateau. Therefore, search for novel agents focused on different mechanisms is mandatory to further improve the survival of osteosarcoma patients. Sorafenib is the first oral multi-kinase inhibitor that directly blocks the auto-phosphorylation of several receptor tyrosine kinases (VEGFR1, 2 and 3, PDGFRα, c-Kit and RET) and inhibits Raf kinase isoforms (wild-type Raf1, and B-Raf and mutant b-raf V600E) activity to prevent tumour growth by anti-angiogenic, antiproliferative and/or pro-apoptotic effects. Here, we describe the effect of sorafenib in human OS cell lines on the proliferation and migration. And we also report combination effects with irradiation (IR) and cisplatin. We measured cell proliferation by MTT assay and used Annexin V and flow cytometry to assess whether sorafenib induce apoptosis in the OS cells. Next the migration of sorafenib-treated OS cells was determined by wound-healing assay and the synergistic effect between sorafenib and IR was evaluated using colony-forming assay. Also CI values of drug combinations of cisplatin and sorafenib in OS cells were calculated using Calcusyn software to assess whether sorafenib can be useful when used in conjunction with cisplatin. We found that sorafenib effectively inhibits cell proliferation, induced apoptosis, and prevents cellular migration. And our results demonstrate that the combination of two drugs, sorafenib and cisplatin, showed synergistic effects and colony-forming assay showed that sorafenib enhanced the radiosensitivity of OS cells. In conclusion, we found that sorafenib exerts therapeutic potentials in OS cells and suggests the possibilities of using sorafenib as a potential adjuvant therapy for the treatment of osteosarcoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2824. doi:1538-7445.AM2012-2824
Abstract 2834: Discovery of a novel class of prostaglandin e2 synthesis inhibitors with anti-tumor activity in colorectal cancer
Authors: Sells Earlphia , Medda Federico , Chang Hui-Hua , Gokhale Vijay , Hulme Christopher , Meuillet Emmanuelle J. 
Published: August 2012

Abstract
Prostaglandin E2 (PGE2), a key mediator of inflammation, is the most common prostanoid with various bioactivities and has been associated with many pathologies. Thus, inhibition of PGE2 synthesis and its action has been suggested in the treatment of inflammatory-associated diseases, including cancer. Microsomal Prostaglandin E2 Synthase-1 (mPGES-1) is an enzyme downstream of the cyclooxygenases (COXs) in the PGE2 biosynthesis pathway. mPGES-1, which is one of the three PTGES isoforms, is constitutively expressed in many cancers, including colon cancer. The potential role for this enzyme in tumorigenesis has been reported. Since inhibition of COXs lead to side effects due to the global reduction of other key prostaglandins, targeting downstream m-PGES-1 might be a better therapeutic strategy for cancers. In order to identify novel small molecule inhibitors of mPGES-1, we have screened several libraries in silico and used published scaffolds exhibiting anti-inflammatory properties to initiate our study. As a result, 10 compounds were identified by molecular docking simulations using the reported crystal structure of mPGES-1. Subsequently a total of 32 analog compounds were synthesized or purchased and tested for their ability to inhibit COX-2 in vitro activity as well as for their ability to inhibit PGE2 production in an HCA-7 colorectal cancer cell line. We show that 16 of the 32 compounds reduced PGE2 synthesis by over 80% at 1 µM, with only one of these compounds inhibiting more than 30% of COX-2 activity at 5 µM in vitro. Furthermore, one compound, PGE0056 (EC50= 0.37 ± 0.06 µM), exhibited anti-tumor activity after 10 days at 100mg/kg i.p. in HCA-7 colon cancer xenograft mouse model. Following treatment with PGE0056, PGE2 production was reduced in the blood of scid mice. In summary, our data suggest that these new identified compounds exert anti-tumor activity at least in part through inhibition of the COX2/mPGES-1 enzymes within the PGE2 synthesis pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2834. doi:1538-7445.AM2012-2834
Abstract 2841: A simplified approach to measuring thymidine kinase activity in cells, tumors, and blood as a biomarker of tumor proliferative potential
Authors: Li Wenlin , Kang Xiaolin , Kindt Kristian E. , Zhang Cathy , Spilker Mary , Berlinski Pamela J. , Eisenbraun Michael , Yan Zhengming , Elliott Mark , Arbuckle J. Alan , Faria Morse , Karnes H. Thomas , O'Brien Peter J. 
Published: August 2012

