bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B115: The epithelial to mesenchymal transition is impaired in colon cancer cells with microsatellite instability
Authors: Pino Maria S. , Kikuchi Hirotoshi , Zeng Min , Herraiz Maria-Teresa , Sperduti Isabella , Berger David , Park Do-Youn , Iafrate A. John , Zukerberg Lawrence R. , Chung Daniel C. 
Published: June 2012

Abstract
Colorectal cancers (CRC) displaying DNA microsatellite instability (MSI) are associated with a favorable natural history, but the molecular basis for this observation has not been defined. We sought to determine whether the epithelial-to-mesenchymal transition (EMT), a highly conserved process involved in embryogenesis as well as in tumor progression, invasion, and metastasis, is impaired in MSI-positive CRCs that characteristically have a mutant transforming growth factor-β receptor type II (TGFBR2) gene. The induction of EMT by TGF-β1 was analyzed by phase contrast microscopy, immunofluorescence, qRT-PCR, immunoblotting, and cellular migration and invasion assays in MSS (SW480 and HT29) and MSI (DLD1 and HCT116) colon cancer cell lines. Expression of epithelial (E-cadherin) and mesenchymal (vimentin and N-cadherin) markers was evaluated by immunohistochemistry and qRT-PCR in 129 human colorectal tumors. TGF-β1 induced changes in cellular morphology from an epithelial to a fibroblasticlike morphology, changes in gene and protein expression with a reduction in E-cadherin and induction of vimentin, and changes in motility and invasion consistent with the occurrence of EMT only in MSS colon cancer cells. These effects did not require Smad4 but depended upon the recruitment of ERK. Cells with MSI and mutant TGFBR2 failed to exhibit any of these changes in response to TGF-β1. However, tumor cells with MSI but wildtype TGFBR2 underwent EMT in response to TGF-β1, indicating that TGFBR2 genotype is a key determinant of the EMT response in tumors with MSI. In human colorectal tumors, expression of the EMT markers N-cadherin and vimentin was significantly associated with adverse clinicopathologic features and the absence of MSI. These findings define a unique genotype-phenotype relationship between TGFBR2 and EMT that may contribute to the improved prognosis consistently observed in colon cancers with MSI. Furthermore, these results suggest a potential rationale for the therapeutic inhibition of TGF-β signaling in MSS colorectal tumors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B115.
Abstract B119: Insulin-like growth factor 1 receptor mutants are inhibited by figitumumab (CP-751, 871) in vitro
Authors: Reynolds Jennifer M. , Lloyd David B. , Bentivegna Steven C. , Seymour Albert B. , Borzillo Gary V. , Gualberto Antonio 
Published: June 2012

Abstract
To test the hypothesis that mutant insulin-like growth factor 1 receptor (IGF-1R) protein may differentially respond to inhibition by figitumumab (CP-751, 871), potentially necessitating patient screening, we studied the in vitro efficacy of figitumumab against seven identified non-synonymous somatic IGF-1R mutations. The IGF-1R signaling pathway has been implicated in numerous aspects of tumor biology, and inhibition of this pathway has been shown to provide beneficial anti-tumor effects. Figitumumab is a fully human monoclonal IgG2 antibody against IGF-1R that has been shown to block ligand binding, inhibit IGF-1R tyrosine kinase activity, and induce IGF-1R down-modulation. There have been reports in the literature of targeted cancer therapies being affected by somatic mutations within the target of the therapy itself as well as downstream in the signaling cascade. To identify somatic DNA mutations within the IGF1R gene, 46 colon and 46 lung matched normal/tumor sets were screened using a mismatch repair detection method. The screening process identified seven unique mutations in either colon or lung cancer samples that altered the IGFIR coding sequence; 5 in colon and 2 in lung. These mutations were distributed across various domains of the receptor with three located in the extracellular alpha chain and four in the intracellular beta chain. Of the four located in the intracellular beta chain, three were in the tyrosine kinase domain. To study the effects of these mutations on the kinase activity of the receptor and the ability to inhibit the mutant receptors with figitumumab, stable cell lines containing wild-type and the mutant receptors were created and evaluated by ELISA for down-regulation of the IGF-1R protein and IGF-1R phosphorylation. All seven mutant forms of the protein, as well as wild-type IGF-1R were inhibited by figitumumab. Six of the seven mutant proteins maintained dependency on ligand stimulation for kinase activity while one mutant, a glycine to arginine change at amino acid position 1199, lacked kinase activity all together. The results of our experiments suggest that figitumumab effectively inhibited the wild-type and mutant IGF-1R receptors in this study and therefore screening of figitumumab patients for these mutations should not be necessary.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B119.
Abstract B122: Human monoclonal antibodies to sialyl-Lewis-A with potent CDC and ADCC activity
Authors: Sawada Ritsuko , Sun Shu-Man , Hong Feng , Ragupathi Govind , Livingston Philip O. , Scholz Wolfgang W. 
Published: June 2012

