bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C153: New approaches to target mevalonate biosynthesis in cancer.
Authors: Brodsky Alexander , Casella Cinzia 
Published: August 2014

Abstract
To support rapid growth, tumors need to synthesize lipids and cholesterol, and stopping production of these metabolites can inhibit tumors. Statins are among the most prescribed and well-tolerated drugs in the world to treat cardiovascular disease by inhibiting cholesterol synthesis. Statins are known to be toxic to cancer cells and have attracted renewed attention because of the increased appreciation of the importance of the regulation of metabolism in tumors. Statins have not progressed beyond clinical trials because some patients significantly benefit, while others do not in a range of cancers. Our strategy is to improve our understanding of the mechanisms of tumor responses to statins and thereby enhance statin toxicity to cancer cells. We have found that combining statins with oxysterols synergistically enhances statin toxicity by 10-fold. Oxysterols are oxidized cholesterol metabolites that naturally occur during cholesterol synthesis. We hypothesize that oxysterols inhibit the expression of cholesterol synthesis through a master regulator of metabolism, SREBP-2, making cells more sensitive to statins. We find that oxysterols enhance statin induced apoptosis and suppress the expression of SREBP-2 along with SREBP-2 targets including HMGCR. We have tested a number of oxysterols that work with a range of efficacies in seven representative ovarian cancer cell lines. P53 status is not a major factor in mediating oxysterol activity. Oxysterols inhibit expression of SREBP-2 leading to lower expression of the statin target, HMGCR, along with lower expression of most of the mevalonate and cholesterol biosynthesis pathways. These observations suggests that the cell's response to statins and not initial expression levels may be most critical to determine which patients may benefit from statin therapy. Current studies are testing the combination in mouse models and evaluating the function and regulation of SREBP-2 in ovarian cancer. In summary, we have discovered an approach to suppress cancer cell's response to statins leading to greatly improved statin efficacy highlighting the importance of the mevalonate and cholesterol pathways in mediating growth and survival.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C153.
Citation Format: Alexander Brodsky, Cinzia Casella. New approaches to target mevalonate biosynthesis in cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C153.
Abstract C159: A human monoclonal antibody targeting the stem cell factor receptor (c-Kit) blocks tumor cell signaling and inhibits tumor growth.
Authors: Lebron Maria , Brennan Laura , Damoci Chris , Prewett Marie , Starodubtseva Marina , Amatulli Michael , Zhang Yiwei , Burtrum Douglas , Balderes Paul , Persaud Kris , Surguladze David , Loizos Nick , Paz Keren , Kotanides Helen 
Published: August 2014

Abstract
Stem cell factor receptor also known as c-Kit is a receptor tyrosine kinase that mediates cell growth, survival, and differentiation signals in response to its ligand stem cell factor (SCF). Aberrant c-Kit expression and/or activation through mutations or autocrine/paracrine signaling mechanisms occur in various malignancies and promote tumor development. Specific therapeutic targeting of c-Kit in cancer is warranted given its cancer role. In this study, we characterize the biological properties of CK6, a fully human IgG1 monoclonal antibody against the extracellular region of human c-Kit. CK6 specifically binds human c-Kit receptor with high affinity (EC50= 0.06nM) and strongly blocks its interaction with SCF (IC50= 0.41nM) in solid phase assays. Flow cytometry shows CK6 binding to the cell surface of small cell lung carcinoma (SCLC), melanoma, leukemia, and other human c-Kit expressing tumor cell lines. Furthermore, exposure to CK6 inhibits SCF stimulation of c-Kit tyrosine kinase activity and downstream signaling pathways in these tumor cell lines. Reduced levels of phosphorylated c-Kit, mitogen-activated protein kinase (MAPK) and protein kinase B/Akt were observed. Given these findings, we evaluated the antitumor growth efficacy of CK6 in several human xenograft tumor models in vivo. CK6 monotherapy treatment significantly suppressed tumor growth of NCI-H526 SCLC (T/C%= 50) and Malme-3M Melanoma (T/C%= 58) xenograft models. The combination of CK6 with standard of care (SOC) chemotherapy agents, cisplatin and etoposide for SCLC or dacarbazine for melanoma, led to enhanced tumor growth inhibition (SCLC T/C%= 12; melanoma T/C%= 38) compared to CK6 monotherapy or SOC alone. In summary, our results demonstrate that CK6 is a c-Kit antagonist antibody with tumor growth neutralizing properties and are highly suggestive of potential therapeutic application in treating human cancers harboring c-Kit receptor.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C159.
