bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C149: The PKC inhibitor Sotrastaurin selectively inhibits the growth of GNAQ mutant uveal melanoma.
Authors: Barrett Rosemary , Guo Ribo , Yuan Jing , Cooke Vesselina , Vattay Anthony , Korn Joshua , Liang Guiqing , Li Xin , Thiruvamoor Ramu , Wylie Andrew , Bric Anka , Keen Nicholas , Sellers William 
Published: August 2014

Abstract
GNAQ mutations are early and frequent events in the pathology of Uveal Melanoma. These mutations hyper-activate PLCb-PKC-ERK1/2 signaling resulting in PKC dependence. Targeting GNAQ mutant Uveal Melanoma Cells with the PKC inhibitor AEB071 (Sotrastaurin) leads to pathway modulation and growth inhibition. The Myristoylated Alanine-rich C-kinase Substrate (MARCKS) is directly phosphorylated by PKC and can be used as a readout for PKC activation.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C149.
Citation Format: Rosemary Barrett, Ribo Guo, Jing Yuan, Vesselina Cooke, Anthony Vattay, Joshua Korn, Guiqing Liang, Xin Li, Ramu Thiruvamoor, Andrew Wylie, Anka Bric, Nicholas Keen, William Sellers. The PKC inhibitor Sotrastaurin selectively inhibits the growth of GNAQ mutant uveal melanoma. [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 C149.
Abstract C150: Depletion of cellular NAD using the NAMPT inhibitor GNE-617 leads to oncosis blister cell death.
Authors: O'Brien Thomas , Del Nagro Christopher , Xiao Yang , Oeh Jason , Rangell Linda , Reichelt Mike , Liang Xiaorong , Liederer Bianca M. , Dragovich Peter S. , Sampath Deepak 
Published: August 2014

Abstract
Nicotinamide adenine dinucleotide (NAD) is a critical cellular metabolite and the key enzyme in the NAD salvage pathway is nicotinamide phosphoribosyl transferase (NAMPT). Here we describe GNE-617, a novel orally bioavailable NAMPT inhibitor, and show that this compound promotes rapid depletion of NAD both in cells and in xenograft tumor models. Moreover, GNE-617 rapidly induced tumor regressions in colorectal (HCT-116), fibrosarcoma (HT-1080), prostate (PC3) and pancreatic (MiaPaca2) xenograft models. Despite increasing interest in exploiting cancer cell metabolism as a therapeutic strategy, there is still a poor understanding of cell death mechanisms following disruption of key metabolic processes. Here we show that depletion of NAD in cells induces a series of cellular events that leads to oncosis-Blister Cell Death (oncosis-BCD). In all cell lines examined, NAD was depleted &gt;95% within 25-39 hours, which was rapidly followed by a loss of ATP (&gt;95% depleted by 41-76 hours). Depletion of NAD correlates with loss of cell motility and a reduction in mitotic index, which may be explained by reduced activity of NAD-dependent protein deacetylases. In support of this, we find that α-tubulin-K40 is hyper-acetylation, a modification that is known to reduce tubulin dynamics and cell motility. Additionally, there is no evidence of histone H3-K9 deacetylation, which normally occurs as cells enter mitosis. Using a combination of approaches including live cell imaging and electron microscopy we found that cell lines with a more rapid depletion of ATP display signs of necrosis and oncosis-BCD, while cell lines with a slower depletion of ATP show signs of autophagy, apoptosis, necrosis and oncosis-BCD. In all cases however, oncosis-BCD is the predominant form of cell death and is characterized by plasma membrane swelling to form large organelle-free blisters. Finally, we conclude that cell death is due to loss of plasma membrane ion-homeostasis associated with ATP depletion. In conclusion, our data shows that there is an ordered progression of events that occurs in cancer cells following NAD depletion and reveals that oncosis-BCD is the predominant form of cell death in response to NAD depletion.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C150.
Citation Format: Thomas O'Brien, Christopher Del Nagro, Yang Xiao, Jason Oeh, Linda Rangell, Mike Reichelt, Xiaorong Liang, Bianca M. Liederer, Peter S. Dragovich, Deepak Sampath. Depletion of cellular NAD using the NAMPT inhibitor GNE-617 leads to oncosis blister cell death. [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 C150.
Abstract C185: CIP2A is a novel therapeutic target for an erlotinib derivative in EGFR wild-type NSCLC cells.
Authors: Chao Ting-Ting , Wang Cheng Yi , Chang Fang-Yu , Chen Yen-Lin , Shiau Chung-Wai , Chen Kuen-Feng 
Published: August 2014