Abstract
The carbohydrate antigen sialyl-Lewis A (sLea) is widely expressed on epithelial tumors of the gastrointestinal tract, on breast cancer cells, and also on small cell lung cancer cells, but is expressed minimally or not at all on normal tissues. sLea serves as a ligand for epithelial leukocyte adhesion molecules and higher expression of sLea was observed in patients with greater node involvement. Since over-expression of sLea appears to be a key event in invasion and metastasis of many tumor cells and tumor cells expressing sLea are highly susceptible to antibody mediated lysis mechanisms, sLea presents an attractive molecular target for tumor therapy in a minimal disease setting.
Here we report the discovery and initial characterization of fully human antibodies that were generated from blood lymphocytes from individuals immunized with sLea vaccine at MSKCC. Antibodies were identified by ELISA using sLea-HSA conjugates and binding to the native antigen was verified by FACS analysis on DMS-79 cells. Two antibodies were selected for further studies based on the apparent high affinity, which was estimated by Biacore at 0.14 nM for 5B1 (IgG/λ) and 0.04 nM for 7E3 (IgM/κ). These antibodies did not bind to sialyl-Lewis X, Lewis A and other related carbohydrates. Both antibodies have been expressed as fully functional human recombinant antibodies in CHO cells. Complement dependent cytotoxicity (CDC) against DMS-79 cells was approximately 60% and 70–90% for r5B1 and r7E3, respectively. Moreover, r5B1 antibodies showed approximately 50% ADCC of DMS-79 cells with human NK cells (at 5:1 ratio) and 80–90% ADCC with human peripheral blood mononuclear cells with two different blood donors (at 100:1 ratio). These results are very encouraging and we believe that further studies to scale up and test these antibodies in various tumor challenge models are warranted. Since sLea is widely expressed on human cancers, such antibodies could eventually find utility in approximately half of the new cancer cases occurring each year.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B122.
Abstract B126: Potent antigen-specific anti-tumor activity observed with antibody-drug conjugates (ADCs) made using a new class of DNA-crosslinking agents
Authors: Miller Michael , Fishkin Nathan , Li Wei , Leece Barbara , Mayo Michele , Jones Gregory , Reid Emily , Archer Katie , Maloney Erin , Kovtun Yelena , Pinkas Jan , Singh Rajeeva , Chari Ravi 
Published: June 2012

Abstract
The clinical support for ADC therapeutics has expanded as more highly-engineered ADCs advance in human clinical testing. Most of the ADCs now in clinical testing contain a tubulin-acting compound (a maytansine or dolastatin derivative) as the cytotoxic agent. While tubulin-acting agents can be effective against many different types of cancers, some cancers are more responsive to DNA-acting agents. To expand the therapeutic potential for ADCs, we sought to develop a new class of cytotoxic agents with a novel, DNA-acting mechanism of action for use with tumor-targeting antibodies. Herein, we report the development of our IGN family of cytotoxic agents. These IGN agents comprise indolino-benzodiazepine dimers that are highly potent by virtue of their ability to alkylate and crosslink DNA. This novel class of compounds demonstrated sequence-selective DNA adduct formation in vitro and cytotoxicity in the picomolar range towards cultured human cancer cells. The intense potency of these compounds, along with their desired aqueous solubility and stability, make them ideally suited for use in ADCs. A lead compound from this class was conjugated to an EpCAM-binding antibody, B38.1, and to a CD33-binding antibody, huMy9-6, through amide bonds. The B38.1-IGN conjugate was highly potent against three different EpCAM-expressing cell lines - COLO 205, LoVo and OVCAR-3 - with IC50 values of 1 pM, 5 pM and 18 pM, respectively. The addition of excess unconjugated B38.1 antibody abolished this cytotoxic effect, demonstrating that the activity of the conjugate is antigen specific. The B38.1-IGN conjugate was considerably less potent towards the antigen-negative Namalwa cell line, with an IC50 value of &gt;1 nM, further demonstrating antigen specificity. Similar potent cytotoxicity was seen with a huMy9-6-IGN conjugate targeting the CD33-positive human promyelocytic leukemia cell line, NB4 (IC50 ∼4pM), in spite of the low antigen expression level (∼10,000 molecules/cell) in this cell line. Of particular interest, the B38.1-IGN conjugate also was potent towards multidrug resistant cancer cells. B38.1-IGN had a IC50 value of 14 pM for COLO 205MDR, a COLO 205 clone engineered to overexpress MDR1 transporter, and 7 pM for HCT-15, an EpCAM-expressing cell line that naturally expresses MDR1. Antibody-IGN conjugates demonstrated dose-dependent activity in multiple human tumor xenograft models in mice, with anti-tumor activity observed at non-toxic doses. The unique mechanism of action of the IGN class of compounds, and the high antigen-specific potency of antibody-IGN conjugates seen in vitro and in vivo, provides a promising new cytotoxic agent for use in the development of new ADCs.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B126.
Abstract B128: Affinity optimization of an anti-MUC1 antibody, (HuHMFG1) also enhances ADCC activity
Authors: Doran Ben , Ritchie Christy , Dhokia Babu , Rogers Paul , Jones David 
Published: June 2012

