bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 1818: The Aurora B inhibitor ABT-348 is not susceptible to known resistance mechanisms of other Aurora B inhibitors
Authors: Guo Jun , Curtin Michael L. , Heyman Robin , Anderson Mark G. , Marcotte Patrick A. , Tapang Paul , Palma Joann , Rodriguez Luis E. , Niquette Amanda , Bouska Jennifer J. , Albert Daniel H. , Donawho Cherrie K. , Frey Robin R. , Michaelides Michael , Tse Chris , Glaser Keith B. , Shah Omar J.
Published: August 2012

The Aurora kinases (Aurora A, B, and C) play essential roles in regulating cell division in mammalian cells and their over-expression in diverse tumor types makes them appealing oncology targets. ABT-348 is a novel, ATP-competitive, multi-targeted kinase inhibitor that exhibits potent activity in multiple solid tumor-derived and leukemia cell lines. ABT-348 is active against Aurora B (IC50 7 nM) and Aurora C (IC50 1 nM), Aurora A (IC50 120 nM). The activity against Aurora B is demonstrated by inhibition of histone H3 phosphorylation and induction of polyploidy. ABT-348 is also active against Aurora-B Y156H, a mutant resistant to other Aurora-B inhibitors. In addition, ABT-348 potently inhibits most members of the VEGFR and PDGFR family of receptor tyrosine kinases, which play a critical role in stromal angiogenesis. In contrast to other Aurora kinase inhibitors, the cellular efficacy of ABT-348 is retained in cells over-expressing P-glycoprotein (Pgp) or breast cancer resistant protein (BCRP), indicating that ABT-348 is not a substrate for these commonly upregulated ATP-binding cassette drug transporters. Consistent with these in vitro studies, ABT-348 was broadly efficacious as a single agent against a wide range of tumor types in vivo, including 3 multi-drug resistant xenograft models. In summary, the potent activity and unique kinase selectivity of ABT-348 against the Aurora kinases and VEGF and PDGF receptor tyrosine kinases, engender its ability to block multiple mechanisms of tumor progression. In addition, our data provide evidence that ABT-348 may be active in tumors resistant to other well-characterized inhibitors targeting Aurora-B. ABT-348 is presently under clinical evaluation in adult patients with advanced solid and hematological neoplasms.

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 1818. doi:1538-7445.AM2012-1818
Abstract 1827: Developing chemotherapeutics which selectively disable the actin cytoskeleton of tumor cells
Authors: Stehn Justine R. , Haass Nikolas K. , Desouza Melissa , Kottyan Gregg , Treutlein Herbert , Zeng Jun , Nascimento Paula R. , Han Min Hi , Hill Timothy A. , McCluskey Adam , Palmer Stephen , Hardeman Edna C. , Weninger Wolfgang , Cripe Timothy P. , Gunning Peter
Published: August 2012

The actin cytoskeleton is an important regulator of a variety of cellular functions making it an ideal chemotherapeutic target. Despite this promise no anti-actin compounds are used in current chemotherapy, primarily due to the inability of existing anti-actin agents to discriminate between the actin cytoskeleton of tumor cells and that of the muscle sarcomere. We have previously shown that tropomyosin, an integral component of the actin cytoskeleton, defines functionally distinct actin filament populations. We have designed a new class of compounds which target a specific cancer associated tropomyosin isoform, Tm5NM1. Anti-tropomyosin (Tm) compounds were selected based on ability to target the actin cytoskeleton and efficacy against a panel of neuroblastoma and melanoma cell lines. The lead compound, TR100, was shown to be effective against a panel of tumor cell lines (average EC50 3µM). Preliminary studies demonstrate that TR100 induces cell death via the intrinsic (mitochondrial) apoptotic pathway and the mechanism appears to be independent of the pro apoptotic factors BAX and BAK. In 3D melanoma spheroid models, which more accurately mimic the tumor microenvironment, TR100 inhibited cell growth and motility. This translated to a reduction in tumor cell growth in neuroblastoma and melanoma xenograft models. Analysis of drug treated animals showed no evidence of cardiac damage as measured by blood Troponin I levels and the intraventricular septum thickness of isolated hearts. These results demonstrate the possibility of targeting distinct actin filament populations based on tropomyosin composition. Next generation anti-Tm compounds with improved efficacy and specificity have now been developed. Preliminary data demonstrate that these compounds exhibit increased selectivity for transformed cells. Taken together, our findings suggest that the anti-Tm compounds show a significant improvement in the therapeutic window compared to existing anti-actin agents. This novel approach and the development of the new class of anti-Tm compounds may be the key for disabling a long sought after target, the actin cytoskeleton, and may lead to a new class of chemotherapeutics active against a broad range of cancer types.

