bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5502: Vintafolide: a first-in-class small molecule drug conjugate targeting folate receptor positive tumors.
Authors: Leamon Christopher P. , Reddy Joseph A. , Haines Brian B. , Dussault Isabelle 
Published: August 2014

Abstract
Targeted anti-cancer therapies offer the promise of more efficacious treatments with fewer side effects. Vintafolide (also known as EC145) is a rationally designed small molecule drug conjugate consisting of one folic acid moiety which serves as a stable high affinity binding ligand for the folate receptor, and one vinca alkaloid unit (desacetylvinblastine hydrazide; DAVLBH), which serves as the cytotoxic warhead. Vintafolide is thus designed to target cancer cells by binding with high affinity to folate receptors which are more commonly expressed at high levels on tumors compared to normal tissues. Vintafolide is internalized following binding to folate receptors and is cleaved in endosomes to release DAVLBH. Like all vinca alkaloids, DAVLBH binds to tubulin and disrupts the mitotic spindle which leads to cell death. Pre-clinical in vitro and in vivo experiments show that vintafolide requires interaction with the folate receptor for its activity and that it is more efficacious and better tolerated than untargeted DAVLBH. Vintafolide is currently being investigated in clinical trials in ovarian (Phase III) and lung (Phase II) cancer patients who express folate receptors on their tumors as determined by the investigational companion imaging agent, etarfolatide. Etarfolatide is also a folate-based conjugate consisting of folic acid linked to a peptidic metal-chelating moiety labeled with 99mTechnetium. In a randomized Phase II study in patients with advanced ovarian cancer, patients treated with vintafolide had a significantly longer period of progression free survival compared with the control. This was driven by patients who were identified by etarfolatide as having tumors with functional folate receptors. Vintafolide and etarfolatide is the first pair of therapeutic and non-invasive, imaging diagnostic to be co-developed for the treatment of cancer.
Citation Format: Christopher P. Leamon, Joseph A. Reddy, Brian B. Haines, Isabelle Dussault. Vintafolide: a first-in-class small molecule drug conjugate targeting folate receptor positive tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5502. doi:10.1158/1538-7445.AM2013-5502
Abstract 5503: Targeting thymidine metabolic pathways in cancer cells with a novel thymidine conjugate.
Authors: Zhou Qibing , Wei Qiong , Zhang Dejun 
Published: August 2014

Abstract
Cellular thymidine metabolism involves two pathways: the catabolic and salvage pathways. The catabolic pathway breaks down thymidine to carbon dioxide for energy while the salvage pathway converts thymidine to its 5′-triphosphate as one of building blocks for DNA synthesis. Cytosolic level of thymidine is regulated by both thymidine phosphorylase (TYMP) of the catabolic pathway and thymidine kinase (TK) of the salvage pathway. In tumor tissues and cancer cells, abnormally high levels of these two proteins have been consistently reported. Therefore, thymidine metabolic pathways in cancer cells are a potential therapeutic target for novel drug design and development. We recently developed a novel thymidine analog, 3′-deoxythymidine phenylquinoxaline conjugate (dT-QX) that selectively killed a series of cancer cell lines including human liver carcinoma HepG2 and Hep3B, breast adenocarcinoma MCF-7, rat brain glioma C6 and mouse liver cancer H22 cells and showed low cytotoxicity on the normal liver hepatocyte HL-7702 cells. dT-QX is a conjugate of 3′-deoxythymidine and a DNA intercalating moiety with a triazole linkage achieved by click chemistry. The selective killing of cancer cells was attributed to the selective inhibition of DNA synthesis in the cancer cells but not in normal liver HL-7702 cells, resulting in extensive production of mitochondrial superoxide stress. The conjugation of 3′-deoxythymidine was found to be critical for dT-QX to achieve the selective killing of cancer cells. The killing by dT-QX was revealed to be directly due to the expression levels of TYMP and TKs in cancer cells, confirming that dT-QX successfully targeted the thymidine metabolic pathways as designed. Finally, a preliminary mouse study with subcutaneous liver tumors confirmed that dT-QX effectively inhibited the growth of tumors in vivo.
Citation Format: Qibing Zhou, Qiong Wei, Dejun Zhang. Targeting thymidine metabolic pathways in cancer cells with a novel thymidine conjugate. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5503. doi:10.1158/1538-7445.AM2013-5503
Abstract 5525: Development of novel high-throughput screening assay system for exploring EMT inhibitors.
Authors: Arai Kazuya , Sakamoto Ruriko , Itoh Manabu , Miura Hiromi , Shimomura Manami , Nakatsura Tetsuya 
Published: August 2014