Abstract
HuHMFG1 (AS1402) is a humanized antibody which binds to MUC1, a cell surface glycoprotein which is over-expressed on tumor cells. A phase II clinical trial of huHMFG1 in metastatic breast cancer was recently terminated prior to completion as it was thought unlikely to give sufficiently positive efficacy findings.
HuHMFG1 contains a potential glycosylation site within the variable region; this is partially glycosylated in the drug product. The presence of the glycan reduces the affinity of the antibody for MUC1, and enzymatic deglycosylation of huHMFG1 increases affinity 3-fold. The asparagine residue which undergoes partial glycosylation (N56) was mutated to all other amino acids and binding affinities to antigen determined: several mutants exhibited enhanced binding to MUC1. The mutation to glycine (N56G) demonstrated approximately 10-fold increased affinity as assessed by antigen binding ELISA and cell binding ELISA against a variety of MUC1-expressing cell lines; BIAcore analysis further supported these observations.
The primary mechanism of action by which huHMFG1 is proposed to function is antibody dependent cell mediated cytotoxicity (ADCC). The N56G mutant exhibited 10 to 20-fold increased ADCC activity compared to huHMFG1 (5-10% of the huHMFG1 dose was required to elicit maximum cell kill); in addition the percentage of target cells killed also increased.
This second generation huHMFG1 exhibits increased antigen affinity and ADCC activity and furthermore has the potential to offer improved in vivo activity.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B128.
Abstract B129: Preclinical assessment of targeting insulin-like growth factor-2 in bone metastasis from prostate cancer by a human neutralizing antibody (m610) and human adult bone implanted model
Authors: Kimura Taichi , Kuwata Takeshi , Ashimine Satoshi , Nagai Kanji , Feng Yang , Dimitrov Dimiter S. , Saito Seiichi , Ochiai Atsushi 
Published: June 2012

Abstract
Background: Insulin-like growth factor (IGF)-2 activates IGF-1 receptor (IGF-1R) as well as insulin receptor (IR). Recently, it is becoming increasingly evident that IR activation by IGF-2 enhances the growth of neoplasms such as Ewing sarcoma and breast cancer in addition to the IGF-1R activation. Advanced prostate cancer frequently and organ-specifically metastasizes to the bone, where the IGF-2 is abundant. However, the role of IGF-2 in bone metastasis from prostate cancer is still uncertain. The present study was aimed at exploring the role of IGF-2 in the growth of prostate cancer cells in a human bone environment and the therapeutic potential of inhibiting IGF-2 by a neutralizing antibody in the bone metastasis.
Materials and Methods: Using our human neutralizing antibody to IGF-2 (m610) and human adult bone implanted mouse model, we investigated whether inhibiting IGF-2 suppresses the growth of prostate cancer cells in the human bone environment. Human MDA PCa 2b prostate cancer cells were inoculated into human adult bone implanted into mammary fat pad of NOD/SCID mice or inoculated into mammary fat pad of the mice without human bone implantation. The mice were treated with m610 or a control antibody once weekly for 4 weeks immediately after inoculation with MDA PCa 2b cells. At 4 weeks after the treatments, histological analyses of the obtained specimens were performed.
Results: M610 treatment significantly decreased the MDA PCa 2b tumor area in the human bone compared with the control. Ki-67 immunostaining revealed that the percentage of proliferating cancer cells in the m610-treated bone tumor sections was significantly lower than that in the control. M610 had no effect on MDA PCa 2b tumor growth in the absence of implanted human bone. IGF-1R and IR expressions on the MDA PCa 2b tumors were confirmed by immunostaining. M610 prevented in vitro IGF-2-induced cell proliferation, phosphorylation of the receptors and phosphorylation of Akt in MDA PCa 2b cells.
Conclusions: These results demonstrate that IGF-2 plays a crucial role in the prostate cancer cell growth in human bone. Targeting IGF-2 by neutralizing antibodies would be a promising therapeutic approach to preventing bone metastasis from prostate cancer.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B129.
Abstract B150: Toyocamycin inhibits ER stress-induced XBP1 mRNA splicing through IRE1α activation
Authors: Tashiro Etsu , Yokouchi Yumi , Yamamoto Kohta , Imoto Masaya 
Published: June 2012

