bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1772: PDL192, a humanized anti-Tweak receptor monoclonal antibody, mediates antitumor effects in primary human breast carcinoma xenografts
Authors: De Plater Ludmilla , Vincent-Salomon Anne , Culp Patricia , Nicolas André , Gravier Eléonore , Assayag Franck , Dahmani Ahmed , Elbaz Clément , Chao Debra , Afar Daniel , Diéras Véronique , Decaudin Didier 
Published: August 2014

Abstract
Background: PDL192 is a humanized IgG1 monoclonal antibody that binds the human TWEAK receptor (TweakR). TweakR, a member of the TNFR (Tumor Necrosis Factor Receptor) superfamily, is overexpressed in several human cancers including breast cancer (BC). In BC, it may also play a role in the invasive and metastatic potential of the disease (Willis et al, Mol Cancer Res 2008). In TweakR-expressing cancer cell lines or mouse xenograft models, PDL192 has a potent antitumor effect (Culp et al., CCR 2010). All these data therefore suggest that anti-TweakR targeting could be a promising new therapeutic approach for human BC patients.
Material and methods: TweakR expression was assessed by IHC (immunohistochemistry) on 3 Tissue-Micro-Array (TMA) banks of BC samples (basal-like, ERBB2, and luminal A/B), and 25 primary human BC xenografts (HBCx). The cut-off of positivity was defined as at least 25% cells with membraneous or cytoplasmic staining or by a combined score of percentage of positive staining cells x intensity &gt; 50. The in vivo antitumor effect of PDL192 was then assessed on 7 TweakR-positive models (10 mg/kg thrice a week for 3 weeks by intraperitoneal route) in which one in combination with chemotherapy as maintenance therapy, as previsouly reported (Marangoni et al., BJC 2009).
Results: TMA analyses showed that TweakR was expressed in 16/37 basal like BC (43%), 23/37 ERBB2-positive BC (62%), and 38/71 luminal BC (54%). A high TweakR expression was correlated with double estrogen receptor- and Her2-positive tumors. Moreover, 13/25 xenografts have been found to be TweakR-positive (52%). Nine human BC models have been treated with PDL192, with 4 models (44%) showing a tumor growth inhibition (TGI) ranging between 59% and 91%. No correlation has been observed between TweakR expression and in vivo TGI. Moreover, when PDL192 was administered in complete remission after chemotherapy (doxorubicin + cyclophosphamide), we observed a highly significant delay of relapse greater than 2 months.
Conclusions: TweakR is expressed in 77/145 human BC samples (53%). In in vivo experiments, PDL192 showed potent TGI in 4/9 models, and significantly delayed tumor relapses after chemotherapy-induced complete remission. All these data therefore support the use of anti-TWEAK receptor monoclonal antibodies in the treatment of TweakR-positive BC patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1772. doi:10.1158/1538-7445.AM2011-1772
Abstract 1774: Development of potent trimeric DR4 agonist Atrimers with therapeutic potential
Authors: Ferrini Roger , Oltean Daniela I. , Renshaw Mark W. , Chen Elise , Batzer Glenda , Gonzalez Maria J. , Lin Bing , da Silva Correia Jean , Wild Martha A. , Zhu Weiguang , Bowdish Katherine S. , Kretz-Rommel Anke 
Published: August 2014

Abstract
TRAIL death receptor DR4 is a promising therapeutic target in oncology with expression in a wide variety of tumors. DR4 agonists, including TRAIL and monoclonal antibodies, can induce p53-independent apoptosis and are currently being evaluated in clinical trials in combination with chemotherapy. We aimed to surpass currently available therapeutics by developing trimeric death receptor agonists with properties expected to significantly exceed that of recombinant human TRAIL. The agonists can mimic the natural trimer-trimer interaction of the native ligand/receptor, but do not cross-react with the decoy receptors.