Abstract
Background: EMT (Epitherial-Mesenchymal transition) is a significant event in tumor metastasis and malignancy. Cancer cells are stimulated by EMT-inducible agonists from the surrounding stromal cells, and cause transformation such as weakening of cell-cell adhesion and the accompanying acceleration of cell migration and invasion. Inhibition of EMT is considered to enable controlling of malignant transformation. In this study, we developed a high-throughput assay system of EMT inhibitor screen in 3D cell culture.
Method: We adopted 3D cell culture method on NanoCulture® Plate (NCP), a scaffold type spheroid culture plate, as a culture method which can confirm spheroid morphologies. TGF-β and its inhibitor, SB431542, were used as an EMT inducer and as a positive control for EMT inhibitor, respectively. Expressions of E-cadherin, N-cadherin, vimentin and zeb-1, represent EMT maker genes, were evaluated by qRT-PCR. As hypoxia inside the spheroids reflected the spheroid size and cell-cell adhesion strength, we visualized the intra-spheroid hypoxia, and used it as an indicator for EMT induction and inhibition.
Result: A549 cell spheroids gradually collapsed, by the weakening of cell-cell adhesion, and cells migrating out from the spheroids, by treating with TGF-β. This collapse of the spheroids was inhibited by SB431542 treatment. SB431542 treatment also accompanied inhibition of E-cadherin down-regulation, and N-cadherin, vimentin and zeb-1 up-regulation. These results indicate that this method is clearly reproducing EMT and its inhibition. And we elucidated that intra-spheroid hypoxicity was closely correlated with spheroid morphology. From this, it is demonstrated that this method is simple but high-precision assay.
Conclusion: We developed a high-throughput assay system for EMT inhibitor screen, by evaluating intra-spheroid hypoxicity as an indicator for alternation of the spheroid morphology. This method is an unique method which enables to evaluate EMT condition, by monitoring the collapse of spheroids directly. We are now running a screen for EMT inhibitor candidate compounds, by using this assay system.
Citation Format: Kazuya Arai, Ruriko Sakamoto, Manabu Itoh, Hiromi Miura, Manami Shimomura, Tetsuya Nakatsura. Development of novel high-throughput screening assay system for exploring EMT inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5525. doi:10.1158/1538-7445.AM2013-5525
Abstract 5533: Novel targets and monoclonal antibodies for cancer therapy.
Authors: Grandi Alberto , Parri Matteo , Campagnoli Susanna , Nogarotto Renzo , De Camilli Elisa , Naldi Ilaria , Cinti Caterina , Sarmientos Paolo , Grandi Guido , Terracciano Luigi , Viale Giuseppe , Pileri Piero , Grifantini Renata Maria 
Published: August 2014