Abstract
Poorly vascularized solid-tumor cells encounter a range of cytotoxic conditions such as hypoxia, nutrient deprivation and pH changes. These cytotoxic conditions in solid tumor are considered to cause ER stress. There is now abundant evidence to suggest that ER stress response is activated in various tumors to protect tumor cells from cytotoxic condition-induced apoptosis. XBP1 is considered to be a critical transcription factor of this process and required for tumor survival. Therefore, small molecule inhibitors of XBP1 activation would provide a new type of therapeutic strategy for cancer treatment. In this study, we screened small molecule inhibitors of ER stress-induced XBP1 activation from culture broth of microorganisms and we identified toyocamycin (H, Nishimura et al.: J. Antibiot., 9, 60 (1956)). Thus, we investigated the mechanism by which toyocamycin inhibited ER stress-induced XBP1 activation.
XBP1 is activated by IRE1α-mediated unconventional splicing of XBP1 mRNA, which resulted in creating a translational frame shift to produce an active XBP1 transcription factor. In HeLa cells, toyocamycin inhibited the transcriptional activity of XBP1, since toyocamycin suppressed tunicamycin or 2-deoxy-glucose, a well known ER stressor, -induced GRP78, EDEM, and ERdj4 expression that are known to be transcriptionaly regulated by active XBP1. Furthermore, toyocamycin inhibited ER stress-induced endogenous XBP1 mRNA splicing evaluated by RT-PCR. Although toyocamycin is known as RNA synthesis inhibitor, toyocamycin could not decrease the expression level of XBP1 mRNA. Thus, the inhibitory activity of toyocamycin against XBP1 activation is not due to the RNA synthesis inhibition. On the other hand, toyocamycin was unable to suppress IRE1α-mediated XBP1 mRNA cleavage in vitro. Therefore, toyocamycin is strongly suggested to inhibit ER stress-induced IRE1 activation.
Finally, we examined the effect of toyocamycin on cell viability under ER stress condition, because XBP1 inhibitor is considered to suppress ER stress-induced cytoprotective effect thereby inducing selective killing of stressed cells. Although toyocamycin had only a weak activity to induce cell death in HeLa cells, toyocamycin synergistically induced cell death when toyocamycin was incubated with 2-deoxy-glucose or tunicamycin. These results indicated that toyocamycin selectively induces cell death under ER stress condition. Taken together, our results suggested that XBP1 is a potent molecular target for developing anti-cancer drug.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B150.
Abstract B155: Effects of bamboo extract on breast cancer
Authors: Ton That Nam Tran S. , Samonte Sabrina-Lynn , Berry Marla J. , Panee Jun 
Published: June 2012

