bluuebunny/crossref_metadata_2025 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

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 > 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

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

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

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

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 < 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 < 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 < 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 < 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

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

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

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
Abstract 1862: Capsaicin mediated activation of JNK/FOXO/BIM causes apoptosis in pancreatic cancer cells
Authors: Pramanik Kartick C. , Srivastava Sanjay K.
Published: August 2014

Capsaicin, a homovanillic acid derivative (N-vanillyl-8-methyl-nonenamide) is an active component of chili pepper. We previously reported that capsaicin mediated generation of reactive oxygen species (ROS) causes apoptosis in pancreatic cancer cells. In the present study, we investigated the potential mechanism of capsaicin mediated apoptosis in pancreatic cancer cells. In a time and concentration dependent study, capsaicin treatment activated c-Jun N terminal kinase (JNK) in BxPC-3, AsPC-1 and L3.6PL pancreatic cancer cells. Further, capsaicin induced activation of JNK in turn activated FOXO1 by phosphorylating at Ser 256 and pro-apoptotic protein BIM at Ser 69. The expression of BIM also increased in response to capsaicin treatment. Capsaicin treatment also caused cleavage of caspase-9, caspase-3 and PARP resulting in apoptosis. Blocking capsaicin mediated activation of JNK by JNK-specific inhibitor SP600125 attenuated nuclear localization of FOXO-1, activation of BIM and abrogated capsaicin-induced apoptosis. To confirm the involvement of ROS in the activation of JNK, FOXO and Bim, cells were treated with antioxidants catalase and EUK (mimetic of catalase) prior to capsaicin treatment. Our results reveal that both the antioxidants blocked capsaicin mediated JNK/FOXO/BIM activation and protected the cells from apoptosis. Furthermore, silencing FOXO1 by siRNA blocked capsaicin-mediated activation of BIM and apoptosis. To further confirm the involvement of Bim in capsaicin-induced apoptosis, cells were transfected with BIM siRNA. Silencing Bim drastically reduced capsaicin-mediated cleavage of caspase-3 and PARP indicating the role of Bim in inducing apoptosis in our model. Taken together, our results suggest that ROS generated by capsaicin activates JNK and FOXO-1 which in turn activates BIM resulting in the cleavage of caspase-9/3 and PARP leading to apoptosis in pancreatic cancer cells. [Supported in part by R01 grants CA106953 and CA129038 (to S.K.S) awarded by the National Cancer Institute].

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 1862. doi:10.1158/1538-7445.AM2011-1862
Abstract 1867: The natural product sulforaphane protects epidermal tissue from individuals at increased risk for melanoma from the effects of UV radiation
Authors: Cassidy Pamela B. , Quackenbush John , Campbell Jennifer , Moos Philip J. , Leachman Sancy A.
Published: August 2014

Our study focuses on the design and testing of melanoma-prevention strategies for use in high-risk populations. Individuals who have germline loss-of-function (LOF) mutations at the highly polymorphic MC1R locus are at 4-fold increased risk for melanoma. Much of this increase likely arises from the loss of MC1R-mediated upregulation of antioxidant, DNA repair, pigment synthesis and anti-apoptotic pathways that protect epidermal melanocytes from the mutagenic effects of UV radiation. We have found that the natural product sulforaphane (SF) protects normal human melanocytes in culture from UV-induced apoptosis and oxidative stress in the absence of MC1R stimulation by its ligand α-MSH. This led us to propose that SF might be useful for protecting the skin of human subjects with LOF MC1R mutations from the harmful effects of UV light. We have sequenced MC1R in volunteers both with and without the red hair phenotype that is typical for humans with LOF mutations. Sequencing was necessary in all volunteers because many individuals with heterozygous LOF mutations do not have the signature pigmentary phenotype, but are still at increased (2-fold) risk for melanoma. Shave biopsies were harvested from those with either wild-type MC1R or two LOF alleles. The epidermal tissues were treated ex vivo with UV and/or SF then analyzed histologically and by qPCR. We found that SF ameliorated many of the effects of UV radiation in tissues from donors with LOF MC1R. This study demonstrates the promise of SF as an agent for protection of human skin in individuals with high-risk MC1R genotypes from the harmful effects of UV radiation.