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 1827. doi:1538-7445.AM2012-1827
Abstract 1843: Overexpression of polyisoprenylated methylated protein methyl esterase in triple negative breast cancer
Authors: Lamango Nazarius S. , Duverna Randolph , Amissah Felix , Aguilar Byron J. , Poku Rosemary A.
Published: August 2012

Lack of targeted, more effective therapies for triple negative breast cancer (TNBC) has necessitated the continuous search for protein biomarkers and targets for novel therapeutic development. Polyisoprenylated monomeric G-proteins such as Ras and Rab are hyperactive in about 30% of cancers and have profound effects on cell growth. Inhibition of polyisoprenylated methylated protein methyl esterase (PMPMEase) causes the death of cancer cells thus suggesting that hyperactivity of PMPMEase may result in cancers. The current studies were to address the hypothesis that PMPMEase activity is elevated in breast cancer. PMPMEase activity was determined in breast tumors and normal adjacent tissues (NAT) in snap-frozen tissues from 10 breast cancer cases. Five- to over 20-fold increases in PMPMEase activity compared to the respective NATs were detected in 8 of the 10 cases. Specific activities ranging from 0.25 ± 0.02 to 1.58 ± 0.07 nmol/h/mg were detected in the tumors compared to 0.09 nmol/h/mg or less in the NATs. Breast cancer tissue microarrays (TMAs) consisting of 125 independent breast cancer cases and NATs were analyzed for PMPMEase expression by immunohistochemistry and scored for their immunoreactive staining intensities. Intermediate to very strong immunoreactivities were detected in the breast cancer TMA core slices compared to only trace staining in those of the NATs. The mean scores ± SEM ranged from 310 ± 21, 290 ± 7, 350 ± 15, 360 ± 18, 390 ± 14, 360 ± 29, 390 ± 13, 275 ± 10 to 65 ± 10 for TNBC, ER(+), ER(+)PR(+), ER(+)HER2(+), ER(+)PR(+)HER2(+), PR(+)HER2(+), HER2(+), PR(+) and NATs, respectively. These results show that PMPMEase overexpression in breast cancer may explain the increased enzymatic activity in the tumors. PMPMEase enzymatic activity and/or immunoreactivity may serve as diagnostic procedures for breast cancer. PMPMEase may also serve as valid target for anticancer drug development.

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 1843. doi:1538-7445.AM2012-1843
Abstract 1845: ADAM10: A new player in breast cancer progression
Authors: Mullooly Maeve , McGowan Patricia M. , Sukor Sumainizah , Madden Stephen F. , McDermott Enda , Crown John , Duffy Michael J.
Published: August 2012

Background: The ADAMs are a family of proteases, best known for their role in releasing the extracellular domain of transmembrane proteins. One of the ADAMs, i.e., ADAM10, is involved in the activation of 2 important signaling systems controlling cell growth, invasion and metastasis, i.e. the EGFR and NOTCH signaling systems. Because of its ability to activate both EGFR and NOTCH, ADAM10 is likely to play a role in cancer formation or progression. The aim of this study was therefore to investigate the role of ADAM10 in breast cancer and test its therapeutic potential, especially in patients with the triple-negative form of this disease. Materials and Methods: ADAM10 mRNA expression was examined in a pooled collection of publically available databases (n ∼ 4000). ADAM10 protein was examined in a cohort of 120 breast tumor extracts by ELISA. In addition, ADAM10 expression was decreased by RNAi and the effects of this on cell proliferation, invasion and migration were determined. Using the novel ADAM10 inhibitor GI254023X (GSK), we examined the effect of ADAM10 inhibition on a panel of 13 breast cancer cell lines. Results: Using the pooled collection of databases, ADAM10 mRNA was found to be significantly elevated in HER2+ breast cancer compared to other subtypes (p < 0.0001). High ADAM10 mRNA expression was also observed in basal like breast cancer and was associated with poorer overall survival in this subgroup (p = 0.0196). In a cohort of 120 breast tumor extracts, ADAM10 protein was found to be significantly higher in ER-negative compared to ER-positive tumors (p = 0.005), in high grade versus low grade tumors (p < 0.0001), and in younger than older women (p = 0.018). Downregulation of ADAM10 in MDA-MB-231 breast cancer cells resulted in a significant reduction in invasion (p = 0.0006) and cellular migration (p = 0.0002). Treatment of 13 breast cancer cell lines with GI254023X resulted in variable growth inhibition (from 0 to 52%). Furthermore, GI254023X significantly decreased invasion in the MDA-MB-231 cell line (p = 0.001). Conclusions: Our findings of a correlation between ADAM10 and features of aggressive disease and the fact that its downregulation/inhibition decreased growth, invasion and migration suggests that this ADAM10 protease is involved in the progression of breast cancer. Inhibition of ADAM10 with GI254023X may be a new treatment for breast cancer. Acknowledgements: The authors thank SFI and the Molecular Therapeutics for Cancer Ireland (SRC award, 08/SRC/B1410 to MTCI) for funding this work.

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 1845. doi:1538-7445.AM2012-1845
Abstract 1846: Cyr61 a therapeutic target for breast carcinomas
Authors: Venkatapoorna Chandra Mohan Kurapaty , Espinoza Ingrid , Park Cheol-Hong , Busby Robert , Wiley Elizabeth , Rademaker Alfred , Lupu Ruth
Published: August 2012