Abstract
Cancer therapeutic targets is an extremely active research field in both academia and pharmaceutical companies. In our recent research activities we identified by a high-throughput immunohistochemistry screening of Tissue microarray (TMA), a panel of 89 novel candidate tumor markers for prevalent cancers representing breast, lung colon ovary and prostate carcinomas. The novel marker candidates were found over-expressed in one or more of the five tumors under analysis, with significant frequency. Three of them seems to be promising therapeutic targets for monoclonal antibody therapy, being exposed on the surface of cancer cells. They include: 1) a lectin binding protein, over-expressed in breast, lung and ovary cancer; 2) a protein involved in iron homoeostasis and over-expressed in breast, colon, lung and ovary cancers, 3) a cadherin homologous protein detected in colon, lung and ovary cancers. Gene silencing using siRNA technology and/or over-expression experiments using marker-encoding plasmids significantly alter cell proliferation, migration, invasiveness and clonal growth in vitro, indicating that expression of the three proteins confers cell phenotypes relevant for tumor progression. Highly specific murine monoclonal antibodies (mAbs) were generated against the three proteins and proved to bind the surface of cancer cells lines. Of particular interest is a murine mAb targeting the cadherin-like protein that, upon binding to the cell surface, is efficiently internalized by cancer cells, suggesting that it is amenable to the development of antibody-drug conjugates. This mAb did not show any relevant IHC cross-reactivity in the 35 human tissues requested by FDA to demonstrate antibody specificity. Furthermore this mAb significantly inhibited tumor growth in athymic nude mice bearing HCT15 and HT29 colon cancer xenograft models. Finally, IHC analysis of approximately 300 colon cancer clinical samples indicates that the antibody stains a large fraction of colon cancer samples, and gives intense membranous staining in specific patients’ group. Overall, data indicate that this antibody could be developed as a novel tool for a targeted therapy of colo-rectal cancer, alone or in combination with other treatments
Citation Format: Alberto Grandi, Matteo Parri, Susanna Campagnoli, Renzo Nogarotto, Elisa De Camilli, Ilaria Naldi, Caterina Cinti, Paolo Sarmientos, Guido Grandi, Luigi Terracciano, Giuseppe Viale, Piero Pileri, Renata Maria Grifantini. Novel targets and monoclonal antibodies for cancer therapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5533. doi:10.1158/1538-7445.AM2013-5533
Abstract 5556: Discovery of RKI-18, a small molecule that inhibits Rho kinases 1 and 2, migration and invasion of human tumors.
Authors: Patel Ronil A. , Lui Yan , Wang Binglin , Li Ronshi , Sebti Said M. 
Published: August 2014

Abstract
Signal transduction pathways that are mediated by ROCK1 and ROCK2 trigger cell migration, invasion and metastasis. This prompted us to design and synthesize novel Rho-kinase inhibitors (RKIs). Here, we show that one of our most potent RKIs, RKI-18 (IC50 397 nM (ROCK1) and 349 nM (ROCK2)) but not its inactive closely related analogue RKI-11 suppresses potently the phosphorylation of the ROCK substrate MLC2 in intact human cancer cells. Furthermore, RKI-18 is highly selective at inhibiting P-MLC2 over P-Akt, P-S6 and P-Erk ½ levels. RKI-18 suppresses ROCK-mediated actin fiber formation following stimulation with LPA as well as PAK-mediated lamelipodia and filopodia formation following bradykinin or PDGF stimulation. Furthermore, RKI-18 but not RKI-11 inhibits migration, invasion and anchorage-independent growth of human breast cancer cells. The fact that RKI-18, the active ROCK inhibitor, but not RKI-11, its inactive analogue, is effective at suppressing malignant transformation suggests that preventing migration, invasion and anchorage-independent growth with RKI-18 is likely due to inhibition of ROCK. Further advanced preclinical studies are required to determine the potential of RKI-18 as an anti-metastatic agent.
Citation Format: Ronil A. Patel, Yan Lui, Binglin Wang, Ronshi Li, Said M. Sebti. Discovery of RKI-18, a small molecule that inhibits Rho kinases 1 and 2, migration and invasion of human tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5556. doi:10.1158/1538-7445.AM2013-5556
Abstract 5558: Lurbinectedin (PM01183) specifically targets RNA Pol II for degradation via the proteasome pathway in a TC-NER-dependent fashion.
Authors: Santamaria Gema , Martinez-Leal Juan F. , Cuevas Carmen , Garcia-Fernandez Luis F. , Galmarini Carlos M. 
Published: August 2014