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 1867. doi:10.1158/1538-7445.AM2011-1867
Abstract 1868: Sep15 knockout in mice provides protection against chemically-induced aberrant crypt formation
Authors: Tsuji Petra A. , Carlson Bradley A. , Yoo Min-Hyuk , Xu Xue-Ming , Naranjo-Suarez Salvador , Fomenko Dmitri , Gladyshev Vadim N. , Hatfield Dolph L. , Davis Cindy D.
Published: August 2014

The essential nutrient selenium appears to have cancer preventive properties that are partly mediated through selenoproteins. This study investigated the role of the 15 kDa selenoprotein (Sep15) in cancer by examining Sep15 knockout in mice. Weanling homozygous Sep15 knockout, heterozygote and wild type littermate controls (N=12/genotype) were given four weekly subcutaneous injections of the known colon carcinogen azoxymethane (10 mg/kg). Sep15 knockout mice developed significantly (p<0.001) fewer aberrant crypt foci (ACF) than controls. Dietary selenium (0, 0.1 or 2.0 μg selenium/g diet) did not significantly affect ACF formation in Sep15 knockout mice. To investigate molecular targets affected by Sep15 knockout, gene expression patterns in colonic mucosal cells of knockout and wild type mice were compared with microarrays and Ingenuity Pathway Analysis. Quantitative PCR and western blot analysis revealed guanylate binding protein-1 (GBP1) mRNA and protein expression to be strongly upregulated in Sep15 knockout mice. Furthermore, serum analysis indicated significant differences in cytokine expression in Sep15 knockout mice. Our results suggest that Sep15 knockout mice are protected against chemically-induced ACF formation possibly through alterations in inflammatory pathways. Funded by NCI Intramural support, the Cancer Prevention Fellowship Program, NIH grants and the Division of Cancer Prevention.

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 1868. doi:10.1158/1538-7445.AM2011-1868
Abstract 1871: Ecological association of trace element exposure and lung and colorectal cancer incidence in Southeastern Kentucky
Authors: Shelton Brent J. , Johnson Nancy , Tucker Thomas , Li Li , Unrine Jason , Christian Jay , Huang Bin , Arnold Susanne , Hopenhayn Claudia , Chen Li , Sanderson Wayne , Shi Xianglin
Published: August 2014

Background: Based on National Program of Cancer Registries data from 2002-2006, Kentucky has the highest incidence rate for invasive lung and the second highest rate for invasive colorectal cancer in the US, and these rates may not be fully explained by common risk factors such as smoking. An association between exposure to certain trace elements such as arsenic(As), chromium(Cr) VI, and nickel(Ni) and these two cancers has been documented (As, Cr, Ni in lung and Cr in colorectal). Geologic maps displaying concentrations of As in Kentucky show higher amounts in the Appalachian region compared to the remainder of KY. The objective of this study was to investigate the levels of trace elements in toenail samples from subjects living in southeastern KY compared to subjects living in the urban area of Louisville, KY (Jefferson County). Trace elements in nail samples may indicate environmental exposures and reflect differences in exposure risk across KY.

Methods: Trace element exposure levels were measured in toe-nail samples provided by 503 subjects sampled across 26 KY counties in the southeastern Appalachian region of KY (n=223) and in Jefferson County KY (n=280). The nail samples were analyzed using inductively coupled plasma-mass spectroscopy (ICP-MS) for the metals Al, As, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, Se, and Zn. Using Kentucky Cancer Registry data from 2003-2007, incidence rates and their 95% CIs for lung and colorectal cancer were compared between southeastern Appalachian KY and the remainder of KY. Trace element concentrations in many samples fell below method detection limits primarily due to limited toenail sample mass. Trace element distributions were estimated using the “Reverse Kaplan-Meier” method for left-censored data. Gamma-based confidence intervals for lung and colorectal incidence rates in each of the two regions were calculated.

Findings: As, Cr, Ni, Se, Cu, Fe, and Pb were found to be significantly higher in southeastern Appalachian KY compared to Jefferson County (all p<0.01). Lung and colorectal cancer incidence rates were also significantly higher in southeastern Appalachian KY (108.89 vs 97.07 and 59.5 vs 55.97; rate per 100,000, respectively). These findings show potentially greater exposure to trace elements for residents of southeastern Appalachian KY and may indicate a cause of greater risk for lung and colon cancer among them. The results of this study provide rationale for further study to assess potential links between trace element exposure and incidence of these two cancers in Kentucky.