Background: Cyr61, also known as CCN1, is a survival and pro-angiogenic factor overexpressed in invasive breast tumors that promotes tumorigenicity. We investigated whether Cyr61 plays important roles in breast cancer and evaluated its potential role as a chemotherapeutical target. Methods: We analyzed Cyr61 expression in a tissue microarray from breast cancer patients consisting of primary breast carcinomas and recurrences. Cyr61 was silenced in the metastatic MDA-MB-231 cells using a Cyr61-specific short hairpin RNA (Cyr61-shRNA). The effect of Cyr61 silencing on anchorage dependent- and independent growth, migration and invasiveness was characterized in vitro. The mechanism by which Cyr61 mediates the proliferation effects was investigated. The effect of Cyr61 in tumor growth was investigated in a subcutaneous orthotopic tumor xenograft model and the histological and immunohistochemical analysis ware performed. All statistical tests were two-sided. Results: Cyr61 is highly expressed in about 47% of the metastatic breast cancer patients analyzed. The expression is higher in the recurrences than in the primary tumors. Silencing Cyr61 inhibits cell proliferation, prevents anchorage-dependent and -independent growth, and suppresses the invasive potential of the cells by inhibiting migration in vitro. We also found that silencing Cyr61 decreases the expression of its own receptor αvβ3, and decreases its signaling activities. Remarkably, the in vivo studies showed that after silencing Cyr61 the tumor burden is significantly decreased and there is poor vascularized compared to control tumors. Conclusions: Our findings provide the proof of concept that Cyr61 is a key promoter of breast cancer tumorigenicity. It should be considered as a potential target for developing therapies to breast cancers patients that overexpress Cyr61.

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 1846. doi:1538-7445.AM2012-1846
Abstract 1848: Expression of an androgen transporter, organic anion transporting polypeptide 1B3, impacts progression and treatment of prostate cancer
Authors: Pressler Heather M. , Sissung Tristan M. , Price Douglas K. , Figg William D.
Published: August 2012

Organic anion transporting polypeptides (OATPs) are membrane transporters that facilitate the movement of large substrates into cells. One family member, organic anion transporting polypeptide 1B3 (OATP1B3) is aberrantly overexpressed in prostate cancer and has been shown to influx both endogenous small molecules and chemotherapy reagents. Our hypothesis is that the OATP1B3 affects tumor growth by influxing testosterone. However, little is known about the cause of OATP1B3 expression in cancer and the impact of OATP1B3 transport on tumor growth. Therefore, we completed a study investigating putative hypoxia elements in the OATP1B3 promoter region, characterizing the impact of OATP1B3 androgen transport on prostate cancer growth, and examining the effect of OATP1B3 on the efficacy of standard prostate cancer treatments. The results showed that OATP1B3 co-localized with HIF 1-alpha in prostate cancer tissues from patients, correlated significantly to HIF1A in xenograft tumors under castration (P=0.005), and confirmed HIF-1alpha elements in the SLCO1B3 promoter region. In addition, radioactive transport assays with Xenopus oocytes showed that OATP1B3 transports testosterone and dihydrotestosterone 50- to 250-fold over passive diffusion at low physiological concentrations. A prostate cancer cell line expressing OATP1B3 grew faster than untransfected in response to androgens at all concentrations. Finally, OATP1B3 increased cell sensitivity to docetaxel treatment. In summary, these data show that hypoxia and castration increases OATP1B3 expression in cancer, OATP1B3-mediated androgen transport significantly impacts prostate cancer growth and OATP1B3 impacts the efficacy of docetaxel. These data provides evidence that OATP1B3 impacts prostate cancer growth and treatment. Future studies could screen for specific inhibitors of OATP1B3-mediated androgen transport.

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 1848. doi:1538-7445.AM2012-1848
Abstract 1852: Identification of the UV-inducible RNA binding protein hnRNP A18 as a new target for melanoma progression
Authors: Yang Qingyuan , Carrier France
Published: August 2012

Melanoma is the most dangerous form of skin cancer. If recognized and treated early, it is nearly 100 percent curable. However, invasive melanoma is hard to treat and consequently presents an extremely poor prognosis with a 5-year survival of about 6% and a median survival duration of 7.5 months. We have identified the UV-inducible RNA binding protein hnRNP A18 as a new target for melanoma progression and responses to anticancer drugs treatments. hnRNP A18 basal levels are up-regulated in melanoma cells as compared to normal melanocytes and UV radiation increases hnRNP A18 levels in 5 of the 6 melanoma cell lines we studied. More over, down regulation of hnRNP A18 reduced by more than 80% melanoma tumor growth in mice xenograft and sensitized melanoma cells to Temozolimide (TMZ) and the hypoxic mimetic agent CoCl2. In addition, levels of hnRNP A18 expression in response to UV radiation are proportional to melanoma cells capacity to survive UV-induced cellular damage. We have identified an hnRNP A18 RNA binding signature motif in the 3′ UTR of key regulatory proteins such as HDAC 8, 9, 11, HIF-1α and ATR that can confer resistance to UV induced DNA damage and hypoxic conditions. Therefore by targeting of a single molecule, hnRNP A18, it may be possible to shut down an entire network of protective proteins conferring melanoma cells, and potentially other solid tumors, growth advantage and resistance to conventional therapies.