Abstract
Breast cancer is the most common cancer among women in the United States, and worldwide over one million new cases are diagnosed each year. Preliminary studies by Panee and colleagues demonstrated that 0.5% (w/w) dietary supplementation with an ethanol/water extract from bamboo Phyllostachys edulis inhibited the incidence of 7,12-dimethylbenz[a]anthracene (DMBA, a carcinogen)-induced mammary tumors in female Sprague-Dawley rats by 44% and dramatically reduced tumor multiplicity. This project has aimed to delineate the anti-breast cancer mechanisms of this bamboo extract (BEX) in the aforementioned rat model. We hypothesized that BEX may alter the gene expression of key proteins involved in estrogen- and/or growth factor-signaling pathways and xenobiotic biotransforming enzymes in the mammary tumors. To test this hypothesis, we extracted RNA from individual mammary tumors that were harvested from each rat. Then, we synthesized complementary DNA (cDNA) and combined the cDNA samples according to each rat's dietary group— BEX-supplemented rat diet or control rat diet. Using quantitative real-time polymerase chain reaction, we measured expression levels of target genes that included the following: estrogen receptors alpha and beta (ER-α and -β), human epidermal growth factor receptor 2 (HER2), and all glutathioine-s-transferase (GST) isoforms. Comparison between study groups revealed that BEX-supplementation significantly downregulated the gene expression of ER-α, ER-β, and HER2 in the mammary tumors by 65%, 70%, and 67% respectively (p &lt; 0.0001). Additionally, the mammary tumors expressed all GST isoforms, whereby GSTa4 and GSTp1 resulted in high abundant values. Interestingly, BEX supplementation also significantly downregulated the gene expression of GSTa4 and GSTp1 by 32% and 31% respectively (p &lt; 0.005). Our observations have indicated that the downregulation of ER-α, ER-β, and HER2 gene expression in the mammary tumors may contribute to the anti-breast cancer effect of BEX, and that BEX may also reduce chemoresistance in the mammary tumors by inhibiting the gene expression of xenobiotic biotransforming enzyme GST.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B155.
Abstract B16: Anti-angiogenic therapy using brivanib, a combined VEGF and FGF pathway inhibitor, in a mouse model of pancreatic neuroendocrine cancer (PNET), results in sustained vascular blockade, without evidence for evasive/acquired resistance in the form of VEGF-independent revascularization, in contrast to other VEGF inhibitors
Authors: Allen Elizabeth , Walters Ian B. , Rivera Ianne C. , Hanahan Douglas 
Published: June 2012

Abstract
Previous studies using a mouse model of PNET (RIP-Tag2) demonstrated that anti-angiogenic therapy using an antibody that specifically targets murine VEGFR-2, DC101, led to a transitory period of stable disease followed by VEGF-independent revascularization and relapse leading to tumor progression (Casanovas, et al. Cancer Cell. 2005; 8: 299–309). Profiling analysis indicated that FGF was strongly upregulated upon failure of anti- VEGF therapy. Addition of a recombinant adenovirus expressing an FGF-Trap near the end of the response phase impaired revascularization and slowed tumor growth, implicating the FGF family of ligands in evasion of VEGF-targeted anti-angiogenic therapy in this model of PNET.
Brivanib, a selective small molecule inhibitor of VEGFR-2,3 and FGFR-1,2,3 (Cai, et al. J Med Chem. 2008; 51:1976–80), is currently being evaluated in clinical trials in CRC and HCC. Brivanib's activity against FGFR signaling prompted investigation of its effects on evasive/adaptive resistance to selective VEGF inhibition. In the work to be presented, the efficacy of brivanib has been characterized as a first line inhibitor versus two different VEGF inhibitors, DC101 and sorafenib, and as a second line inhibitor following the failure of the aforementioned compounds. DC101 is a pure VEGF inhibitor, while sorafenib is a multikinase RTK inhibitor of VEGFR-2, PBGFR , and RAF/MEK/ERK currently approved in renal and liver cancer, and in Phase 3 trials for multiple other indications.
Brivanib was comparable to FGF-trap as a second line inhibitor following DC101 failure, reducing tumor size and vascularity compared to continued DC101 monotherapy. Brivanib also showed reasonable efficacy in second line following sorafenib in short term trials. Notably, however, it could not reverse revascularization and tumor growth when sorafenib was allowed to fail in longer term trials. In contrast, first line brivanib therapy over comparable time courses that produced failure of both VEGF inhibitors resulted in tumor stasis and, in some cases, regression. Additionally, first-line brivanib therapy produced sustained blockade of angiogenesis, exhibited a trend for reduced invasiveness and metastasis in comparison to anti-VEGFR2 therapy alone, and significantly extended the lifespan of treated animals. Thus, while brivanib has clear benefits in second line therapy following failure of VEGF inhibitors, it may in some indications, as illustrated by this PNET model, be even more efficacious when used in a first line setting. The results from this mouse model of cancer may inform and facilitate design of future clinical trials of brivanib and other inhibitors of FGFR signaling.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B16.