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 1871. doi:10.1158/1538-7445.AM2011-1871
Abstract 1874: Public health impact of occupational carcinogens exposure and lung cancer
Authors: De Matteis Sara , Consonni Dario , Lubin Jay H. , Wacholder Sholom , Tucker Margaret , Peters Susan , Vermeulen Roel C. H. , Kromhout Hans , Bertazzi Pier Alberto , Caporaso Neil , Pesatori Angela Cecilia , Landi Maria Teresa
Published: August 2014

Background. Exposure to occupational carcinogens is an important preventable cause of lung cancer. Most previous studies were in highly exposed industrial cohorts. Our aim was to quantify lung cancer burden attributable to occupational carcinogens in a general population.

Methods. We estimated lung cancer risk associated with occupational carcinogens using a new validated job-exposure matrix (JEM), in the Environment And Genetics in Lung cancer Etiology (EAGLE) study, a large (2100 cases and 2120 controls) population-based case-control study conducted in Lombardy, Italy, between 2002-2005. The JEM translated lifetime work-histories coded into standard job-titles into never, low, and high exposure levels for six known/suspected occupational lung carcinogens. We calculated odds ratios (OR) and 95% confidence intervals (CI) in men (1537 cases and 1617 controls), by multiple logistic regression, adjusted for potential confounders, e.g., tobacco smoking and co-exposure to JEM carcinogens. We estimated the Population Attributable Fraction (PAF) as impact measure.

Results. Exposure to asbestos (OR=1.76, 95%CI=1.42 to 2.18), crystalline silica (OR=1.31, 95%CI=1.00 to 1.71), or nickel-chromium (OR=1.18, 95%CI=0.90 to 1.53) was associated with increased risk even at low exposures, with positive trends for intensity and duration. We found an excess risk for exposure to polycyclic aromatic hydrocarbons only among highly exposed workers (OR=1.64, 95%CI=0.99 to 2.70). The PAFs for any exposure to asbestos, crystalline silica and nickel-chromium were 18.1%, 5.7%, and 7.0%, respectively, corresponding to ≈300-800 lung cancer cases/year.

Conclusion. These findings support the substantial role of selected occupational carcinogens on lung cancer burden, even in a low exposed general population. Health policy interventions are warranted.

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 1874. doi:10.1158/1538-7445.AM2011-1874
Abstract 1875: Lung cancer risk among hairdressers in SYNERGY – pooled analysis from case-control studies in Europe and Canada with detailed smoking data
Authors: Olsson Ann C. , Guha Neela , Brüning Thomas , Pesch Beate , Kendzia Benjamin , Wichmann Heinz-Erich , Brüske Irene , Consonni Dario , Landi Maria Teresa , Caporaso Neil , Siemiatycki Jack , Gustavsson Per , Plato Nils , Merletti Franco , Mirabelli Dario , Richiardi Lorenzo , Ahrens Wolfgang , Pohlabeln Hermann , Jöckel Karl-Heinz , Zaridze David , Cassidy Adrian , Lissowska Jolanta , Szeszenia-Dabrowska Neonila , Stücker Isabelle , Benhamou Simone , Bencko Vladimir , Foretova Lenka , Janout Vladimir , Rudnai Peter , Fabianova Eleonora , Dumitru Rodica Stanescu , Forastiere Francesco , Bueno-de-Mesquita Bas , Gross Isabelle M. , Benhaim-Luzon Veronique , Peters Susan , Vermeulen Roel , Boffetta Paolo , Kromhout Hans , Straif Kurt
Published: August 2014

“Occupational exposure as a hairdresser or barber” was classified as probably carcinogenic to humans by the International Agency for Research on Cancer in volume 99 (2010). Small increases in lung cancer risk (20-40%) are found in most cohort studies but without adequate adjustment for smoking. Studies in Scandinavia and the USA show a higher prevalence of smokers among hairdressers than in the general population.

The SYNERGY project has pooled information on lifetime work histories (ISCO-68) and tobacco smoking from 13479 cases and 16350 controls, including 20% women, from 11 case-control studies in 12 European countries and Canada. The original studies were conducted between 1985 and 2005. Odds ratios (OR) for lung cancer and 95% confidence intervals (CI) were estimated by unconditional logistic regression, adjusted for age, sex, study, cigarette pack-years and time since quitting smoking.