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 1852. doi:1538-7445.AM2012-1852
Abstract 1857: Intracellular protein GP128 is a novel tumor angiogenesis marker on gastric cancer cell lines and GI tissues: Ectopic expression on the cell surface defined by MS38-2.1 mAb
Authors: Li Ming , Chen XueHua , Tao ShengCe , Zhang XiaoLei , Yin Jue , Sun JianYu , Zhou YiPing , Gao JianPeng , Liu YunCheng , Zhang DongQing , Li WanBo , Hong JingXin , Lee Jeffery E. , Liu BingYa , Feng ZhenQing , Lu Mason
Published: August 2012

Our aim is to generate monoclonal antibodies (mAbs) against novel markers on the cancer cell surface using an innovated high throughput screening (HTS) strategy. Mixed live cells from four gastric cancer cell lines (MKN45, SGC7901, BGC823 and MKN28) were used as the immunogen for A/J mice: spleen cells were then fused with mouse SP2/0 myeloma cells to generate monoclonal antibody hybridomas. The 16 highly positive hybridoma colonies were selected from 20,000 colonies in sixty-seven 96-well plates through screening using live cell (gastric cancer cells versus normal PBMC) staining and FACS-HTS technology. Protein-A affinity purified mAbs were used to define the antigens, which were confirmed as novel biomarkers on the cancer cell surface using microarray, mass and proteomic analyses. Protein microarray analysis with the MS38-2.1 mAb identified an intracellular protein GP128 (e.g., SPRR3) as the most likely a novel cancer biomarker. The immunohistochemical profiles of MS38-2.1 mAb in GI (gastric and colorectal) cancer tissues were found to be significantly higher (P<0.01) than those in normal GI tissues, and confirmed to be restricted to the small- and medium-sized blood vessels and the cancer cells. Human SPRR3 belongs to a family of small proline-rich repeat proteins that is normally expressed intracellularly. Our findings demonstrate that GP128, like SPRR3, could be ectopically expressed in the extracellular matrix in GI cancers. Conclusion: Our results demonstrate that the intracellular protein GP128 might play a role in gastrointestinal cancer development. This investigation also provides an example of identification of potential cancer biomarkers through a novel screening technique.

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 1857. doi:1538-7445.AM2012-1857
Abstract 1858: Targeting FoxM1 in p53-null tumors
Authors: Wang Zebin , Raychaudhuri Pradip
Published: August 2012

Forkhead box transcription factor FoxM1 is overexpressed in many types of human cancers and promotes tumor development in multiple ways. It is also considered as a potential target for cancer therapy. Because greater than half of the human cancers harbor p53 mutations, we investigate the effect of FoxM1-targeting in spontaneous p53-null tumors. We show that reducing FoxM1 inhibits growth of the p53 null thymic lymphoma and sarcoma cells. In addition, ablation of FoxM1 retards the growth of the p53-null tumors in mouse xenograft model. Moreover, induction of apoptotic cell death is observed in p53 null cells after deletion of FoxM1, accompanied by decreased expression of the FoxM1 target gene Survivin. The ARF26-44 peptide, which inhibits the activity of FoxM1 by targeting it to the nucleolus, is able to effectively induce apoptosis in the p53 null spontaneous tumors. Together, our observations suggest that FoxM1 functions are critical for p53-null tumors and FoxM1 is a therapeutic target of human tumors carrying loss of function p53 mutations.

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 1858. doi:1538-7445.AM2012-1858
Abstract 1868: Response biomarkers to IGF1R and mTOR inhibitor combination therapy in ovarian carcinoma
Authors: Haines Brian B. , Wick Michael J. , Papadopoulos Kyriakos P. , Tolcher Anthony W. , Tammam Jennifer G. , Chaney Marya F. , Nebozhyn Michael , Zhang Theresa , Ebbinghaus Scot W. , Cheng Jonathan D. , Zawel Leigh , Sathyanarayanan Sriram
Published: August 2012

Ovarian cancer, the sixth most frequent cause of cancer death among women in the developed world, is a heterogeneous disease characterized by a diverse set of genetic alterations. These factors underscore the need for more effective treatment options accompanied by biomarker strategies to identify patients who will have a greater likelihood to respond to novel therapy. A combination strategy to target the PI3K pathway with the mTOR inhibitor ridaforolimus and anti-IGF1R antibody dalotuzumab is currently undergoing clinical development. Previous translational work has suggested that low RAS activity, as determined by a RAS gene expression signature score, and high levels of IGF1R pathway activation may enrich for response to this combination therapy. Ranking of tumors in the Moffitt tumor database with a low RAS and high IGF profile suggested that ER+ breast and ovarian cancers are enriched for these putative response biomarkers. Consistent with these observations, clinical responses were noted for several ER+ breast or ovarian cancer patients in a Phase I trial for ridaforolimus and dalotuzumab combination therapy. To provide further support for low RAS and high IGF as response biomarkers, the anti-tumor activity of ridaforolimus and dalotuzumab was assessed in 12 patient derived primary ovarian cancer xenograft models developed at START. These models have been extensively characterized by the South Texas Accelerated Research and Therapeutics (START) group for response to standard of care drugs, and the status of many commonly mutated genes in ovarian cancer. Molecular analyses of these tumors suggest that they represent a diverse cross section of ovarian cancer. Similarly, responses to ridaforolimus and dalotuzumab combination therapy ranged from minimal to significant regression. Importantly, the responsive tumor models were associated with a low RAS gene signature and a moderate to high IGF expression level. Tumors with KRAS mutations or a high RAS gene score were generally resistant to therapy. These results support the further development of low RAS and high IGF as enrichment biomarkers for ridaforolimus and dalotuzumab combination therapy in ovarian carcinoma.

