bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C19: Nelfinavir-induced autophagy and cell death as potential anticancer therapy for KSHV-associated lymphomas.
Authors: Kalu Nene , Biswas Sunetra , Shirley Courtney , Shamay Meir , Ambinder Richard F. 
Published: August 2014

Abstract
Kaposi sarcoma associated herpes virus (KSHV) is implicated in primary effusion lymphoma (PEL) and several other malignancies. Following infection, the virus evades the immune system by maintaining its genome in a latent state and only expressing few viral genes. Activation of KSHV lytic replication in vitro leads to viral lytic gene expression, the production of infectious virus and cell death. We previously showed that activation of herpes virus lytic replication can be achieved by treating PEL tumor cells with the proteasome inhibitor, bortezomib which induces endoplasmic reticulum (ER) stress. Here, we investigate the effects of nelfinavir, a FDA approved human immunodeficiency virus (HIV) protease inhibitor with anti-cancer activity. Anti-cancer effects of nelfinavir range from the induction of ER stress and apoptosis to Akt inhibition. Treatment of PEL cell lines with nelfinavir resulted in increased expression of ER stress markers: ATF4, CHOP and spliced XBP-1. Additionally, we observed nelfinavir-induced autophagy and cell death as indicated by an increase in LC-3B processing and a decrease in cell viability. We also observed the formation of autophagosomes by electron microscopy. In KSHV-infected tumor cells treated with nelfinavir, ER stress and autophagy precedes viral lytic gene expression. However, we show that while nelfinavir activates lytic gene expression, it also inhibits the export and cell-to-cell spread of infectious herpes viruses. At clinically relevant concentrations, nelfinavir induces autophagy and cell death in PEL cells while inhibiting virus export making it an attractive candidate for virus-associated cancer therapies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C19.
Citation Format: Nene Kalu, Sunetra Biswas, Courtney Shirley, Meir Shamay, Richard F. Ambinder. Nelfinavir-induced autophagy and cell death as potential anticancer therapy for KSHV-associated lymphomas. [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 C19.
Abstract C190: A novel monoclonal antibody for colon cancer therapy.
Authors: Grandi Alberto , Campagnoli Susanna , Parri Matteo , De Camilli Elisa , Naldi Ilaria , Gherardini Lisa , Cinti Caterina , Terracciano Luigi , Jin Boquan , Sarmientos Paolo , Viale Giuseppe , Grandi Guido , Pileri Piero , Grifantini Renata Maria 
Published: August 2014

Abstract
In our recent research activities, we identified 89 novel candidate markers for prevalent cancers by a systematic Tissue microarray analysis (TMA) of a large collection of polyclonal antibodies (approximately 1600) raised against membrane-associated and secreted human proteins currently marginally characterized. Monoclonal antibodies were generated towards 20 distinct antigens that are being characterized and validated for diagnostic and therapeutic applications.
Here we describe a monoclonal antibody (mAb) targeting a protein of the protocadherin- family in colo-rectal cancer (CRC). The antibody specifically recognizes its target protein in cancer tissues, with concomitant negligible or marginal reactivity in normal colon. The protein was not previously described as CRC target. IHC data from CRC samples of approximately 200 patients, (collected at the bio-bank of the institute for Pathology of Basel, Switzerland and at the European Institute of Pathology of Milan, Italy) showed that the antibody binds up to 80% CRC cases (stages from 1 to 4) with high or moderate intensity. In most cases, the antibody gives plasma membrane by Immune Histochemistry (IHC). An expanded analysis on approximately 1000 CRC cases is ongoing to assess whether the membranous IHC staining associates with specific clinic-pathological parameters.
IHC analysis of 35 normal human tissues revealed that it gives intracellular staining in skeletal muscle, pituitary glands and prostate, whereas it gives background irrelevant staining in the other 32 tissues. The antibody is able to bind the surface of different colon cancer cells in vitro and in vivo. Upon binding it is efficiently internalized by colon cancer cells, suggesting that it can be exploited for the development of Antibody-Drug-Conjugate (ADC). Moreover, it inhibits tumor growth in athymic nude mice bearing HCT15 and HT29 colon cancer xenografts. Overall, data indicate that this monoclonal antibody could be developed for a targeted therapy of colo-rectal cancers, alone or in combinatorial strategies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C190.
Citation Format: Alberto Grandi, Susanna Campagnoli, Matteo Parri, Elisa De Camilli, Ilaria Naldi, Lisa Gherardini, Caterina Cinti, Luigi Terracciano, Boquan Jin, Paolo Sarmientos, Giuseppe Viale, Guido Grandi, Piero Pileri, Renata Maria Grifantini. A novel monoclonal antibody for colon cancer therapy. [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 C190.
Abstract C204: GTPase/GAP/GEF-Glo™: A bioluminescent system to measure GTPase, GAP, and GEF activities.
Authors: Mondal Subhanjan , Goueli Said , Hsiao Kevin 
Published: August 2014