Abstract
Lurbinectedin (PM01183), a new synthetic tetrahydroisoquinoline alkaloid, is a minor groove specific DNA binder that interacts directly with specific factors involved in DNA repair and transcription pathways. In living cells, PM01183-DNA adducts stall replication and transcription giving rise to double strand breaks, inducing accumulation of cells in the S-phase of the cell cycle and triggering apoptosis. In both the ongoing phase II trials (pancreas and platinum-resistant ovarian cancer) the first stage was concluded with positive results in clinical activity, ensuring the continuity of the studies. Also, phase I trials in combination with doxorubicin and gemcitabine as well as in advanced acute leukemia are ongoing. Here, we examined the effects of PM01183 on the activity and stability of the RNAPol II as well as on other factors of the transcriptional machinery, including TBP (TFIID), p62 (TFIIH), XPG and XPF. Our results showed that PM01183 induced a rapid, time- and concentration-dependent degradation of RNA Pol II in a panel of different human tumor cell lines, including HCT-116 (colon), A549 (NSCLC), HeLa (cervix) and A763 (sarcoma). This degradative process was efficiently abrogated in the presence of transcriptional (DRB or Actinomycin D) or proteasome inhibitors (MG132), demonstrating that PM01183 specifically targets the transcriptionally active RNA Pol II for degradation via the proteasome pathway. In addition, it was also shown that the effect of PM01183 on the RNA Pol II was dependent on the presence of a functional TC NER repair machinery. PM01183 induced degradation of RNA Pol II in global NER (XPC) deficient cells, but failed to do it in TC NER (CSB, XPD and XPG) deficient cells. Importantly, these effects were confirmed to be specific for the RNA Pol II, since other factors of the transcriptional machinery, such as TBP (TFIID), p62 (TFIIH), XPG or XPF or the RPA194 subunit of the RNA Pol I were not affected. Together, these results show up the complex mechanism of action of the drug on tumor cells.
Citation Format: Gema Santamaria, Juan F. Martinez-Leal, Carmen Cuevas, Luis F. Garcia-Fernandez, Carlos M. Galmarini. Lurbinectedin (PM01183) specifically targets RNA Pol II for degradation via the proteasome pathway in a TC-NER-dependent fashion. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5558. doi:10.1158/1538-7445.AM2013-5558
Abstract 5559: Molecular mechanisms of elesclomol cytotoxicity.
Authors: Hasinoff Brian B. , Yalowich Jack C. , Patel Daywin , Yadav Aron , Wu Xing 
Published: August 2014

Abstract
Elesclomol is an anticancer drug that has received both fast track and orphan drug status from the FDA and is currently undergoing clinical trials. Elesclomol forms a strong 1:1 complex with Cu2+ and may exert its anticancer activity through the induction of oxidative stress or its ability to transport Cu2+ into the cell. The complexes of elesclomol with redox inactive Pt2+ and Ni2+ were much less cytotoxic than its Cu2+ complex which suggests a role for Cu2+-induced oxidative stress. Elesclomol and Cu2+-elesclomol inhibited the growth of human erythroleukemic K562 cells in the low nanomolar concentrations with even a brief 1.5 hr exposure. The cell growth inhibitory effects of elesclomol were decreased with an increase in cell density, likely due to Cu2+ depletion of the medium. Consistent with this, the addition of the Cu2+ chelator Trien to the medium decreased cytotoxicity. Cu2+-elesclomol induced caspase 3/7 in K562 cells, indicating it was apoptosis inducing. The Cu2+-elesclomol complex inhibited topoisomerase I activity and induced topoisomerase I-covalent complexes in K562 cells at a relatively high concentration of 50 μM. It did not, however, inhibit or poison topoisomerase II or produce topoisomerase II-covalent complexes in cells. Cu2+-elesclomol, but not elesclomol, was able to induce γH2AX formation in K562 cells, indicative of DNA double strand breaks. Ascorbic acid, GSH and NADH were all able to slowly reduce the Cu2+-elesclomol complex. However, EPR spin trapping experiments, either in the presence or absence of added H2O2, showed that the reduced copper complex could not directly generate damaging hydroxyl radicals. Depletion of GSH in K562 cells by treatment with BSO sensitized cells to elesclomol and its copper complex, indicating oxidative stress may be responsible for cytotoxicity. In conclusion, these results show that elesclomol may inhibit cell growth through Cu2+-mediated oxidative stress. Support: CIHR, a Canada Research Chair in Drug Development to B.B.H., and a National Institutes of Health grant CA090787 to J.C.Y.
Citation Format: Brian B. Hasinoff, Jack C. Yalowich, Daywin Patel, Aron Yadav, Xing Wu. Molecular mechanisms of elesclomol cytotoxicity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5559. doi:10.1158/1538-7445.AM2013-5559
Abstract 5562: Generation and characterization of highly selective cathepsin S inhibitors with potentials against pancreatic cancer.
Authors: Chang Wun-Shaing W. , Liao Chien-Yu , Chang Yi-Hsun , Wu Tzu Chin , Wu Rou-Jhen , Chang Tien-Ning , Chang Jang-Yang , Lin Chun-Cheng 
Published: August 2014