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 1868. doi:1538-7445.AM2012-1868
Abstract 1874: The role of functional polymorphisms in folate metabolism on 6-mercaptopurine-mediated hematological toxicity in children with acute lymphoblastic leukemia
Authors: Patchva Dorababu , Linga Vijay Gandhi , Digumarti Raghunadharao
Published: August 2012

Purpose: Defective S-methylation of 6-mercarptopurine (6-MP) either due to reduced activity of thiopurine s-methyltransferase (TPMT) or due to reduced synthesis of S-adenosyl methionine (SAM) induces hematological toxicity in children undergoing 6-MP treatment for acute lymphoblastic leukemia (ALL). Recently, we have demonstrated the genetic variants of TMPT results in hematological toxicity when on 6-MP. In the current study, we have aimed to explore the role of seven functional polymorphisms in folate metabolism as pharmacogenomic determinants of 6-MP mediated toxicity. Experimental Procedures: In 126 children with ALL being treated with 6-MP, Glutamate carboxypeptidase II (GCPII) C1561T, Reduced folate carrier 1 (RFC1) G80A, cytosolic serine hydroxymethyl transferase (cSHMT) C1420T, Thymidylate synthase (TYMS) 3′-UTR ins6/del6, Methylene tetrahydrofolate reductase (MTHFR) C677T, Methionine synthase (MTR) A2756G polymorphisms were analysed by PCR-RFLP method while TYMS 5′-UTR 28 bp tandem repeat analysis was done by PCR-AFLP method. Summary: Univariate analysis showed positive association of GCPII C1561T (r= 0.23) and cSHMT C1420T (r=0.15) variants with hematological toxicity. Multi dimensionality reduction analysis confirmed synergetic gene-gene interaction between these two loci (×2=5.9, p=0.02) apart from showing an interesting tri-variate interaction i.e, RFC1 G80A/cSHMT C1420T/TYMS 5′-2R3R. RFC1 G80A showed additive interaction with cSHMT while TYMS 2R alleles showed counteracting interaction. Toxicity grade prediction model was developed using multiple linear regression approach, which showed moderate predictability of aberrations in folate metabolism and TPMT*3C (Area under the receiver operating characteristic curve=0.69) thus explaining 36% variation in toxicity. Conclusion: Aberrations in folate metabolism and TPMT*3C contribute to 36% 6-MP mediated toxicity.

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 1874. doi:1538-7445.AM2012-1874
Abstract 1875: Identifying genetic variants contributing to cellular susceptibility to tamoxifen using a genome-wide cell-based model
Authors: Ziliak Dana , Weng Liming , Gamazon Eric R. , Im Hae Kyung , Desta Zeruesenay , Skaar Todd C. , Flockhart David A. , Huang Rong Stephanie
Published: August 2012

Tamoxifen is one of the most commonly used agents in the treatment and prevention of estrogen receptor positive breast cancers. Beyond the presence of hormone receptors, there are no validated predictors of tamoxifen efficacy and toxicity. Therefore, we utilized a genome-wide cell-based model to comprehensively evaluate genetic variants for their contribution to cellular susceptibility to tamoxifen. Our model incorporates multi-dimensional datasets including genome-wide genotype, gene expression, and cellular growth inhibition following treatment in lymphoblastoid cell lines from the International HapMap project. Growth inhibition was measured using AlamarBlue Assay in 60 unrelated CEU (individuals of northern and western European decedent) and 60 unrelated YRI (individuals from Ibadan, Nigeria) samples. All cell lines were treated with increasing concentrations of endoxifen, an active metabolite of tamoxifen, for 72 hours. Log2 transformed percent survival at each concentration and IC50 were used as cellular susceptibility to drug phenotypes. A step-wise genome-wide association studies were performed among SNPs, mRNA expression, and endoxifen sensitivity phenotypes. We identified 10 and 74 SNPs associated with endoxifen sensitivity through the expression of 13 and 92 genes in the separate CEU and YRI population. Interestingly 3 genes (STS, TES and SMARCA2) identified through this method are known to play a role in hormone biosynthesis pathway. Furthermore, a large portion of identified genes was found to play a role in tamoxifen sensitivity in the NCI60 cancer cell lines including CHPT1, a known tumor progression marker. This approach has made possible the identification of genetic variants/genes that have not been previously associated with tamoxifen response. Further validation of these cell-based model findings may significantly improve our ability to predict tamoxifen treatment efficacy and toxicity in breast cancer patients.

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 1875. doi:1538-7445.AM2012-1875
Abstract 1886: Activation of IL-6R/JAK1/STAT3 signaling induces de novo resistance to irreversible EGFR inhibitors in non-small cell lung cancer with T790M resistance mutation
Authors: Cho Byoung Chul , Kim Sun Mi , Solca Flavio , Kim Joo-Hang
Published: August 2012