Abstract
It is well known that GTPases play major roles in cell functions such as GPCR signaling, cell proliferation, cell differentiation, cytoskeleton modulation, and cell motility. Deregulation or mutation of these proteins has considerable consequences resulting in multiple pathological conditions. Targeting GTPases and its regulators have been challenging due to lack of convenient assays. GTPases act as molecular switches cycling between an activated GTP-bound state (“ON”-state) and an inactive GDP-bound state (“OFF”-state). They have very high affinity for guanine nucleotides GDP or GTP and are extremely slow acting GTP-hydrolases. To mediate the process of shuttling between the active and inactive forms, GTPases are modulated by two groups of enzymes, guanine nucleotide exchange factors (GEF) and guanine nucleotide activating proteins (GAPs). The GEFs proteins substitute GTP for the bound GDP and thus activating them while the GAP family activates the hydrolysis of GTP and terminating their effector function. We have developed a homogenous bioluminescent assay for monitoring the enzyme activity of GTPase, GAP, and GEF proteins. Mg2+ plays a critical role in influencing affinity of GTPases with GTP/GDP, and manipulating Mg2+ concentrations in the reaction buffer allows continuous progression of the GTPase cycle and hydrolysis of GTP. The assay relies on the conversion of remaining GTP to ATP and detection of the latter using luciferin/luciferase combination. The assay system for measuring GTPase/GAP/GEF-Glo™ is enabling to monitoring the intrinsic GTPase-, GAP-stimulated GTPase-, GAP-, and GEF- activities. The assay system has a high dynamic range and signal-to-background ratio; it is in a convenient “add-mix-read” format and applicable to high throughput screening.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C204.
Citation Format: Subhanjan Mondal, Said Goueli, Kevin Hsiao. GTPase/GAP/GEF-Glo™: A bioluminescent system to measure GTPase, GAP, and GEF activities. [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 C204.
Abstract C217: Prognostic significance and molecular mechanism of ATP-Binding Cassette subfamily C member 4 in resistance to neoadjuvant radiotherapy of locally advanced rectal carcinoma.
Authors: Yu Zhiqi , Zhang Chang , Chai Rui , Du Yan , Gao Xianhua , Xing Junjie , Cao Guangwen , Fu Chuangang 
Published: August 2014