Citation Format: Maria Lebron, Laura Brennan, Chris Damoci, Marie Prewett, Marina Starodubtseva, Michael Amatulli, Yiwei Zhang, Douglas Burtrum, Paul Balderes, Kris Persaud, David Surguladze, Nick Loizos, Keren Paz, Helen Kotanides. A human monoclonal antibody targeting the stem cell factor receptor (c-Kit) blocks tumor cell signaling and inhibits tumor growth. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C159.
Abstract C192: Protein L-isoaspartyl methyltransferase negatively regulates p53 activity.
Authors: Lee Min-Gyu , Lee Jae-Cheol , Nam Ki-Hong , Yoo Jihee , Park Jeehun , Han Jeung-Whan 
Published: August 2014

Abstract
Protein L-isoaspartyl methyltransferase (PIMT), the “protein repair enzyme,” specifically methylates the isoaspartyl residue generated by the spontaneous deamidation of asparagine, and this methylation is an essential step for converting isoaspartate to aspartate. However, the role of the PIMT in the regulation of protein functions is relatively less understood. Here, we show that PIMT negatively regulates the tumor suppressor protein p53 by reducing the p53 protein levels, thereby suppressing the p53-mediated transcription of target genes. In addition, PIMT depletion up-regulates the proapoptotic and checkpoint activation functions of p53. Moreover, PIMT destabilizes p53 by enhancing the p53-HDM2 interaction. These PIMT effects on p53 stability and activity are attributed to the PIMT-mediated methylation of p53 at isoaspartate residues 29 and 30. Our study provides a new insight into molecular mechanisms by which PIMT suppresses the p53 activity through carboxyl methylation, and suggests a novel therapeutic target for cancers.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C192.
Citation Format: Min-Gyu Lee, Jae-Cheol Lee, Ki-Hong Nam, Jihee Yoo, Jeehun Park, Jeung-Whan Han. Protein L-isoaspartyl methyltransferase negatively regulates p53 activity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C192.
Abstract C22: The effect of irinotecan-induced in k-Ras wild and mutant type colon cancer cell lines.
Authors: Kang Myoung Hee , Kim Bo Ram , Lee Sun il , Kim Jun Suk , Oh Sang Cheul 
Published: August 2014

Abstract
Irinotecan (IRI) prevents DNA from unwinding by inhibition of topoisomerase [[Unable to Display Character: &#1030;]]. Its main use is in colon cancer, in particular, in combination with other chemotherapy agents. Recent studies, those with irinotecan treatment has a synergistic effect appears. However, there is no study on the effect of the irinotecan mono-treatment. In addition their roles and the underlying mechanism in anti-tumorigenic function of solid tumor, especially kras wild and mutant type colon cancer, are not yet known. Bax protein is a key mediator of apoptosis and might be related to chemosensitivity. In this work, we evaluated the anti-tumorigenic action of these irinotecan anti-cancer agents with especially k-ras wild and mutant type colon cancer cell lines, and investigated their apoptosis-inducing effects as the potential mechanism in this process. The results show that the growth inhibitory effects of 5-fuorouracil (5-FU), Oxaliplatin(OX) produced a dose- and time dependent fashion in k-ras wild (HT29, Colo205) and mutant type (HCT116, DLD-1) colon cancer cell lines. Otherwise, irinotecan produced a cell growth of k-ras wild type cell lines were resistant versus that shown in the sensitive k-ras mutant type cell lines. Cell cycle analysis by FACS indicated that IRI-treated cell lines showed an increase in the proportion of cells in sub-G1 phase, compared to untreated cells. Exposure of colon cancer cells to IRI also resulted in the increase in the percentage of annexin V- positive and PI-negative cells. The results by multiple in vitro experimental model, showed that IRI induces these k-ras mutant type colon cancer cells to undergo apoptosis with increased the Bax protein and a release of cytochrome C from mitochondria, the activation of caspase9, the cleavage of PARP. But Bax protein was inactivation in k-ras wild type colon cancer cell lines. Importantly, inhibition of ERK kinase activity demonstrated that IRI-induced apoptotic pathway was regulated by the ERK signaling cascade. These data indicate that anti-cancer agent, irinotecan, promotes Bax-mediate apoptosis of colon cancer cell lines by sequential activation of the ERK signaling pathway followed by the up-regulation of intrinsic pathway of caspase 9.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C22.