Advanced non-small cell lung cancers (NSCLCs) with activating epidermal growth factor receptor (EGFR) mutation respond preferentially to reversible first-generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib, but drug resistance invariably emerges. Acquisition of secondary T790M mutation in EGFR is the most common mechanism of acquired resistance to EGFR TKIs in these tumors. Although second-generation irreversible EGFR TKIs, such as BIBW2992 or PF00299804, have been introduced to overcome acquired resistance by the T790M mutation, showing they showed a limited clinical activity in patients with T790M mutant tumors. In this study, we first demonstrated in vitro and in vivo that JAK1-dependent STAT3 activation via autocrine IL-6 production was the key mechanism of de novo resistance to the irreversible EGFR TKIs in NSCLC cells harboring T790M mutation. Both BIBW2992 and PF00299804 induced STAT3 activation via JAK1, but not JAK2 or TYK2, and inhibition of JAK1/STAT3 signaling by small interfering RNA or pyridone 6 (P6, pan-JAK inhibitor) significantly increased sensitivity to BIBW2992 in H1975 or PC9-GR cells. BIBW2992-induced JAK1/STAT3 activation is mediated by interleukin-6 receptor (IL-6R) signaling pathway via autocrine IL-6 production. Cancer cells showed a stronger STAT3 activation and enhanced resistance to BIBW2992 in the presence of conditioned medium from MRC-5 (MRC5-CM) fibroblasts. Blocking of IL-6R/JAK1 signaling significantly inhibited MRC5-CM-induced STAT3 activation and increased the sensitivity to BIBW2992 in the presence of MRC5-CM, suggesting a critical role of IL-6R/JAK1/STAT3 signaling between fibroblasts and cancer cells in the development of drug resistance. Treatment of PC9-GR cells with BIBW2992 for 10 days in the presence of MRC5-CM significantly increased expression of several mesenchymal markers including snail, twist, vimentin, and N-cadherin. The epithelial-mesenchymal transition (EMT) upon short-term BIBW2992 treatment was not suppressed by the addition of P6, but was prevented by early concurrent administration of P6 with BIBW2992. In PC9-GR xenograft model, combination treatment with BIBW2992 and P6 showed a synergistic anti-tumor activity compared with BIBW2992 or P6 alone. Taken together, we suggest that inhibition of IL-6R/JAK1/STAT3 signaling can be a potential target to enhance therapeutic efficacy of irreversible EGFR TKIs in patients with a T790M resistance mutation.

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 1886. doi:1538-7445.AM2012-1886
Abstract 1887: Targeting oncoprotein stability overcomes lapatinib-resistance due to ERBB2 kinase domain mutations
Authors: Kancha Rama Krishna , Blaeschke Franziska , Bartosch Natalie , Peschel Christian , Duyster Justus
Published: August 2012

ERBB2 kinase domain mutations were recently reported in some solid cancers. Moreover, certain ERBB2 mutations were shown to cause lapatinib resistance in vitro thus predicting their emergence in treated patients. We have recently shown that ERBB2-L755S, ERBB2-L755P and ERBB2-T798M mutants cause lapatinib resistance by stabilizing the active kinase conformation (DFG-in), which is incompatible with lapatinib binding (DFG-out). Using an in vitro cell-based drug resistance screen we also showed that these lapatinib resistant mutations might cause secondary resistance in patients treated with lapatinb. Thus, it is important to search for alternate treatment strategies to overcome lapatinib resistance. ERBB2 kinase is a client for HSP90 and is degraded by HSP90 inhibitor treatment. We thus tested if targeting ERBB2 mutant stability by inhibiting HSP90 overcomes lapatinib resistance. Since the kinase domain is important for the ERBB2 interaction with HSP90, we tested whether ERBB2 kinase domain mutants retained their interaction with the chaperone. Co-immunoprecipitation analysis showed that the interaction of ERBB2 mutants with HSP90 is intact. Importantly, HSP90 inhibitor treatment resulted in the degradation of lapatinib-resistant ERBB2 mutants as observed with the wild type ERBB2 kinase. Thus, HSP90 inhibitors may offer an alternative treatment option to overcome primary or secondary lapatinib resistance in patients harbouring ERBB2 mutations. Moreover, combined targeting of different physiological aspects (enzyme activity and protein stability) may prevent the emergence of secondary drug resistance due to kinase domain mutations.

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 1887. doi:1538-7445.AM2012-1887
Abstract 1896: Hepatocyte growth factor induces resistance to anti-epidermal growth factor receptor antibody in lung cancer
Authors: Nanjo Shigeki , Yamada Tadaaki , Takeuchi Shinji , Yano Seiji
Published: August 2012

Introduction: Epidermal growth factor receptor (EGFR) is an attractive drug target in lung cancer, with several anti-EGFR antibodies and small-molecule inhibitors showing efficacy in lung cancer patients. Patients, however, may develop resistance to EGFR inhibitors. We demonstrated previously that hepatocyte growth factor (HGF) induced resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI) in lung cancers harboring EGFR mutations. We therefore determined whether HGF could induce resistance to the anti-EGFR antibody (EGFR Ab) cetuximab in lung cancer cells, regardless of EGFR gene status. Methods: Cetuximab sensitivity and signal transduction in lung cancer cells were examined in the presence or absence of HGF, HGF-producing fibroblasts, and cells tranfected with the HGF gene in vitro and in vivo. Results: HGF induced resistance to cetuximab in H292 (EGFR wild) and Ma-1(EGFR mutant) cells. Western blotting showed that HGF-induced resistance was mediated by the Met/Gab1/Akt signaling pathway. Resistance of H292 and Ma-1 cells to cetuximab was also induced by co-culture with lung fibroblasts producing high levels of HGF and by cells stably transfected with the HGF gene. This resistance was abrogated by treatment with anti-HGF neutralizing antibody. Conclusions:HGF-mediated resistance is a novel mechanism of resistance to EGFR Ab in lung cancers, with fibroblast-derived HGF inducing cetuximab resistance in H292 tumors in vivo. The involvement of HGF-Met-mediated signaling should be assessed in acquired resistance to EGFR Ab in lung cancer, regardless of EGFR gene status.