Abstract
Mechanism of radioresistance in rectal carcinoma remains largely unknown. The aim of this study is to verify the predictive value of ATP-Binding Cassette subfamily C member 4 (ABCC4) in locally advanced rectal carcinoma and explore possible molecular mechanisms by which ABCC4 confers the resistance to neoadjuvant radiotherapy. Methods: Expression of ABCC4 protein in pretreated biopsy tissue specimens from locally advanced rectal carcinoma patients was examined using immunohistochemistry. The 3-year overall survival and disease-free survival were used to determine long-term prognosis, and significant clinicopathological factors were identified by univariate log-rank test and multivariate Cox regression analysis. Lentivirus-mediated small hairpin RNA inhibited ABCC4 expression in colorectal carcinoma cell lines, and altered radiosensitivity was confirmed by xenograft model in vivo. Intracellular cyclic adenosine monophosphate concentration and cell cycle distribution following irradiation were further detected. Results: High expression of ABCC4 in pretreated tumors, p53 mutant type, high serum CEA and positive lymph node predicted an unfavorable postoperative prognosis for locally advanced rectal carcinoma patients after neoadjuvant radiotherapy in univariate analysis. Multivariate Cox regression analysis further demonstrated that high expression of ABCC4 and p53 mutant type were significant factors independently predicted an unfavorable long-term prognosis. Downregulation of ABCC4 expression significantly enhanced irradiation-induced suppression of tumor growth in xenograft model in vivo. Furthermore, inhibition of ABCC4 expression induced intracellular cyclic adenosine monophosphate accumulation and a noticeable deficiency of G1-S phase checkpoint in cell cycle following irradiation. Conclusions: Our study suggests ABCC4 as a novel predictive biomarker in predicting radioresistance and prognosis for locally advanced rectal carcinoma.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C217.
Citation Format: Zhiqi Yu, Chang Zhang, Rui Chai, Yan Du, Xianhua Gao, Junjie Xing, Guangwen Cao, Chuangang Fu. Prognostic significance and molecular mechanism of ATP-Binding Cassette subfamily C member 4 in resistance to neoadjuvant radiotherapy of locally advanced rectal carcinoma. [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 C217.
Abstract C227: High-throughput anchorage independence assay for screening inhibitors of cancer metastasis.
Authors: de Pril Remko , Oerlemans-Bergs Carla , Elstak Edo , Maghrani Ilhem , Janssen Richard 
Published: August 2014

Abstract
Tumor cells are capable of expanding without the requirement for cell adherence which is an indicator for their ability to form metastatic tumors in vivo. To do so, cells need to overcome cell cycle inhibitory signaling and/or apoptosis. This so-called anchorage-independent growth is an indicator of oncogenic transformation and deregulated cell growth and can be mimicked in vitro by culturing cells in soft agar. Our aim was to set up a high-throughput assay to identify inhibitors of anchorage-independent growth. Cancer cell lines were mixed with agar and seeded into 96-well plates. After polymerization, medium was added to the agar and subsequently refreshed twice a week. Depending on the cell line used the colonies in the agar were fixed after 8-14 days of culture and stained with phalloidin. The BD Pathway 435 was used to generate two collapsed stacks of 20 images per well. The inhibition of colony formation was analyzed using the Attovision software with an in-house developed algorithm. This approach was optimized using adenoviral knock-down constructs targeting known targets involved in anchorage independence as well as tool compounds which inhibited colony formation. This assay will be used for screening an adenoviral knock-down library to identify novel targets involved in anchorage independence as well as testing of compounds directed against the identified targets. We successfully developed an automated high-throughput anchorage independence assay in multiple cancer cell lines. This assay can be used for discovery and validation of novel targets and compounds for their potential to inhibit uncontrolled growth of cancer cells. Discovery of novel targets in metastasis may lead to the development of small molecule compounds or antibody therapeutics in cancer therapy.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C227.
Citation Format: Remko de Pril, Carla Oerlemans-Bergs, Edo Elstak, Ilhem Maghrani, Richard Janssen. High-throughput anchorage independence assay for screening inhibitors of cancer metastasis. [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 C227.
Abstract C237: Overcoming gemcitabine resistance with TRAIL plus enhancer of anti-survival potential in pancreatic cancer.
Authors: Lee Seungha , Kim So Y. , Kang Dongxu , Choi Hye J. , Kim Joo-Hang , Song Jae Jin 
Published: August 2014