Citation Format: Myoung Hee Kang, Bo Ram Kim, Sun il Lee, Jun Suk Kim, Sang Cheul Oh. The effect of irinotecan-induced in k-Ras wild and mutant type colon cancer cell lines. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C22.
Abstract C239: Development of EphA10/CD3 bispecific tandem scFv as a drug candidate against breast cancer.
Authors: Taki Shintaro 
Published: August 2014

Abstract
Background: Monoclonal antibodies (mAbs) are clinically used to treat several types of cancer due to their high specificity and potential to activate immune systems. The therapeutic effects of mAbs are unsatisfactory, however, in cases of aggressive cancer or low expression level of target protein. Recently, various antibody formats has been developed through genetic engineering technologies to improve therapeutic effect. Most notably bispecific antibodies (BsAb) are a highly promising form of target therapy. A BsAb that simultaneously targets the antigens on cancer cells and activated T-cells reportedly has the potential to show cytotoxicity more effectively than conventional mAbs. In our efforts to develop a new bispecific monoclonal antibody drug against breast cancer, we attempted to generate a tandem single-chain variable fragment (taFv) targeting both the T-cell CD3 antigen and Ephrin receptor A10 (EphA10), which were previously identified as breast cancer novel biomarker proteins.
Methods: We constructed the taFv (EphA10/CD3) expression vector that contain two single chain Fv (scFv) derived from the anti-EphA10 antibody and anti-CD3 antibody joined by a flexible five amino acid linker (G4S). The taFv was expressed transiently in CHO-S cells and verified for identity by Western blot analysis, was purified via its C-terminal His tag by metal ion affinity chromatography (IMAC). Flow cytometry was used to confirm dual specificity of taFv against cells expressing the appropriate targets. The ability of cytotoxic for taFv from PBMC was analyzed by lactate dehydrogenase (LDH) release assay.
Results: The taFv monomer was purified from CHO-S cells together with the taFv dimer. By flow cytometry analysis, each monomer and dimer bound both antigens EphA10 and CD3 while binding to CD3 was lower than full-body IgG. And each taFvs showed highly cytotoxicity specifically against EphA10 over-expression cancer cell line. Most notably, the cytotoxicity of taFv dimer was higher than taFv monomer at low Effector/Target ratio and low concentration.
Conclusion: In this research, it's proved that this taFv (EphA10/CD3) could induce EphA10 specific cytotoxicity. So, we are now ongoing to evaluate the therapeutic effects of each taFvs (monomer and dimer) in vivo.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C239.
Citation Format: Shintaro Taki. Development of EphA10/CD3 bispecific tandem scFv as a drug candidate against breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C239.
Abstract C248: Novel PORCN inhibitors are safe and effective in the treatment of WNT-dependent cancers.
Authors: Madan Babita , Ke Zhiyuan , Lim Shermaine Q.y. , Alam Jenefer , Ho Soo Yei , Jeyaraj Duraiswamy A. , Ghosh Kakaly , Chew Yun Shan , Aliyev Jamal , Ding Li Jun , Pendharkar Vishal , Wang Sifang , Sangthongpitag Kanda , Keller Thomas , Lee May Ann , Virshup David M. 