Potent DR4 agonist AtrimersTM were engineered using human tetranectin, a trimeric human serum protein of 60 kDa, as a scaffold. A panel of unique DR4 binders was selected from novel phage libraries displaying the C-type lectin domain (CTLD) of tetranectin containing randomized loop sequences. DR4 Atrimers have sub-nanomolar affinity to recombinant DR4-Fc and showed no detectable binding to recombinant forms of DR5 or the decoy receptors. In vitro, the DR4 Atrimers efficiently killed DR4-positive cancer cell lines with sub-nanomolar EC50, but did not kill DR4-negative cell lines. DR4 Atrimers induced cell death of DR4-expressing tumor cells through the caspase pathway, but did not kill primary human B cells and hepatocytes. Interestingly, DR4 Atrimers have differential activities on various cell lines, and also vary in their degree of internalization. While some Atrimers show potent killing of Colo-205 and are rapidly internalized, other agonist Atrimers did not show measurable internalization. These unique properties open the possibility of developing potent naked Atrimers with prolonged half-lives due to lack of internalization, as well as leveraging rapidly internalizing DR4 Atrimers for design of Atrimer-drug conjugates. Further characterization of DR4 Atrimers is ongoing in Colo-205 xenograft models.
DR4 agonist AtrimersTM with their superior potency and expected improvement in tumor penetration (vs. antibodies) represent a novel class of targeted cancer therapeutics for efficient induction of apoptosis and provide a promising approach for the treatment of a broad range of cancer types.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1774. doi:10.1158/1538-7445.AM2011-1774
Abstract 1853: PDE5 suppression selectively induces apoptosis of human breast tumor cells and attenuates Wnt/β-catenin mediated transcription
Authors: Tinsley Heather N. , Keeton Adam B. , Lu Wenyan , Li Yonghe , Piazza Gary A. 
Published: August 2014

Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac sulfide (SS) display promising antineoplastic properties in experimental models, but toxicities from cyclooxygenase (COX) inhibition limit their clinical use for cancer chemoprevention. While COX inhibition is responsible for the anti-inflammatory activity of SS, recent studies suggest that phosphodiesterase (PDE) 5 inhibition and activation of cGMP signaling are closely associated with its ability to induce apoptosis of tumor cells. However, the underlying mechanisms responsible for apoptosis induction and factors that influence sensitivity to SS have not been well studied. Here we show that SS can induce apoptosis of breast tumor cells that express PDE5, but not normal mammary epithelial cells, which do not express PDE5. Inhibition of PDE5 and subsequent activation of PKG by SS was associated with increased β-catenin phosphorylation, decreased β-catenin mRNA and protein levels, reduced β-catenin nuclear localization, decreased Tcf/Lef promoter activity, and decreased expression of Wnt/β-catenin regulated proteins such as survivin. Suppression of PDE5 by siRNA or known PDE5 inhibitors was sufficient to selectively induce apoptosis and attenuate β-catenin mediated transcription in breast tumor cells with no effect on normal mammary epithelial cells. These findings provide evidence that PDE5 expression can influence the sensitivity of human breast tumor cells to SS and that cGMP can inhibit Wnt/β-catenin signaling and suppress the transcription of key apoptosis regulatory proteins. We conclude that PDE5 represents a novel molecular target for the discovery of safer and more efficacious drugs for the prevention and treatment of breast cancer. Funding provided by NIH/NCI grants CA131378 and CA148817.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1853. doi:10.1158/1538-7445.AM2011-1853
Abstract 1856: Sustained release curcumin microparticles delay mammary tumorigenesis in BALB-neuT transgenic mice
Authors: Grill Alex , Panyam Jayanth 
Published: August 2014

Abstract
This work examined the chemopreventive efficacy of curcumin delivered by poly(lactide-co-glycolide) (PLGA) microparticles in a HER-2 transgenic mouse mammary tumor model. HER-2 positive breast cancers have a high incidence of metastasis to the brain and are not well treated by conventional means. Curcumin, a dietary polyphenol derived from turmeric, is a powerful antioxidant and has shown chemopreventive activity in vitro. Curcumin suffers from poor oral bioavailability, requiring the need for a controlled release system that could maintain steady plasma levels over a long period of time. Our lab has formulated a curcumin loaded microparticle formulation using the FDA approved polymer, PLGA. Previously published data using this system showed steady curcumin plasma concentrations for a month and efficacy against MDA-MB-231 tumor xenografts (Shahani et al, Cancer Res. 70(11):4443-52).