Abstract
Although the combination of gemcitabine with a variety of cytotoxic and targeted agents has generally shown no significant survival advantage as compared with gemcitabine alone, still, many targeted agents against various pathways remain to be tested in pancreatic cancer. Previously, we have observed that the combined treatment with TRAIL plus shRNA of HSP27 induced complete cell death in MiaPaCa-2 pancreatic cell. Here three different targets were invited with TRAIL for chemotherapy combination with gemcitabine using three pancreatic cancer cell lines. We observed that TRAIL treatment to all three pancreatic cells have relieved gemcitabine-induced resistance. More importantly, three different pancreatic cancer cell lines showed their own unique differential sensitivities to targeted agents examined. For example, in case of MiaPaCa-2, gemcitabine/TRAIL/shRNA of survivin was more effective to cell death than HPAC, whereas TRAIL plus downregulation of survival-related molecules (survivin, XIAP, Bcl-xL) effectively enhanced cell death of Panc-1 even without gemcitabine. Then, we extended the survival-related molecules to upstreams such as Src, PI3K-Akt, or NF-κB and inhibited their downstream signals using PP2, wortmannin, SN50, respectively. From their results, TRAIL plus SN50 decreased NF-κB activation and concomitant significant cell death in MiaPaCa-2 which has an acquired resistance of NF-κB after gemcitabine. Based on this result, it was found that combination of gemcitabine/TRAIL/SN50 dramatically increased cell death of MiaPaCa-2, whereas in case of Panc-1 or HPAC, gemcitabine/TRAIL/PP2 dramatically increased cell death. Taken all together, a better knowledge of the multiple molecular pathways implicated in pancreatic carcinogenesis should be much more specifically considered to control the various gemcitabine-resistant pancreatic cancer cells.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C237.
Citation Format: Seungha Lee, So Y. Kim, Dongxu Kang, Hye J. Choi, Joo-Hang Kim, Jae Jin Song. Overcoming gemcitabine resistance with TRAIL plus enhancer of anti-survival potential in pancreatic 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 C237.
Abstract C251: Dianotecan: A novel water-soluble CPT prodrug as a potential anticancer agent with less susceptility to multidrug resistance than irinotecan.
Authors: Zhou Wenqiang , Fu Li-Wu 
Published: August 2014

Abstract
Camptothecin (CPT) and its derivatives are topoisomerase I inhibitors. Among these, irinotecan and topotecan have shown significant clinical activity against a broad range of malignancies. Irinotecan is approved for use in the treatment of advanced colorectal cancer, as first-line therapy in combination with 5-FU or as a salvage agent after failure of 5-fluorouracil-based chemotherapy. However, recent studies have revealed that SN-38 (the active metabolite of irinotecan) is the substrate of BCRP (ABCG2), an ATP-binding cassette (ABC) transport protein which confers multidrug resistance and is also characterized as the marker of stem and progenitor cells. In tumor cell lines over-expressing BCRP, selective BCRP efflux of SN-38 leads to decrease in cellular drug accumulation, resulting in drug resistance phenotype. Here we report discovery of a novel water-soluble CPT prodrug (dianotecan) which can be efficiently metabolized to CPT in vivo after i.v. Injection. In the tumor xenograft studies, dianotecan has been established as a potent inhibitor against a number of human solid tumors including HT-29, S1, NCI-446, MCF-7. Significantly, dianotecan has demonstrated anti-tumor efficacy far superior to irinotecan in the xenograft studies using the BCRP-overexpressing S1-M1-80 cell line. These findings suggest dianotecan, as a potential anticancer agent, is less susceptible to multidrug resistance than irinotecan. The preclinical data of dianotecan will be discussed in the poster.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C251.
Citation Format: Wenqiang Zhou, Li-Wu Fu. Dianotecan: A novel water-soluble CPT prodrug as a potential anticancer agent with less susceptility to multidrug resistance than irinotecan. [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 C251.
Abstract C266: Evaluation of Src as a therapeutic target in biliary tract cancer.
Authors: Oh Do-Youn , Nam Ah-Rong , Kim Tae Yong , Han Sae-Won , Song Sang-Hyun , Im Seock-Ah , Kim Tae-You , Bang Yung-Jue 
Published: August 2014