Published: August 2014

Abstract
Dysregulation of the Wnt signaling cascades is implicated in multiple disorders. There are 19 human Wnts that mediate signaling through diverse downstream pathways. To achieve maximum benefit from inhibition of Wnt signaling, targeting all of these pathways may be useful. The secretion and biological activity of all human Wnts requires palmitoylation mediated by Porcupine (PORCN), an endoplasmic reticulum-localized membrane bound O-acyltransferase. Several small molecule inhibitors of PORCN have been developed. Here we report a novel pharmacophore with derivatives that are nanomolar inhibitors of Wnt signaling. By a number of criteria, these compounds potently inhibit PORCN catalytic activity and hence suppress downstream Wnt-activated signaling pathways. The compounds effectively reduce autocrine Wnt signaling activity in selected cancer cell lines. The inhibitory activity is stereospecific, as an (R) enantiomer is inactive. Compounds with good oral bioavailability were tested for their in vivo activity and found to be highly efficacious in reversing tumor growth in both MMTV-WNT1 mice and of tumor xenografts. Treated tumors showed marked nuclear exclusion and decreased cytoplasmic staining of beta-catenin compared to vehicle controls. Importantly the treatment modulated downstream markers of Wnt signaling. No signs of toxicity were observed in mice at therapeutically effective doses. These results and our published results on C59 demonstrate that inhibiting the Wnt/beta-catenin pathway by targeting PORCN with small-molecule inhibitors is a feasible and nontoxic strategy. Use of porcupine inhibitors overcomes the problem of redundancy of Wnts, thereby, providing new options for therapy in diseases with high Wnt activity.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C248.
Citation Format: Babita Madan, Zhiyuan Ke, Shermaine Q.y. Lim, Jenefer Alam, Soo Yei Ho, Duraiswamy A. Jeyaraj, Kakaly Ghosh, Yun Shan Chew, Jamal Aliyev, Li Jun Ding, Vishal Pendharkar, Sifang Wang, Kanda Sangthongpitag, Thomas Keller, May Ann Lee, David M. Virshup. Novel PORCN inhibitors are safe and effective in the treatment of WNT-dependent cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C248.
Abstract C250: Concurrent targeting Bcl-2/Bcl-xL and MDM2 as a new therapeutic strategy for acute leukemia.
Authors: Hoffman-Luca C. Gianna , McEachern Donna , Ziazadeh Daniel , Zhao Yu-Jun , Sun Wei , Debussche Laurent , Wang Shaomeng 
Published: August 2014

Abstract
Acquired resistance of tumor cells to anticancer drugs is a major cause of cancer therapy failure in the clinic. In this study, we have investigated the acquired resistance mechanisms in vitro and in vivo for two novel anticancer drugs currently in clinical trials, a Bcl-2/Bcl-xL inhibitor ABT-263 and a MDM2-p53 interaction inhibitor MI-77301/SAR405838. In adult relapsed ALL (RS4;11) xenograft model, both ABT-263 and SAR405838 induced rapid and complete tumor regression but tumors regrew shortly after treatment cessation for both drugs. In pediatric AML (MV4;11) xenograft model, ABT-263 induced tumor growth inhibition and SAR405838 induced rapid and complete tumor regression but tumors also regrew after treatment stopped. Analysis of RS4;11 and MV4;11 resistant tumors to both drugs show that tumor cells evade apoptosis induction by the MDM2 inhibitor by mutation of p53 gene or compromised p53 function, whereas in RS4;11 tumor cells lose their sensitivity to the Bcl-2/Bcl-xL inhibitor through down-regulation of pro-apoptotic Bcl-2 family member BAX. Interestingly, RS4;11 tumors which became resistant to SAR405838, retained sensitivity to ABT-263 and rapid tumor regression was observed upon treatment with ABT-263. Similarly, in both RS4;11 and MV4;11 models, tumor cells which became highly resistant to ABT-263 were still very sensitive to SAR405838 and tumors resistant to the treatment of ABT-263 underwent rapid and complete tumor regression upon treatment with SAR405838. Furthermore, in both leukemia xenograft mouse models, sequential treatment with ABT-263 followed by SAR405838 achieved rapid and complete tumor regression with extended tumor free survival compared to the single agents. Additionally, the combination of SAR405838 and ABT-263 achieved a higher degree of long-term tumor regression than either agent alone. Our study provides new insights into the resistant mechanisms for both Bcl-2/Bcl-xL and MDM2 inhibitors in acute leukemia. Importantly, our preclinical data suggest that the combination and sequential treatment of these two distinct classes of novel apoptosis-inducing agents should be explored as an innovative treatment strategy for acute leukemia in the clinic with the goal to overcome acquired drug resistance and to improve the long-term clinical outcome for acute leukemia patients.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C250.