Abstract
Rationale: Cancerous inhibitor of protein phosphatase 2A (CIP2A), a proto-oncogene inhibiting proteolytic degradation of c-MYC, is overexpressed in various types of human cancers, including lung cancer.
Objective: To determine if erlotinib and its derivative can inhibits EGFR mutation-negative NSCLC via CIP2A inactivation.
Methods: EGFR mutation-negative NSCLC cell lines (H358, H460, and H322) were treated with erlotinib or TD-19, an erlotinib derivative that closely resembled erlotinib structurally but devoid of tyrosine-kinase inhibitory activity. Apoptosis and signal transduction were analyzed. In vivo efficacy was determined in nude mice with H460 xenografts.
Results: Erlotinib showed differential effects on apoptosis in 3 human NSCLC cell lines. Erlotinib induced significant apoptosis in H358 cell line; however, H460 and H322 cell lines showed resistance to erlotinib-induced apoptosis at all tested doses. Down-regulation of CIP2A, a cellular inhibitor of protein phosphatase 2A (PP2A), mediated the apoptotic effect of erlotinib in H358 cell line. Erlotinib inhibited CIP2A in a dose- and time-dependent manner in sensitive NSCLC cells whereas no alterations in CIP2A were found in resistant cells. Overexpression of CIP2A upregulated phospho-Akt and protected H358 cells from erlotinib-induced apoptosis. In addition, silencing CIP2A by siRNA restored the effects of erlotinib in H460 cells. Moreover, adding okadaic acid, a PP2A inhibitor, abolished the effects of erlotinib on apoptosis in H358 cells. TD-19 had better effects than erlotinib on growth inhibition and apoptosis in erlotinib-resistant H460 and H322 cell lines through CIP2A-PP2A-Akt pathway. Overexpression of CIP2A upregulated phospho-Akt and protected H460 cells from TD-19-induced apoptosis. Moreover, adding okadaic acid, a PP2A inhibitor, abolished the effects of TD-19 on apoptosis in H460 cells. Furthermore, in vivo xenograft data showed that TD-19 inhibited the growth of H460 tumor but erlotinib had no effect on H460 tumor. TD-19 downregulated CIP2A and upregulated PP2A activity in H460 tumors, but erlotinib did not.
Conclusions: Inhibition of CIP2A determines the effects of erlotinib and its derivative on apoptosis in EGFR mutation-negative NSCLC. CIP2A may be useful as a therapeutic target for erlotinib and its derivative in EGFR mutation-negative NSCLC treatment.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C185.
Citation Format: Ting-Ting Chao, Cheng Yi Wang, Fang-Yu Chang, Yen-Lin Chen, Chung-Wai Shiau, Kuen-Feng Chen. CIP2A is a novel therapeutic target for an erlotinib derivative in EGFR wild-type NSCLC cells. [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 C185.
Abstract C21: Molecular mechanism of Mangiferin induced cytotoxicity in cervical carcinoma cells.
Authors: Komal Komal , Singh Mayank , Sharma Alpana , Deshwal Vishal 
Published: August 2014

Abstract
Background: Cervical cancer is the leading cause of mortality in women amongst all cancers. Mangiferin is a plant natural polyphenol of C-glycosylxanthone structure and various pharmacological activities. It can be found in many plant species, among which the mango tree (Mangifera indica) is one of the primary sources. Several studies indicated also its ability to inhibit carcinogenesis and cancer cells growth by apoptosis induction in vitro and in vivo.
Methods: HPV-positive cervical cancer cell lines HeLa, CaSki and SiHa were cultured in DMEM/RPMI media respectively, supplemented with 10% FBS in a humidified atmosphere of 5% CO2 at 37°C. They were treated with 5 and 10μg/ml Mangiferin for 24 hrs. Apoptosis was measured by flow cytometery and TUNEL assay. Expression of various proteins levels were assessed by western blotting while caspase -3 and -9 activation was measured by fluorimetry.
Results: Mangiferin induced dose dependent cytotoxicity in both HPV 16 and HPV 18 positive cell line. Mangiferin repressed activation of NFkB Transcription factor. The observed apoptosis was caspase dependent. Caspase dependent apoptosis was mediated through mitochondrial intrinsic pathway involving release of cytochrome c with increase in level of proapoptotic Bax and decrease in levels of Antiapoptotic Bcl XL. Mangiferin also repressed activation of NFkB Transcription factor and its nuclear translocation. Mangiferin also repressed the level of E6 oncoproteins.
Conclusion: The present study establishes the potency of Mangiferin as a potential chemotherapeutic agent in female cancers as it targets cervical cancer cells by repression of NFkB transcription factor and inducing dose dependent cytotoxicity.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C21.
Citation Format: Komal Komal, Mayank Singh, Alpana Sharma, Vishal Deshwal. Molecular mechanism of Mangiferin induced cytotoxicity in cervical carcinoma cells. [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 C21.
Abstract C223: Network-based approach aids in the discovery of context-specific druggable targets for treatment of glioblastoma.
Authors: Dhruv Harshil D. , Kim Seungchan , Kiefer Jeff , Emig-Agius Dorothea , Finlay Darren , Jung Sungwon , Vuori Kristiina , Berens Michael 
Published: August 2014