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 1896. doi:1538-7445.AM2012-1896
Abstract 19: Desmoplakin has a tumor suppressive function through inhibition of Wnt/β-catenin signalling pathway in human lung cancer
Authors: Yang Linlin , Chen Yuan , Cui Tiantian , Knösel Thomas , Zhang Qing , Albring Kai , Huber Otmar , Petersen Iver
Published: August 2012

Desmosomes are intercellular junctions that confer strong cell-cell adhesion thus provide resistance against mechanical stress on epithelial tissues. A body of evidence indicates that decreased expression of desmosomal proteins is associated with poor prognosis in various cancers. As a key component of desmosomal plaque proteins, the role of desmoplakin (DSP) in lung cancer is not yet elucidated. Here, we investigated the anti-tumourigenic activity of DSP in human non-small cell lung cancer (NSCLC). We found that DSP expression was downregulated in 8 out of 11 lung cancer cell lines and in 34 out of 56 primary lung tumours, and DNA methylation was responsible for gene silencing of DSP in both cell lines and primary lung tumours. Ectopic expression of DSP in NSCLC cell line H157 significantly inhibited cell proliferation, anchorage-independent growth, migration, as well as invasion, and also increased the sensitivity of NSCLC cells to apoptosis induced by an anticancer drug, gemcitabine. Furthermore, overexpression of DSP led to enhanced expression of another desmosomal plaque protein plakoglobin (also called γ-catenin), a competitor of β-catenin, resulting in decreased nuclear β-catenin levels and reduced expression of the Wnt/β-catenin target genes Axin2 and MMP14. Knockdown of DSP by siRNA resulted in downregulation of plakoglobin and upregulation of Axin2 and MMP14. Taken together, our data suggest that DSP is inactivated in lung cancer by DNA methylation, DSP increases the sensitivity to anticancer drug-induced apoptosis, and DSP has tumour suppressive function through inhibition of Wnt/β-catenin signalling pathway in NSCLC. The epigenetic regulation of DSP and its ability to increase the sensitivity to anticancer drug-induced apoptosis imply the clinical application.

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 19. doi:1538-7445.AM2012-19
Abstract 192: MiR-34c has an anti-apoptotic role in non-small-cell lung carcinoma
Authors: Catuogno Silvia , Cerchia Laura , Romano Giulia , Laudato Sara , Matarese Maria , Condorelli Gerolama , de Franciscis Vittorio
Published: August 2012

MicroRNAs (miRNAs) constitute a class of small non-coding RNAs that negatively regulate the expression of their target genes. They are involved in many biological processes, including cell proliferation, apoptosis and differentiation, and are considered as promising new therapeutic targets for cancer. However, the identity of miRNAs involved in apoptosis and their respective targets remain largely unknown. Given the elevated complexity of miRNA regulation of gene expression, we performed a functional screening as an alternative strategy to identify those miRNAs that in lung cancer cells may interfere with the apoptotic process. To this aim we generated a derivative of the non-small cell lung carcinoma A549 cell line in which caspase-8, a critical upstream initiator of apoptosis, can be activated by the administration of the small dimerizer drug AP20187. We found a number of miRNAs that may rescue cell viability from caspase-8 activation. They included miRNAs already described as oncogenic such as miR-17, miR-135, miR-520, but also some miRNAs such as miR-124a and miR-34c for which a tumor suppressive role has been instead described or expected. Among them, miR-34c-5p markedly increased resistance to paclitaxel induced apoptosis. We demonstrate that Bmf (Bcl-2 modifying factor) is a target of miR-34c-5p and that its silencing, together with that of c-myc, a known target of miR-34c-5p, contributes to resistance to apoptosis induced by paclitaxel via p53 downregulation.

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 192. doi:1538-7445.AM2012-192
Abstract 1922: 2-Aminothiazoles as potent and selective PI3Kalpha inhibitors: Discovery of NVP-BYL719 and structural basis for the isoform selectivity
Authors: Caravatti Giorgio , Guagnano Vito , Fairhurst Robin , Imbach Patricia , Bruce Ian , Knapp Mark , Furet Pascal , Fritsch Christine , Pover Alain De , Blasco Francesca , Blanz Joachim , Seiler Frank H. , Fabbro Doriano , Lang Marc
Published: August 2012

PI3Ks are lipid kinases that control signaling pathways involved in cell proliferation, motility, cell death and cell invasion. Class I PI3K contains four isoforms, p110α, p110α, p110α and p110α which carry out non redundant signaling functions. The ≤ and ≤ isoforms are ubiquitously expressed, whereas the ≤ and ≤ isoforms are expressed primarily in lymphocytes and engaged in the regulation of immune responses. A gain of function in PI3K signaling is common to many types of human cancer, specifically mutations in PIK3CA which are found in more than 30% of various solid tumor types, including, breast, endometrium, bladder, colorectal cancers as well as lung cancers. As these mutations constitutively activate the lipid kinase activity of the protein, the cancer-specific mutants of p110α appear to be ideal therapeutic targets for anticancer drug development. p110α isoform specific low molecular weight inhibitors could be efficacious against tumors harboring p110alpha mutations and provide an improved safety profile compared to current pan-PI3K modulators. The 2-aminothiazole scaffold proved to be an excellent starting point for the development of potent PI3K inhibitors. Depending on the substitution pattern good PI3Kalpha selectivity can be achieved. Systematic modification of key residues and further optimization of the drug-like and PK properties have led to the identification of NVP-BYL719, a potent and selective PI3Kalpha inhibitor with a promising biological activity. SAR leading to the discovery of NVP-BYL719 and the structural basis for the PI3Kalpha selectivity will be discussed.