Citation Format: C. Gianna Hoffman-Luca, Donna McEachern, Daniel Ziazadeh, Yu-Jun Zhao, Wei Sun, Laurent Debussche, Shaomeng Wang. Concurrent targeting Bcl-2/Bcl-xL and MDM2 as a new therapeutic strategy for acute leukemia. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C250.
Abstract C270: In vitro and in vivo antitumor activity of DCBCI0901, a potent PI3K/mTORC1/mTORC2 inhibitor.
Authors: Lee Ying-Shuan E. , Kuo Mann-Yan , Huang Yi-Ting , Tseng Yu-Wen , Lin Yu Jie , Liu Yen His , Chiou Shian-Yi , Chen Li Jung , Lu Y.-Y. , Yang Chih-Hsin , Yang Pan-Chyr 
Published: August 2014

Abstract
The mammalian target of rapamycin (mTOR) is a highly conserved Ser/Thr protein kinase and a central controller of cell growth, proliferation, and survival. Studies have linked the hyperactive PI3K-AKT-mTOR signaling pathway in a variety of human cancers. Drugs targeting to PI3K and mTOR are likely to be an effective treatment for human malignancies that rely on these targets for their growth. Institute of Pharmaceutics at Development Center for Biotechnology in Taiwan has developed a novel and potent small molecule DCBCI0901 as PI3K/mTORC1/mTORC2 inhibitor. DCBCI0901 attenuated cell survival and proliferation in both in vitro and in vivo models. DCBCI0901 possessed IC50 of 8.4 nM against mTOR kinase and IC50 of 78 nM against PI3Kα (p110α/p85α) while exerting high selectivity against a panel of 20 other serine/ threonine and tyrosine kinases. In addition, DCBCI0901 is highly active in cellular assays. It causes a significant reduction in phospho-p70S6K (mTORC1 substrate), phospho-AKT (S473) (mTORC2 substrate), and phospho-AKT (T308) (PI3K substrate) levels. The antitumor efficacy of DCBCI0901 was evaluated in diverse human tumor cell lines. DCBCI0901 effectively inhibits cell proliferation of five well-established cell lines (one NSCLC, A549; two prostate cancers, PC-3 and LNCap; two breast cancers, HCC1954 and BT474), with IC50 values ranging from 6 to 48 nM. Notably, DCBCI0901 is effective against a panel of nine lung cancer cell lines (one cell line is EGFR-TKI sensitive model and eight cell lines are EGFR-TKI resistant model), with IC50 in the ten of nanomolar range. DCBCI0901 showed significant antitumor efficacy in mouse xenograft models including lung cancer, prostate cancer, and leukemia with tumor growth inhibition greater than 65%. DCBCI0901 also demonstrated effective suppression of tumor growth in advanced-stage xenograft models (lung cancer (A549), mean tumor volume &gt; 350mm3 at the start of treatment). Furthermore, in an EGFR-TKI resistant lung cancer H1975 xenograft model, DCBCI0901 effectively suppressed tumor growth. Based on the in vitro/in vivo pharmacology data, DCBCI0901 was selected as a drug candidate for further development as anticancer agent.
This publication is dedicated to the memory of Dr. Paonien Chen.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C270.
Citation Format: Ying-Shuan E. Lee, Mann-Yan Kuo, Yi-Ting Huang, Yu-Wen Tseng, Yu Jie Lin, Yen His Liu, Shian-Yi Chiou, Li Jung Chen, Y.-Y. Lu, Chih-Hsin Yang, Pan-Chyr Yang. In vitro and in vivo antitumor activity of DCBCI0901, a potent PI3K/mTORC1/mTORC2 inhibitor. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C270.