Abstract
Systematic discovery of actionable cancer targets could fill an unmet need for improved approaches to manage Glioblastoma Multiforme (GBM). Critical barriers to the discovery of druggable targets in cancer include: 1) molecular heterogeneity of the disease across patients, 2) implementation of a systematic approach to utilize existing knowledge and molecular data for target discovery, and 3) the lack of a relevant, rapid and systematic pipeline to enable empirical testing of hypotheses. We describe a network-based method to stratify GBM clinical samples into molecularly homogeneous subsets based on gene expression, gene copy number, and miRNAs, which we term “molecular contexts," or mCs. Within these mCs, a knowledge-based topological analysis of pathway elements was used to uncover discrete mC-specific targets. An empiric chemical screen probed the target space across different mCs, mC-4 and mC-14, which were molecularly orthogonal to each other. Specimens in mC-4 were enriched with samples previously classified as Mesenchymal-type GBM, while mC-14 was enriched with Proneural-subtype GBM. The chemical screen was carried out using short-term in vitro cultures derived from patient-derived GBM xenografts, which mapped to mC4 and mC14 based on gene expression. We employed a network-based topological approach to discern targets and pathways as candidate druggable vulnerabilities. The chemical validation screen was carried out with an assembled chemical biology fingerprint (CBF) library comprised of 650 small molecules targeting multiple cancer-associated pathways and processes. Matching specific chemical hits to their respective targets allowed for validation of specific gene hits from the topological analysis. Of particular interest were two molecular context specific lethal compounds in the screen, tamoxifen citrate and arsenic trioxide, specific to the mC4 and mC14, respectively. PKC, among the targets of Tamoxifen citrate, was a predicted node of vulnerability for mC-4 GBM, while PML gene, a target of Arsenic Trioxide, was a predicted target for mC-14. In summary, our results suggest that context analysis coupled with knowledge-based enrichment and topological analysis identifies specific GBM contexts with novel unique drugable targets. Supported by NIH U01 CA168397.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C223.
Citation Format: Harshil D. Dhruv, Seungchan Kim, Jeff Kiefer, Dorothea Emig-Agius, Darren Finlay, Sungwon Jung, Kristiina Vuori, Michael Berens. Network-based approach aids in the discovery of context-specific druggable targets for treatment of glioblastoma. [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 C223.
Abstract C230: A platform for discovery of novel stem cell modulators and subsequent development of therapeutic targets.
Authors: Ainsworth Shaun , Hoyle Sarah , Bonavita Aude-Marine , Kemp Laura , Read Jo , Murdoch Alan , Woolford Lorna , Miele Gino , Booth Cath 
Published: August 2014