In the present study, Balb-neuT +/- mice were injected subcutaneously with curcumin loaded or empty microparticles at 4, 7 or 12 weeks of age and then once a month thereafter until all mammary pads developed palpable tumors. Mice that started receiving curcumin microparticles at 4 weeks of age showed a difference in age to 50% tumor multiplicity (16 vs 18.5 weeks) and 100% tumor multiplicity (20 vs 22 weeks) compared to those that received control microparticles. No difference was seen in tumor multiplicity when the treatments were started at 7 or 12 weeks of age. Mammary pads from mice that started receiving curcumin treatment at 4 weeks of age showed a significant decrease in Ki-67 expression compared to those from control mice. Curcumin treated mice also showed a decrease in overall percent area of tissue showing abnormal morphology (lobular hyperplasia and carcinoma in situ). These data suggest that curcumin delays tumorigenesis in this model through inhibition of cell proliferation.
In summary, sustained release curcumin microparticles show promise as a chemopreventive against Her-2 positive breast cancer. Future studies will examine the effect of starting curcumin treatment at 2 weeks of age (prior to induction of hyperplasia) and determine other potential mechanisms of action of curcumin including inhibition of angiogenesis and induction of apoptosis in this transgenic model.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1856. doi:10.1158/1538-7445.AM2011-1856
Abstract 1858: Inhibition of oral carcinogenesis in rats by the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA)
Authors: McCormick David L. , Horn Thomas L. , Johnson William D. , Lubet Ronald A. , Steele Vernon E. 
Published: August 2014

Abstract
Suberoylanilide hydroxamic acid (SAHA; N-hydroxy-N′-phenyl-octanediamide; vorinostat) is a potent inhibitor of cell proliferation, inducer of cellular differentiation, and inducer of apoptosis in cancer cells. The anticancer action of SAHA is likely to result from its activity as an inhibitor of histone deacetylase, which mediates alterations in the expression of cancer-associated genes. SAHA has been shown to be an effective inhibitor of carcinogenesis in animal models for breast, lung, and colon cancer; the present study was performed to evaluate the activity of SAHA as an inhibitor of oral carcinogenesis. Squamous cell carcinomas of the tongue were induced in male F344 rats by administration of 4-nitroquinoline-1-oxide (NQO; 20 ppm) in the drinking water for 10 weeks. After completion of NQO administration, rats were randomized into groups of 25 and received either unsupplemented basal diet (dietary control); basal diet supplemented with SAHA (500 mg/kg diet); or basal diet supplemented with SAHA (1000 mg/kg diet). All experimental diets were fed continuously until the end of the study at week 26. Dietary administration of SAHA induced a dose-related reduction in oral cancer incidence (64% and 29% in the low and high dose groups, respectively, versus 80% in the dietary control group; p &lt; 0.01). In addition, the high dose of SAHA increased the percentage of animals without any evidence of oral pathology from 4% in dietary controls to 25% (p &lt; 0.05). In addition to its effects on cancer incidence, SAHA reduced the invasiveness of induced oral cancers in NQO-treated rats: whereas 60% of rats in the dietary control group demonstrated advanced oral cancers (invasion scores of +3 or +4), advanced cancers were seen in 40% and 25% of rats fed the low and high doses of SAHA, respectively (p &lt; 0.05 for high dose). SAHA increased the incidence of squamous epithelial hyperplasia (28% and 38% in low and high dose