Abstract
Understanding tumor size and growth is essential for preclinical oncology drug development, but costs and technical hurdles can prevent accurate, repeated measurements of cell proliferation and tumor growth. Many investigators instead measure the accumulation of nucleosides and analogs (e.g., [18F]-FLT; [3H]-Thy; BrdU) in cells and tissues, a manifestation of thymidine kinase 1 activity (TK1a). These methods can be costly and laborious, and can generate significant hazardous waste, promoting the use of even less-direct measures of cell division. Seeking further insights into the role of TK1 in cancer, we developed rapid, robust, non-isotopic methods that measure TK1a in tissue extracts and blood. In this approach, samples are exposed to FLT in vivo or in vitro, promoting its phosphorylation. Subsequently, nucleosides and their phosphorylated metabolites are isolated for analysis by a simple organic extraction. Using these methods, TK1a was measured in primary and transformed cells, and showed excellent comparability with established proliferation assays including 3H-thymidine incorporation, ATP generation, and fluorescent dye dilution flow cytometry. In drug screens, our method was as sensitive as commercial viability assays, and typically detected drug effects much sooner than those less-specific measures. We also demonstrated chemotherapy-induced alterations in TK1a in xenografted tumor tissue that were comparable to results obtained using radioisotopes. Finally, this approach was adapted to measure TK1a in blood samples. Consistent with published reports, circulating TK1a correlated well with tumor burden in solid tumor models and primary canine hematological cancer. These methods require only small sample volumes (&lt;50μL serum or other biofluids, or a few thousand cells), allowing serial blood collection for monitoring tumor growth kinetics in rodents. These translational studies are underway, and should greatly inform our understanding of the role of TK1 in tumor responses to treatment in vitro and in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2841. doi:1538-7445.AM2012-2841
Abstract 2851: Cabozantinib (XL184) inhibits prostate tumor growth and bone lesion development
Authors: Dai Jinlu , Zhang Honglai , Karatsinides Andreas , Aftab Dana , Schimmoller Frauke , Keller Evan T. 
Published: August 2012

Abstract
Over 80% of advanced prostate cancers (PCa) metastasize to bone resulting in primarily osteoblastic bone lesions. Cabozantinib (CABO) is a multi-kinase inhibitor that targets MET and vascular endothelial growth factor receptor-2 (VEGFR2). Administration of CABO to men with PCa bone metastases has been shown to induce a marked resolution of lesions on bone scan as well as regression of measurable disease. Modulation of prostate specific antigen (PSA) appeared to be independent of changes in other parameters such as target lesions and bone scan. The current study was designed to determine mechanisms underlying CABO activity in PCa. Expression of MET and VEGFR2 or modulation of their activity were verified in PCa cell lines such as PC-3 or the pre-osteoblast cell line MC3T3-E1. To evaluate if CABO impacts PCa neoplastic phenotypes, PCa cell lines LNCaP, C4-2B and PC-3 were treated. CABO inhibited cell viability, migration and invasive ability and promoted apoptosis in LNCaP, C4-2B and PC-3 cells. To determine if CABO could directly modulate PSA expression, LNCaP (androgen dependent) and C4-2B (androgen independent) cells were incubated in the presence or absence of CABO. CABO increased both PSA and androgen receptor (AR) mRNA and protein expression in the LNCaP cells but did not modulate PSA expression in C4-2B cells. MC3T3-E1 and ST2 cells were treated with CABO to evaluate impact on osteoblastogenesis. CABO decreased cell viability and modulated osteocalcin levels in MC3T3-E1 and ST2 cells. ACE-1 canine osteoblastic PCa cells were injected into the tibia and treatment with CABO was started after tumors had developed to determine the impact on PCa growth in vivo. CABO decreased both ACE-1 tumor burden and tumor-induced osteoblastic activity in bone. In contrast, when PC-3 cells (osteolytic) were injected subcutaneously or into the tibiae of mice, which were treated with CABO or vehicle once tumors were established, CABO slowed the growth of PC-3 tumors in the soft tissue but not in bone. These findings indicate that CABO inhibits prostate tumor growth and tumor-induced bone lesion development through direct targeting of both PCa cells and osteoblasts. These studies provide a strong rationale to further elucidate the effect of CABO on osteoblastogenesis and PSA modulation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2851. doi:1538-7445.AM2012-2851
Abstract 2856: Functional profile of BEZ-235 activity in human tumor primary culture microspheroids by ex vivo analysis of programmed cell death (EVA/PCD)
Authors: Nagourney Robert Alan , Bernard Paula J. , Francisco Federico R. , Evans Steven S. 
Published: August 2012