Abstract
In recent years, there has been a significant and growing interest in specific pathways the human body utilizes in response to damage and their exploitation to induce cell proliferation, differentiation and apoptosis. Epistem's Novel Therapies division has created a discovery platform to allow identification of novel soluble regulators for development of therapeutic targets in oncology, regenerative medicine, and gastrointestinal diseases. Target discovery and identification starts with a known stem cell model and the creation of a disease system in vivo to identify potential stem cell markers. A damage response model of the gastrointestinal tract for stem cell proliferation and apoptosis post-irradiation describes the different phases of the cell recovery process. Post-irradiation, the stem cells, which are located at the base of the intestinal crypt, undergo apoptosis, followed by a rapid phase of regeneration, resulting in an ‘overshoot’ in crypt cell numbers, with homeostasis finally achieved by a ‘shut off’ phase with a decrease in proliferation to basal levels. Using high resolution gene expression profiling of dissected crypts (upper and lower), from small intestine and colon, isolated at various key time points post irradiation, we have identified many candidate novel stem cell regulators involved in damage response. Recombinant proteins have been produced; purified; and characterized, then tested using our proprietary in vitro model assays, looking for efficacy in cell proliferation, apoptosis and differentiation. Proteins that demonstrated robust and reproducible activities were then further evaluated using our industry standard in vivo intestinal stem cell function assays. Pharmocodynamic gene expression profiling was then applied to establish mechanism of action (MOA) linkages between in vitro and in vivo data. Having identified novel protein therapeutics, we are currently focused on pharmacotherapeutics that can modulate the identified pathways.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C230.
Citation Format: Shaun Ainsworth, Sarah Hoyle, Aude-Marine Bonavita, Laura Kemp, Jo Read, Alan Murdoch, Lorna Woolford, Gino Miele, Cath Booth. A platform for discovery of novel stem cell modulators and subsequent development of therapeutic targets. [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 C230.
Abstract C26: Development and validation of a scoring system using insulin-like growth factor to assess hepatic reserve in hepatocellular carcinoma.
Authors: Kaseb Ahmed O. , Xiao Lianchun , Naguib Rania , El-Shikh Wafaa , Hassan Manal , Hassabo Hesham , Lee Jeong-Hoon , Yoon Jung-Hwan , Lee Hyo-Suk , Chae Young Kwang , Abbruzzese James L. , Morris Jeffrey 
Published: August 2014

Abstract
Background: The Child-Turcotte-Pugh (CTP) score inaccurately predicts survival in patients with chronic liver disease, including hepatocellular carcinoma (HCC), yet remains the standard tool for assessing hepatic reserve and guiding therapeutic decisions. CTP scoring relies on objective laboratory values for albumin, bilirubin, and prothrombin time and subjective clinical grading of hepatic encephalopathy and ascites. Since liver production of insulin-like growth factor 1 (IGF-1) is significantly reduced in patients with cirrhosis, we hypothesized that IGF-1 could be a valid surrogate for hepatic reserve to replace the subjective parameters in CTP score.
Methods: We prospectively enrolled patients and collected data and retrospectively tested plasma IGF-1 levels in four independent cohorts: two HCC cohorts from the United States, n=310 (training set) and n=99 (validation set 1); one HCC cohort from Korea, n=188 (validation set 2); and one cirrhosis cohort from Egypt, n=71 (validation set 3). Recursive partitioning identified within the training set three optimal IGF-1 ranges that correlated with survival: &gt;50 ng/mL = 1 point; 26-50 ng/mL = 2 points; and &lt;26 ng/mL = 3 points. We modified the CTP score by replacing ascites and encephalopathy grading with IGF-1 value, subjected both the resulting IGF score and the CTP score to log-rank analysis, and quantified the prognostic values with C-statistics to compare the scores’ performance in all cohorts.
Results: The IGF score was significantly more accurate in predicting survival and improved the stratification of all CTP classes in the training and validation cohorts.
Conclusion: The new IGF score is simple and blood-based, and validated well on multiple independent HCC cohorts. It could identify a subpopulation of patients who may benefit from active therapy because of their preserved hepatic reserve, as distinct from patients for whom therapy can be deferred or avoided.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C26.
Citation Format: Ahmed O. Kaseb, Lianchun Xiao, Rania Naguib, Wafaa El-Shikh, Manal Hassan, Hesham Hassabo, Jeong-Hoon Lee, Jung-Hwan Yoon, Hyo-Suk Lee, Young Kwang Chae, James L. Abbruzzese, Jeffrey Morris. Development and validation of a scoring system using insulin-like growth factor to assess hepatic reserve in hepatocellular 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 C26.
Abstract C263: mTOR inhibition specifically sensitizes colorectal cancers with KRAS or BRAF mutations to BCL-2/BCL-XL inhibition by suppressing MCL-1.
Authors: Coffee Erin M. , Faber Anthony C. , Costa Carlotta , Dastur Anahita , Ebi Hiromichi , Hata Aaron N. , Yeo Alan T. , J Elena , Song Youngchul , Tam Ah Ting , Boisvert Jessica L. , Milano Randy J. , Roper Jatin , Kodack David P. , Jain Rakesh K. , Corcoran Ryan B. , Rivera Miguel N. , Ramaswamy Sridhar , Hung Kenneth E. , Benes Cyril H. , Engelman Jeffrey A. 
Published: August 2014