Less than 1% of the study population had ever worked as hairdresser or barber (0.89% of cases and 0.74% of controls). Hairdressers and barbers experienced a slight increase in lung cancer risk OR 1.16 (95%CI 0.90-1.49), which disappeared after adjusting for smoking OR 0.97 (95%CI 0.73-1.30). Results by duration of employment showed highest risks in hairdressers with short employment. Results were similar by gender, histology of lung cancer, and for women hairdressers. We observed a slight and non-significant increase in risk for male barbers, particularly in barbers with the longest employment and after adjustment for smoking.

We could not detect an association between having worked as hairdresser or barber and increased lung cancer risk overall after adjusting for smoking. However, among male barbers we observed an increasing risk with increasing duration, although non-significant, after adjusting for tobacco smoking. Final results will include several more studies, and thereby increase the precision of our effect estimates.

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 1875. doi:10.1158/1538-7445.AM2011-1875
Abstract 1925: Dietary patterns and the risk of colorectal adenomas: The Black Women's Health Study
Authors: Adams-Campbell Lucile L. , Makambi Kepher H. , Collins Tanya Agurs , Bright-Gbebry Mireille , Rosenberg Lynn , Palmer Julie R.
Published: August 2014

Background: Colorectal adenomas are benign lesions that may be precursors to colorectal cancer. No studies of African American women have investigated dietary patterns and the risk of colorectal adenomas. Objective: We examined data from the Black Women's Health Study (BWHS) to determine whether dietary patterns are associated with the risk of colorectal adenomas. Methods: This is a prospective cohort study of 59,000 participants followed biennially since 1995. During 155,414 person-years of follow-up from 1997 to 2007 among women who had had at least one screening colonoscopy, 620 incident cases of colorectal adenomas were identified. Using Cox regression models, we obtained incident rate ratios (IRR) for colorectal adenoma in relation to quintiles of each of two dietary patterns, adjusting for other colorectal adenoma risk factors. Results: Two dietary patterns, Western and prudent, were utilized to assess the association between dietary intake and adenoma risk. The highest quintile of prudent diet, relative to the lowest quintile, was significantly associated with 34% reduced colorectal adenoma risk overall (incidence rate ratio, IRR=0.66; 95% CI, 0.50-0.87; p for trend, < 0.01). Higher scores on the Western pattern were associated with higher risk of colorectal adenoma (IRR = 1.42, 95% CI 1.09-1.85 for the highest quintile relative to the lowest; p trend, 0.01). Conclusion: Our findings suggest that African American women may be able to reduce their risk of developing colorectal adenomas by following a prudent dietary pattern and avoiding a more Western pattern.

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 1925. doi:10.1158/1538-7445.AM2011-1925
Abstract 1926: The changing incidence of primary central nervous system lymphoma (PCNSL) in the United States (US): A surveillance, epidemiology and end results (SEER) study
Authors: Tieu Christina , Cerhan James R. , O'Neill Brian Patrick
Published: August 2014

Introduction. Up to now PCNSL incidence in the US was presumed to be increasing in all age groups independent of changes in nosology, new diagnostic techniques, and HIV infection. The intent of our study was, firstly, to extend our prior study of PCNSL incidence in the US (Olson et al, Cancer 2002;95:1504-10) with an additional decade of SEER data; and, secondly, to determine time trends during the HAART era in the US.

Methods. PCNSL age-adjusted incidence rates from 1973-2007 were obtained from the nine SEER registries used in the Olson et al. study. Similarly, the same exclusion criteria were used to remove PCNSL most likely associated with HIV (never married males and females; persons of unknown marital status; all cases reported in the San Francisco registry). To assess the accuracy of the criteria in removing HIV associated cases, incidence rates of Kaposi sarcoma (KS) were assessed with and without the use of the same exclusion criteria.

Results. The incidence of PCNSL in the general population decreased from 1995 to 2000. Following this decrease, the incidence stabilized and is now beginning to increase in the last 5 years. Stratifying the incidence rate by age group and employing the exclusion criteria, PCNSL incidence has remained stable in the 20-64 year old population, but has steadily increased in the 65+ population. Removing the exclusion criteria did not alter the data for the 65+ population but demonstrated a sharp drop in incidence after 1996 for the 20-64 year old population. Applying the same HIV exclusion criteria the incidence of KS resulted in no appreciable change in incidence rates over the same time frame.