Abstract
Aberrant signaling through the phospho-inositol pathway via the gain of PI3K function or loss of PTEN is a hallmark of many malignancies. Drugs that inhibit this pathway offer novel therapeutic opportunities. The imidazoquinolone derivative, BEZ-235, reversibly inhibits signaling through PI3K & mTOR by competition at ATP binding sites. We used ex vivo analysis of programmed cell death (EVA/PCD) to examine the activity and clinical potential of BEZ 235 in human tumors isolated from 88 surgical tumor specimens. By interrogating drug effects in primary culture micro-spheroids, replete with vascular, stromal and inflammatory elements, the EVA/PCD platform can provide insights into cellular responses under native-state conditions. Lethal concentration 50% values (LC50's), interpolated from dose response curves, were used to compare the activity of BEZ-235 by diagnosis using modified Z-scores. Comparisons between BEZ activity and related inhibitors of PI3K (LY294002), mTOR (Everolimus) & AKT (Phen B15-kindly provided by Dr. Peter Houghton) were conducted by Pearson-Moment. By rank order, BEZ-235 activity revealed upper gastrointestinal, breast, NSCLC and hematological malignancies to have the most favorable profiles, while renal, ovarian, colon and sarcoma specimens fell in the more resistant range. Pearson moments revealed high correlation coefficients (R values) for LY294002=0.56 (P =0.001); Everolimus=0.51 (P= 0.005) & Phen B15=0.89(P= 0.005) all consistent with BEZ-235's known modes of action. As PI3K signaling is associated with inhibition of apoptosis, its up-regulation may confer collateral resistance to other stressors like growth factor withdrawal or cytotoxic drugs. Relationships between BEZ-235 and other classes of drugs are being examined to explore additional correlations and potential combination that could provide future therapeutic opportunities, as will be reported. Supported in part by the Vanguard Cancer Foundation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2856. doi:1538-7445.AM2012-2856
Abstract 2860: EphA2 and its phosphorylation is a key determinant of dasatinib sensitivity in endometrial cancer
Authors: Huang Jie 
Published: August 2012

Abstract
Background: Growing evidence points to EphA2 having bidirectional signaling to promote or inhibit tumorigenicity in ligand-independent and ligand-dependent manner. But the mechanistic and biological impact of this EphA2 dual switch function in the context of EphA2 targeted therapy in cancer is not known. Materials and Methods: The effects of dasatinib alone or in combination with paclitaxel on human endometrial cancer cell lines were examined using a series of in vitro experiments, including MTT, RPPA, Western blot, ELISA, and plasmid transfection (for inactivated or constitutively activated phosphorylation at EphA2-S897). In vivo, an orthotopic mouse model of endometrial cancer was utilized to identify the biological effects of dasatinib in orthotopic endometrial cancer models. Molecular markers for response prediction were identified by using ELISA, RPPA and immunohistochemistry. Results: In vitro, the effects of dasatinib treatment varied among the different endometrial cancer cell lines tested, (IC50 values ranged from 10 nM to10,000 nM) which was associated with varying levels of EphA2 and EphA2S897 phosphorylation, basal level of p-AKT and caveolin-1 in the EphA2 positive (Hec-1A, Ishikawa, and SKUT-2) and negative cells (SPEC-2). Moreover, in vivo experiments showed that dasatinib monotherapy or in combination with paclitaxel led to tumor inhibition over controls in the EphA2 positive Hec1A and Ishikawa murine models. Specifically, dasatinib treatment resulted in 48% and 71% reduction of tumor growth in these models, respectively (p&lt;0.01). Combination of dasatinib and paclitaxel showed even greater efficacy (87% - 89% reduction in tumor growth, p&lt;0.001). In the EphA2 negative SPEC2 murine models, dasatinib therapy resulted only in modest efficacy (31%, p&lt;0.05), while the efficacy in combination with paclitaxel was better (75%, p&lt;0.01). The antitumor effects of dasatinib were significantly associated with EphA2 and its phosphorylation status at S897, especially in the tumors with high expression of caveolin-1, as detected by RPPA, Western blot analysis and immunohistochemistry. Conclusion: The efficacy of dasatinib therapy in uterine cancer models depends on the status of the EphA2 and its activation of p-EphA2s897. These findings may have clinical implications for future dasatinib-based clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2860. doi:1538-7445.AM2012-2860
Abstract 2863: Development of an AKT1-specific synbody that inhibits MOLT-4 cell growth
Authors: Diehnelt Chris W. 
Published: August 2012