Abstract
Colorectal cancers (CRCs) harboring KRAS or BRAF mutations are refractory to current targeted therapies. Using data from a high-throughput drug screen, we have developed a novel therapeutic strategy that combines targeting of the apoptotic machinery using the BCL-2 family inhibitor ABT-263 (navitoclax) in combination with a TORC1/2 inhibitor, AZD8055. This combination leads to efficient apoptosis specifically in KRAS mutant (MT) and BRAF MT but not wild-type (WT) CRC cells. This specific susceptibility results from TORC1/2 inhibition leading to suppression of MCL-1 expression in mutant, but not wild-type CRCs, leading to abrogation of BIM/MCL-1 complexes. This combination strategy leads to tumor regressions in both KRAS MT colorectal cancer xenograft and genetically-engineered mouse models of CRC, but not in the corresponding KRAS WT CRC models. These data suggest that the combination of BCL-2/XL inhibitors with TORC1/2 inhibitors constitutes a promising targeted therapy strategy to treat these recalcitrant cancers.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C263.
Citation Format: Erin M. Coffee, Anthony C. Faber, Carlotta Costa, Anahita Dastur, Hiromichi Ebi, Aaron N. Hata, Alan T. Yeo, Elena J, Youngchul Song, Ah Ting Tam, Jessica L. Boisvert, Randy J. Milano, Jatin Roper, David P. Kodack, Rakesh K. Jain, Ryan B. Corcoran, Miguel N. Rivera, Sridhar Ramaswamy, Kenneth E. Hung, Cyril H. Benes, Jeffrey A. Engelman. mTOR inhibition specifically sensitizes colorectal cancers with KRAS or BRAF mutations to BCL-2/BCL-XL inhibition by suppressing MCL-1. [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 C263.
Abstract C277: INCB018424 induces apoptotic cell death through the suppression of pJAK1 in human colon cancer cells.
Authors: Choi Eun Kyoung , Ha Seung Hee , An Ho Jung , Kim Jin-Sun , Hong Seung-Woo , Moon Jai-Hee , Shin Jae-Sik , Kim Kyu-Pyo , Hong Yong Sang , Lee Jae-Lyun , Choi Eun Kyung , Lee Jung Shin , Jin Dong-Hoon , Kim Tae Won 
Published: August 2014

Abstract
Janus kinase (JAK) is one of the main upstream activators of signal transducers and activators of transcription (STAT) that are constitutively activated in various malignancies and are associated with cell growth, survival, and carcinogenesis. Here, we investigated to role of JAKs in colorectal cancer in order to develop effective therapeutic targets for INCB018424, which is the first JAK1/2 inhibitor to be approved by FDA. After examining the basal expression levels of phospho-JAK1 and phospho-JAK2, we measured the effects of INCB018424 on the phosphorylation of JAK1/2 using western blot analysis. Cell viability was determined using the trypan blue exclusion assay. The cell death mechanism was identified by the activation of caspase 3 using western blot and annexin V staining. The basal levels of phospho-JAK1 and phospho-JAK2 were cancer cell type dependent. Colorectal cancer cell lines that phosphorylate both JAK1 and JAK2 include DLD-1 and RKO. INCB018424 inactivates both JAK1 and JAK2 in DLD-1 cells but inactivates only JAK1 in RKO cells. Cell death was proportional to the inactivation of JAK1 but not JAK2. INCB018424 causes caspase-dependent cell death, which is prevented by treatment with z-VAD. The inhibition of JAK1 phosphorylation seemed sufficient to allow INCB018424-mediated apoptosis. JAK1 is a key molecule that is involved in colon cancer cell survival and the inhibition of JAK1 by INCB01424 results in caspase-dependent apoptosis in colorectal cancer cells. The use of selective JAK1 inhibitors could be an attractive therapy against colorectal cancer, but further clinical investigations are needed to test this possibility.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C277.
Citation Format: Eun Kyoung Choi, Seung Hee Ha, Ho Jung An, Jin-Sun Kim, Seung-Woo Hong, Jai-Hee Moon, Jae-Sik Shin, Kyu-Pyo Kim, Yong Sang Hong, Jae-Lyun Lee, Eun Kyung Choi, Jung Shin Lee, Dong-Hoon Jin, Tae Won Kim. INCB018424 induces apoptotic cell death through the suppression of pJAK1 in human colon cancer cells. [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 C277.