groups, respectively, versus 16% in dietary controls; p &lt; 0.05 for high dose). This effect suggests that SAHA prevented the progression of hyperplastic lesions into invasive oral cancers. SAHA also prevented the body weight loss that is commonly seen in this model in animals with advanced oral cancer. These data demonstrate SAHA is a potent inhibitor of carcinogen-induced squamous cell carcinoma in rats, and suggest that inhibitors of histone deacetylase should be considered for further development as inhibitors of oral cancer development. (Supported by N01-CN-25113 from the NCI.)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1858. doi:10.1158/1538-7445.AM2011-1858
Abstract 1859: Targeting APE-1/Ref-1 activity for prevention of non-melanoma skin cancer
Authors: Olson Erik R. , Evans Chris C. , Cooke Laurence S. , Mahadevan Daruka , Bowden G. Tim 
Published: August 2014

Abstract
Apurinic/apyrimidinic endonuclease-1/Redox Factor-1 (APE-1) is a dual function protein and novel target for chemoprevention of ultraviolet (UV) light-induced skin carcinogenesis. Each of the primary functions of APE-1, base excision repair of DNA damaged by oxidation and transcription factor reduction after exposure to an oxidizing stimulus like UV, is performed through the activity of a unique functional domain and plays a potential role in skin cancer promotion and progression. Our hypothesis was that APE-1 activity would correlate with survival after UV irradiation due to enhanced AP-1 activity and DNA repair. Preliminary experiments with HaCaT keratinocytes, an initiated cell line with characteristic UV-signature hotspot mutations in p53, using APE-1 siRNA demonstrated that downregulation of APE-1 increased cell sensitivity to UV-induced apoptosis. We then PCR amplified APE-1 from reverse transcribed HaCaT cell RNA and cloned it into an EGFP-tagged expression vector to generate two stable APE-1 overexpressing HaCaT cell lines, HGA9 (high expressing) and HGA10 (low expressing) cells. As expected, HGA9 and HGA10 cells were less sensitive than HaCaT cells to UV-induced apoptosis by 49.6 and 43.6%, respectively. Collectively, these data indicate that APE-1 activity does in fact play a significant role in the cellular response to UV and suggest that inhibiting APE-1 activity could be an effective means of eliminating initiated cells from the skin and preventing tumor development and growth. To further evaluate APE-1 as a therapeutic target, a library of molecules was screened for their ability to dock within one of two known binding pockets on the surface of APE-1 using an in silico docking algorithm. The first pocket screened lies within the AP endonuclease domain of APE-1. Initially, five individual molecules were chosen because they were predicted to bind APE-1 better than resveratrol, a known inhibitor that has been shown to interact with APE-1 directly. These molecules are predicted to have a higher specificity for APE-1 than resveratrol and have been assessed for their ability to inhibit DNA repair in vitro using recombinant human APE-1. Novel molecules that inhibit APE-1 activity could prove valuable in preventing UV-induced skin carcinogenesis by promoting the death of initiated keratinocytes that would otherwise undergo clonal expansion and progress to skin tumors.
This work was supported by NIH grants: 5P01CA027502 and 5P30CA023074 and by a generous gift from Alliance Beverage Distributing Company.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1859. doi:10.1158/1538-7445.AM2011-1859
Abstract 186: NER factor XPC enhances DNA damage-induced apoptosis independently of p53 function
Authors: Wang Qi-En , Han Chunhua , Milum Keisha , Wani Altaf A. 