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 1922. doi:1538-7445.AM2012-1922
Abstract 1933: Ellagic acid induces apoptosis and cell cycle arrest in HeLa cells and inhibits HPV oncogene expression
Authors: Mohammad Hanan F. , Lindner Daniel J. , Kalafatis Michael
Published: August 2012

Ellagic Acid is a naturally occurring compound that demonstrated anti cancer activity in vitro and in vivo. Ellagic acid inhibits protein kinase CK2, which has been identified as a promoter of tumorogenesis. Blocking CK2 activity can reactivate dormant cellular defensive mechanism and further block signaling pathways that induce cancer. In this study, we are testing HPV 18 positive cervical cancer cells (HeLa) to investigate the effect of ellagic acid on CK2 kinase activity, HPV oncogenes E6 and E7 expression and downstream targets leading to cell death in vitro and in vivo. Treating HeLa cells with ellagic acid induced in vitro cell cycle arrest and caspase mediated apoptosis in both time and dose dependent manner. Ellagic acid inhibited CK2 phosphorylation activity, as well as the expression of viral oncogenes E6 and E7. Inhibition of HPV oncogene expression was accompanied by an increase in P53 and a decrease in cyclin A expression. Ellagic acid treatment induced cytochrome c release in the cytosol and subsequent activation of caspase 3, which led to the fragmentation of Poly (ADP) RibosePolymerase (PARP) at the end of the caspase cascade. Finally, mice treated with ellagic acid demonstrated inhibition of cervical cancer xenograft growth and longer survival compared to vehicle-treated mice confirming the potent anti-tumor activity of ellagic acid. Our results suggest that ellagic acid has anti-tumor and anti-viral properties which could make it suitable for the prevention of HPV induced cervical carcinoma.

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 1933. doi:1538-7445.AM2012-1933
Abstract 1940: Anti-tumor action of adenosine A3 receptor in prostate cancer involves suppression of micro RNA-21
Authors: Jajoo Sarvesh , Kaur Tejbeer , Mukherjea Debashree , Sheehan Kelly , Sheth Sandeep , Rybak Leonard P. , Ramkumar Vickram
Published: August 2012

Introduction: Adenosine-based drugs have shown promising results against various solid tumors including prostate cancer. These drugs exert their effects via adenosine receptors (ARs), and in prostate cancer, the A3AR subtype appears to play a major role in its anti-tumor action. MicroRNAs (miRs) are small non-coding RNAs that regulate the coding RNAs at post-transcriptional level. One of these, miR-21, has been shown to promote prostate cancer growth and invasiveness. In the present study, we hypothesized that A3AR agonists suppressed prostate tumor growth by reducing miR-21 expression. Methods: In vivo studies were performed in xenograft model of prostate cancer in severe combined immunodeficient (SCID) mice. Mice were injected subcutaneously with PC3-MM human prostate cancer cells, treated with vehicle, the agonist N’-(3-iodobenzyl) adenosine-5′-N-methyluronamide (IB-MECA), the antagonist 9-Chloro-2-(2-furanyl)-5-((phenylacetyl)amino)-[1,2,4]triazolo[1,5-c]quinazoline (MRS1220) or MRS1220 + IB-MECA, on alternate day for 2-3 weeks, and tumor growth was measured. Primary tumors were then excised and used to determine miR-21 (by TaqMan assay) and maspin, PDCD4 and TPM1 (by Western blotting and RT-PCR). In vitro studies were done in PC3-MM cells grown in cell culture plates. The levels of miR-21 were also detected in RNA samples obtained from human prostate cancer tissues (OriGene Technologies), while the levels of maspin and PDCD4 were determined in the formalin-fixed paraffin-embedded (FFPE) prostate tumor sections by immunohistochemistry. Results: IB-MECA suppressed tumor growth in SCID mice. This effect was blunted in presence of the antagonist, MRS1220. Reductions in tumor volume were associated with reduced expression of miR-21 in the primary tumors. Furthermore, we observed up-regulation of the tumor suppressor proteins maspin, PDCD4 and TPM1, which are known to be negatively regulated by miR-21. Similar findings were obtained in in vitro cell culture studies. In human prostate cancer RNA samples from patients with different stages of prostate cancer there was high expression of miR-21. This finding co-related with down-regulation of its target proteins, maspin and PDCD4, in human prostate tumor sections. Conclusions: Based on the data, we conclude that activation of the A3AR reduces the prostate cancer growth by suppressing miR-21 expression and up-regulating tumor suppressor proteins such as maspin, PDCD4 and TPM1. These data support the use of A3AR agonists as a viable therapeutic option against the advanced forms of prostate cancer.

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 1940. doi:1538-7445.AM2012-1940