Abstract
Cathepsin S (CTSS) is a critical cellular protease required for cancer development and metastasis. This proteolytic enzyme is often over-expressed by malignant tumor cells and secreted into the extracellular milieu to degrade surrounding matrix components. Here, we attempted to systematically generate and evaluate potential CTSS inhibitors in hope to identify potent candidates for use as antitumor agents. Detailed kinetic analysis revealed several lead compounds possess very low Ki values and high specificity against target CTSS protease. Results from ECM degradation assays demonstrated that these small molecules could protect fibronectin from CTSS-mediated degradation and consequently hinder tumor cell movement. Treating various pancreatic tumor cell lines with these CTSS inhibitors further resulted in a drastic decrease in cell migration and invasion. The test compounds also reduced the spread of pancreatic tumor cells in orthotopic animal model and thus prolonged mice survival. Finally, these lead molecules exhibited reasonable pharmacokinetic (PK) profiles, suggesting their potential as antitumor agents against pancreatic cancer.
Citation Format: Wun-Shaing W. Chang, Chien-Yu Liao, Yi-Hsun Chang, Tzu Chin Wu, Rou-Jhen Wu, Tien-Ning Chang, Jang-Yang Chang, Chun-Cheng Lin. Generation and characterization of highly selective cathepsin S inhibitors with potentials against pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5562. doi:10.1158/1538-7445.AM2013-5562
Abstract 5563: Targeting the PH domain of TIAM1 to inhibit prostate cancer metastasis.
Authors: Meuillet Emmanuelle J. , Moses Sylvestor A. , Jandova Jana , Mash Eugene A. , Zhang Shuxing 
Published: August 2014

Abstract
TIAM1 (T-lymphoma invasion and metastasis-inducing protein-1) is a highly conserved guanine nucleotide exchange factor and contains an Dbl Homology (DH)/C-terminal Pleckstrin Homology (PH) domain. The crystal structure of DH-PH of TIAM1 in complex with Rac-1 has been reported. TIAM1 has been found to be over-expressed cancers such as breast, colon and prostate cancers. An increase in TIAM1 expression has been shown to be associated with increased metastatic potential of breast cancer cell lines and is also correlated with poor prognosis of patients with prostate cancer. TIAM1 is thus a novel PH domain-containing drug target directly related to cancer progression, metastasis and patient survival. We have identified and characterized novel small molecule inhibitors targeting the phosphoinositide lipid binding PH domain of TIAM1 in order to selectively inhibit cell migration, invasion and survival. An In Silico screen of our internal and Maybridge library using the crystal structure of TIAM1 has identified 11 compounds that bind to the PH domain. In vitro assays revealed that compounds TPH-3 and TPH-15 significantly reduced the amount of active Rac1 in PC-3 prostate cancer cells (EC50 of 2.73±0.13 and 2.38±0.98 μM) by binding to PH-TIAM1 with high affinity (KD in the micromolar range) using surface plasmon resonance (SPR) spectrometry. Both compounds displaced PtdIns-3,4,5-P3 in a SPR competitive binding assay. TPH-3 and TPH-15 inhibited cell proliferation with EC50 of 19.8±3.2 and 28.7±1.7 μM in prostate cancer cells LnCaP and EC50 of 18.6±1.8 and 33.3±6.7 μM in PC-3. Wound healing assays and lamellipodia formation were both inhibited by the compounds. TPH-15 inhibited ≈70% of PC-3 invasion using a matrigel invasion assay. Finally, TPH-15 exhibits anti-tumor properties in a PC-3 mouse xenograft study (%T/C≈38.8) with good pharmacokinetic properties (T1/2≈5 hours). Cardio-injection of prostate PC-3 cells in SCID mice was used to test the effects of TPH-15 in the prevention of bone metastasis. Mice were treated with 50mg/kg ip of TPH-15 once a day for 5 days. TPH-15-treated mice developed significantly less pelvic bone lesions than the untreated group and TPH-15 treated mice lived longer, on average, than the untreated group. Overall, we have identified novel compounds which exhibit the ability to reduce prostate cancer bone metastasis by binding to the PH domain of TIAM1, an important GEF in the process of metastasis.
Citation Format: Emmanuelle J. Meuillet, Sylvestor A. Moses, Jana Jandova, Eugene A. Mash, Shuxing Zhang. Targeting the PH domain of TIAM1 to inhibit prostate cancer metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5563. doi:10.1158/1538-7445.AM2013-5563