Conclusion. The incidence rate of PCNSL is increasing. This increase is driven by a continued increase in incidence among the 65+ population while the incidence for those aged 20-64 has stabilized during the same time frame. An effect of HAART on PCNSL incidence in the US is suggested by the decline in the incidence among the 20-64 year old population without the HIV exclusion criteria.

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 1926. doi:10.1158/1538-7445.AM2011-1926
Abstract 1930: Trends of invasive and in-situ melanoma diagnosis in the U.S
Authors: Han Jiali , Wei Erin , Qureshi Abrar A.
Published: August 2014

Melanoma, accounts for about 4% of skin cancer cases, but is associated with 79% of skin cancer deaths. The number of new cases of melanoma in the US is rising dramatically. The incidence of in-situ melanoma is increasing at a more rapid rate than for melanoma overall. This may be due to better awareness, improved screening techniques and access to dermatologists that result in early diagnosis of melanoma. There is also concern that over the last few years, pathologists have had a lower threshold to diagnose in-situ melanoma due to medico-legal reasons. However, the lesions that are being called in-situ melanoma are most certainly severely dysplastic (atypical) nevi that are considered melanoma precursor lesions. The distinction is important to make an accurate diagnosis when providing medical care to a patient.

We investigated the trend of diagnosis and melanoma invasive versus in situ in three national prospective cohorts of women and men: Nurses’ Health Study I (1976-2008, age at enrollment 30-55), Nurses’ Health Study II (1989-2007, age at enrollment 25-42), and Health Professionals Follow-up Study (1986-2008, age at enrollment 40-75). We accrued 940 invasive and 424 in situ cases in NHS I, 447 invasive and 326 in situ cases in NHS II, and 310 invasive and 153 in situ cases in HPFS. In each cycle of 2-year follow-up, the incidence rate of melanoma steadily increased, and the increased incidence rate of in-situ melanoma was substantially greater than invasive melanoma. These trends were similar in all three cohorts. The ratio of invasive and in-situ melanoma in each cycle 2-year follow-up decreased more than 5 folds over the follow-up period in the NHS I and II. The decrease was not apparent in HPFS.

In this study, we found that in-situ melanoma incidence has continued to rise in the US in the last few decades, especially among women where the rate of in-situ melanoma increased more sharply compared to invasive melanoma incidence.

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 1930. doi:10.1158/1538-7445.AM2011-1930
Abstract 1932: Bortezomib sensitizes malignant human glioma cells to histone deacetylase inhibitors depends on reactive oxygen species production, mitochondrial dysfunction, Noxa upregulation and Mcl-1 cleavage
Authors: Premkumar Daniel R. , Jane Esther P. , Agostino Naomi R. , Pollack Ian F.
Published: August 2014

Glioblastomas are invasive tumors with poor prognosis despite current therapies. Unfortunately, individual targeted therapies have failed to offer long-term survival benefit. Histone deacetylase inhibitors (HDACIs) represent a class of agents that can modulate gene expression to reduce tumor growth. Suberoylanalide hydroxamic acid (SAHA, vorinostat) and LBH-589 are inhibitors of several members of the HDAC family, and we and others have noted some antiglioma activity, although insufficient to warrant use as single-agent therapy. Proteasome inhibitors represent a promising class of anticancer agents, already in clinical use, as bortezomib (PS-341/Velcade) has been approved for the treatment of multiple myeloma with inactivation of NF-κB signaling pathway. We have recently demonstrated that bortezomib exhibited potent anti-glioma activity and dramatically sensitized highly resistant glioma cells to TRAIL cytotoxicity, suggesting that proteasomal inhibition may be a promising combination strategy for glioma therapeutics. In this study, we examined whether bortezomib could enhance response to HDAC inhibition in glioma cells. These studies showed that bortezomib enhanced vorinostat and LBH-589-induced apoptosis in malignant glioma cells. Although vorinostat or LBH-589 treatment alone did not induce apoptosis in glioma cells, efficacy was enhanced by addition of bortezomib, which promoted activation of proapoptotic mitochondrial injury, generation of ROS, and inhibition of the prosurvival NF-κB signaling pathway. Our results also revealed that cotreatment with bortezomib and vorinostat enhanced apoptosis by increasing Mcl-1, Noxa cleavage and other pro-apoptotic protein expression. The significantly enhanced antitumor activity that results from the combination of bortezomib and HDACIs offers promise as a novel treatment for glioma 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 1932. doi:10.1158/1538-7445.AM2011-1932