Abstract
Background: In biliary tract cancer (BTC), no molecular therapeutic target has been validated so far. Therefore, cytotoxic chemotherapy is the mainstay of treatment of advanced BTC and the prognosis is poor and there is a huge unmet medical need. Src is a nonreceptor tyrosine kinase involved in the crosstalk and mediation of many signaling pathways that promote cell proliferation, invasion and angiogenesis. Elevation of Src activity has been reported in many types of cancers including BTC. The purpose of this study is to evaluate of Src as a therapeutic target in BTC and to elaborate the therapeutic potential of bosutinib, an orally active small molecule c-Src/abl kinase inhibitor.
Methods: Eight human biliary tract cancer cell lines (SNU-245, 308, 478, 869, 1079, 1196, HuCCT1, TFK1) were used. MTT assay, colony formation assay and 3D culture were done for determining growth inhibitory effect of bosutinib, alone or in combination with chemotherapeutic agents (gemcitabine, cisplatin). Cell cycle analysis was done by FACS Calibur flow cytometer. Matrigel invasion assay and wound healing assay were done. The methods described by Chou and Talalay were used to determine whether a synergistic effect existed between drug combination. Tumor xenograft model was made and used for in vivo test of bosutinib/gemcitabine.
Results: Bosutinib inhibited the growth of BTC cells, especially SNU308, SNU478 and HuCCT1 (IC50 0.6-0.8 µmol/L). Bosutinib induced G1 arrest and decreased pSrc, pFAK, pAKT and pERK in these cells. Inhibition of pSrc was accompanied with increase of pSTAT3 in SNU308. Bosutinib inhibited the cell migration and invasion. Interestingly, bosutinib showed synergistic antiproliferative effects with gemcitabine. In the xenograft model of SNU478, bosutinib decreased tumor growth compared to control and bosutinib in combination of gemcitabine showed the synergistic antitumor effect.
Conclusion: These preclinical evaluations support that Src could be a potential therapeutic target in biliary tract cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C266.
Citation Format: Do-Youn Oh, Ah-Rong Nam, Tae Yong Kim, Sae-Won Han, Sang-Hyun Song, Seock-Ah Im, Tae-You Kim, Yung-Jue Bang. Evaluation of Src as a therapeutic target in biliary tract 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 C266.
Abstract C269: Targeting casein kinase 1 delta and epsilon (CK1δ/ϵ) in breast cancer therapeutics.
Authors: Rosenberg Laura H. , Chen Weimin , Nakanishi Shima , Bibian Mathieu , Cameron Michael D. , Cleveland John L. , Roush William R. , Duckett Derek R. 
Published: August 2014

Abstract
The Caesin Kinase 1 (CK1) family consists of 7 ubiquitously expressed serine/threonine kinases that play diverse roles in a number of cellular processes. Interestingly, CK1δ and ϵ are highly expressed in some cancer types where they have been shown to promote cell growth, survival, and tumorigenicity in vivo. For example, exogenous expression of kinase dead mutants of CK1δ block SV40 induced cell transformation as well as mammary carcinogenesis in xenograft models. Furthermore, the effect of CK1δ/ϵ shRNAs on breast cancer cell growth has been shown to correlate with high levels of nuclear β-catenin, a molecular phenotype known to be associated with the invasive TNBC subtype and poor clinical outcome. Therefore, we investigated whether inhibition of CK1 δ/ϵ could represent a viable strategy for the treatment of TNBC, for which there are currently no targeted therapies. Here we report the development of novel small molecule, ATP competitive inhibitors of CK1δ/ϵ, that are highly selective for CK1δ and ϵ and have low nanomolar biochemical and anti-breast cancer cell potency. In particular, our top leads (such as SR-3029) show selectivity toward cancer cells over non-tumorigenic cells and screening of the NCI-60 panel of tumor cell lines suggest potency against a number of additional malignancies, including GBM and melanoma. We show, using genetic tools, that SR-3029 is on-target and functions to promote apoptotic cell death in TNBC cells through negative regulation of β-catenin. Furthermore, SR-3029 is highly efficacious in vivo, promoting regression of human MDA-MB-231 tumors established in the mouse mammary fat pad. Our studies demonstrate pre-clinical proof of concept that targeting of CK1δ/ϵ is an effective anti-TNBC strategy.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C269.
Citation Format: Laura H. Rosenberg, Weimin Chen, Shima Nakanishi, Mathieu Bibian, Michael D. Cameron, John L. Cleveland, William R. Roush, Derek R. Duckett. Targeting casein kinase 1 delta and epsilon (CK1δ/ϵ) in breast cancer therapeutics. [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 C269.