Abstract
Our group has developed bivalent peptide affinity ligands, called synbodies, to a number of proteins, including the serine / threonine kinase, AKT1. However, despite the high affinity of the synbody for AKT1 (KD = 1.5 nM), questions remain about the use of this synbody as a probe to modulate AKT1 activity within the cell due to the impermeability of most peptide ligands. In this presentation, we demonstrate that the AKT1 synbody penetrates mammalian cells and localizes with AKT1 in MOLT-4 acute lymphoblastic leukemia cells. The synbody specifically binds AKT1 but not AKT2 or AKT3 in the cytoplasm of MOLT-4 cells demonstrating a level of specificity typically only achieved by antibodies, which do not normally penetrate the cell. It was also found that after 24 hours of treatment, the synbody inhibits growth of MOLT-4 cells with an IC50 of 5 uM. FACS analysis revealed that the synbody induces apoptosis by altering the downstream activity of AKT1. We are currently confirming the mechanism of action of the synbody as well as preparing modifications to increase the activity and in vivo stability of the synbody.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2863. doi:1538-7445.AM2012-2863
Abstract 2864: Regulation and targeting of Fyn in cutaneous squamous cell carcinoma
Authors: Fenton Sarah , Denning Mitchell F. 
Published: August 2012

Abstract
Over 700,000 cases of cutaneous squamous cell carcinoma (cSCC) occur in the United States every year. Despite this high rate of diagnosis no therapies currently exist that target the molecular mechanism of tumorigenesis. Between 20 and 60% of these tumors contain mutated Ras; however targeting Ras with therapeutics has been unsuccessful in clinical trials. Expression of active H-Ras (G12V) in HaCaT cells (immortalized, non-transformed keratinocytes) results in upregulated expression of Fyn, a Src family kinase that is active in many malignancies and is involved in the elevated invasion/migration of Ras-transformed HaCaT cells. The specific objectives of this project include exploring the mechanism through which Ras activation increases Fyn levels and determining how high levels of Fyn promote cancer cell migration and survival. Using RT-qPCR we verified that Fyn expression is selectively elevated in cells with increased Ras activity, but levels of other Src family kinases (eg Src, Lyn, Yes, Blk, Lck) are not altered. To explore the transcriptional regulation of Fyn in Ras-transformed HaCaT cells we subcloned segments (−2 kb to −50 bp) of the human Fyn promoter in front of firefly luciferase and transfected the reporter constructs into HaCaT and HaCaT-Ras cells (transformed by constitutively active H-Ras). We identified a region −100 to −50 base pairs upstream of the transcription start site that is necessary for Fyn upregulation in HaCaT-Ras cells. The −80 to −65 region of the Fyn promoter contains putative GATA-1, GATA-2, GATA-3, CP2 or TATA transcription factor binding sites. We have also targeted Fyn in Ras-transformed cells using the Src family kinase inhibitor Dasatinib. Already used to treat chronic myelogenous leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia, Dasatinib is also in clinical trials to treat solid tumors. Treatment with varying concentrations of Dasatinib did not reveal greater changes in cell viability, cell cycle progression, apoptosis or autophagy in transformed HaCaT-Ras cells as compared to HaCaT cells. However, upon Dasatinib exposure HaCaT-Ras cells change dramatically in morphology, enhancing cell-cell contacts and reverting from a stellate appearance to the rounded morphology of untransformed HaCaT cells. Due to previous work verifying Fyn's role in promoting the invasion and migration of transformed keratinocytes, we propose that Fyn inhibition in keratinocytes with increased Ras activity will restore cell to cell contacts and provide a potential therapeutic target in the treatment of cSCCs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2864. doi:1538-7445.AM2012-2864