Published: August 2014

Abstract
Xeroderma Pigmentosum complementation group C (XPC) is a 940-aa protein engaged in the DNA damage recognition during nucleotide excision repair (NER). It was reported that one of the XPC polymorphisms, Lys939Gln, is associated to cancer predisposition, although this variant did not affect NER. Thus, another mechanism must exist to contribute to this cancer susceptibility. In addition, this XPC genetic polymorphism correlates with the failure of imatinib treatment in patients with chronic myeloid leukemia. We reasoned that XPC must be influencing other functions unrelated to DNA repair. Here, we demonstrated that XPC can enhance the apoptosis induced by various DNA damaging agents, including ionizing radiation (IR), ultraviolet light (UV), cisplatin, and etoposide. In addition, XPC-mediated apoptosis is independent of p53, as reflected by the findings that knock-down of XPC expression compromised the UV or IR-induced apoptosis in p53-deficient Li-Fraumeni Syndrome (LFS) MDAH041 and HCT116 cell lines, while having no influence on apoptosis in their p53-proficient counterparts. Also, in response to UV irradiation, XPC deficiency did not affect the mitochondrial cytochrome c release or had only slight effect on the activation of caspase-3. However, XPC deficiency compromised the UV-induced activation of caspase-9. Therefore, XPC seems to function downstream of mitochondrial membrane permeabilization (MMP) and upstream of caspase-9 activation during DNA damage-induced apoptosis. We further demonstrated that XPC deficiency impaired the UV-induced caspase-2 activation, as reflected by reduced cleavage of long isoform of caspase-2 (CASP-2L) in XP-C cells compared to XPC-restored XP-C cells following UV irradiation. Meanwhile, the short isoform of caspase-2 (CASP-2S) was found to be induced in XP-C cells at early times following UV irradiation, while it remained unchanged in XPC-restored XP-C cells. Given that caspase 2 gene generates both proapoptotic (CASP-2L) and antiapoptotic (CASP-2S) isoforms by alternative splicing, our data suggest that XPC enhances DNA damage-induced apoptosis by inhibiting the production of anti-apoptotic CASP-2S via regulation of the alternative splicing of caspase-2.
(Supported by NIH grants CA93413, ES2388 and ES12991).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 186. doi:10.1158/1538-7445.AM2011-186
Abstract 1860: 15-Deoxy-Δ12,14-prostaglandin J2 induces 15-hydroxyprostaglandin dehydrogenase expression through activation of Elk-1 in human breast cancer cells
Authors: Lee Ha-Na , Kim Hye-Rim , Park Jong-Min , Surh Young-Joon , Na Hye-Kyung 
Published: August 2014

Abstract
Overproduction of prostaglandin E2 (PGE2) has been reported to be implicated in carcinogenesis. The intracellular level of PGE2 is regulated not only by its biosynthesis, but also by its degradation process. The key enzyme responsible for the biological inactivation of PGE2 is NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). This enzyme catalyzes NAD+-linked oxidation of 15(S)-hydroxyl group of prostaglandins to 15-keto metabolites, thereby inactivating PGE2. In the present study, we have found that 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), one of the terminal products of cyclooxygenase-2 (COX-2), upregulates 15-PGDH expression at both protein and mRNA levels in human breast cancer (MDA-MB-231) cells. The catalytic activity of 15-PGDH was also increased by 15d-PGJ2 treatment. By using deletion constructs of 15-PGDH promoter, we found that Ets is the most essential determinant for 15-PGDH induction. Elk-1, one of Ets transcription factor family members, was phosphorylated by 15d-PGJ2 treatment as determined by Western blot and immunocytochemical analyses. siRNA knockdown of Elk-1 suppressed 15-PGDH expression, indicating that Elk-1 plays a key role in 15-PGDH induction. We also observed that a pharmacological inhibition of ERK1/2 with U0126 abrogated the 15-PGJ2-induced activation of Elk1 and expression of 15-PGDH. Like 15d-PGJ2, its non-electrophilic analog 9,10-dihydro-15d-PGJ2 induced 15-PGDH, suggesting that the α,β-unsaturated carbonyl group of 15d-PGJ2 is not essential for its upregulation of 15-PGDH induction. The induction of Elk-1-mediated 15-PGDH expression by 15d-PGJ2 may account, in part, for its anti-inflammatory and anti-carcinogenic properties of this cyclopentenone prostaglandin.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1860. doi:10.1158/1538-7445.AM2011-1860