bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C102: Identify novel pathways conferring PARP inhibitor resistance in BRCA-associated breast and ovarian cancer.
Authors: He Lei , Chen Li , Ramakrishnan Saranya , Torres-Lockhart Kristine , Ellisen Leif 
Published: August 2014

Abstract
Inhibitors of poly(ADP-ribose) polymerase (PARP) enzymes hold great promise in treating BRCA1/2 associated breast and ovarian cancers, which have profound homologous recombination (HR) defect. However, not all BRCA1/2 patients respond to PARP inhibitor treatment, and the majority of the responders eventually relapsed. Little is known about the resistance mechanisms that are clinical relevant.
We recently developed a highly versatile insertional mutagenesis system, using transposons to insert a CMV promoter randomly into the genome and thereby activate nearby genes. We constructed genome-wide insertional libraries using both human and mouse BRCA1-deficient cancer cell lines. When these mutated cells were treated with the PARP inhibitor, resistant colonies formed at extremely low frequency. Resistant colonies were re-grown and maintained in drug-free medium for extended period of time and robust resistance was retained. Insertion sites for these colonies were then determined, many of which are near genes whose alteration in expression can up-regulate activities of MEK/ERK pathway or PI3K/AKT pathway. Next we hope to investigate the resistance mechanism. We hypothesize that resistance is mediated via decreased DNA damage, improved DNA repair, or increase in general survival pathway after PARP inhibitor treatment. We have access to tumor specimens from a recently-completed clinical trial using ABT-888 in combination with temozolomide in a BRCA1/2 carrier-enriched population. The expression level and mutational status of these genes will be surveyed and correlated with clinical response. Finally based on the insight gained from aforementioned mechanism study, we hope to find inhibitors that specifically target the resistance mechanism; by combining this inhibitor with PARP inhibitor, we could develop effective therapy to treat the subset of patients resistant to PARP inhibitor.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C102.
Citation Format: Lei He, Li Chen, Saranya Ramakrishnan, Kristine Torres-Lockhart, Leif Ellisen. Identify novel pathways conferring PARP inhibitor resistance in BRCA-associated breast and ovarian 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 C102.
Abstract C109: Discovery of new natural anti-tumoral compounds using a parallel target- and phenotypic-driven screening approach.
Authors: Feger Daniel , Weber Holger , Totzke Frank , Birkle Marianne , Siedentopf Oliver , Müller Melanie , Umber Sarah , Lin Wenhan , Proksch Peter , Ehlert Jan E. , Kubbutat Michael H.G. 
Published: August 2014

Abstract
In anticancer drug discovery a common strategy is to start with a target-specific screen followed later by characterization of hit compounds in phenotypic cell-based assays. One important advantage of this sequential screening procedure is the feasibility of high throughput compound testing. However, a significant disadvantage of the approach is the fact that due to the sequential nature of the approach, compounds showing promising phenotypic activities, but addressing so far unknown targets will be lost as false-negative compounds. Here we describe a medium throughput screening strategy, where we characterized 360 natural compounds isolated from marine organisms in a parallel target- and phenotypic-driven screening approach. As target-specific read out, we analyzed biochemically the inhibitory potential of the compounds against 16 recombinant protein kinases, known to be relevant targets in different kinds of human tumors. In parallel we determined the impact of the compounds on cell transformation, migration and angiogenesis by analyzing their behavior in soft agar growth, wound healing and three-dimensional endothelial cell sprouting. Furthermore, unspecific toxicity of the compounds was tested via a viability assay with human peripheral mononuclear cells from healthy donors. Examples of identified compounds showing differential inhibitory profiles in the different assays applied will be presented.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C109.
Citation Format: Daniel Feger, Holger Weber, Frank Totzke, Marianne Birkle, Oliver Siedentopf, Melanie Müller, Sarah Umber, Wenhan Lin, Peter Proksch, Jan E. Ehlert, Michael H.G. Kubbutat. Discovery of new natural anti-tumoral compounds using a parallel target- and phenotypic-driven screening approach. [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 C109.
Abstract C134: EN3356, a novel CYP17A inhibitor for the treatment of castration resistant prostate cancer.
Authors: Laping Nicholas J. , Sivanandhan Dhanalakshmi , Kethiri Raghava Reddy , Dewang Purushottam M. , Vijayendra Ajith , Zainuddin Mohd , Mullangi Ramesh , Rao Niranjan , Venkatesan Aranapakam M. , Reddy Sanjeeva , Gupta Sandeep , Smith Roger A. 
Published: August 2014

Abstract
Androgens are a major driver of prostate cancer growth. As prostate cancer progresses, it can escape standard androgen deprivation therapy by relying on extra-testicular CYP17 enzyme activity for androgen synthesis. EN3356 is a novel non-steroidal CYP17 inhibitor that reduces androgen synthesis and is designed to treat castration-resistant prostate cancer. EN3356 provides potent inhibition of CYP17 lyase activity in rat and human testicular microsomes, and in human adrenocortical carcinoma H295R cells it also inhibits testosterone synthesis potently. In contrast to abiraterone, EN3356 is selective for inhibiting testosterone synthesis over cortisol synthesis. This finding suggests that EN3356 may not require co-administration of prednisone to mitigate mineralocorticoid excess. In pre-clinical studies, EN3356 exhibited high oral bioavailability. EN3356 inhibited serum testosterone levels in the rat and caused a robust decrease of seminal vesicle and prostate weights following 14-days of oral administration. GLP safety studies were completed in two preclinical species and identified a high safety margin. A combination Phase I/II study in metastatic castration-resistant prostate cancer is currently under initiation in the US and is anticipated to start enrolling subjects in the fourth quarter of 2013. Based on the potent inhibitory activity of EN3356 against CYP17 lyase in vitro, selective inhibition of testosterone synthesis versus cortisol synthesis, and robust weight reduction of androgen sensitive organs in vivo, EN3356 has the potential to be a selective and efficacious therapy for the treatment of castration-resistant prostate cancer.
Disclosure: Funding for this research was provided by Endo Pharmaceuticals Inc.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C134.
Citation Format: Nicholas J. Laping, Dhanalakshmi Sivanandhan, Raghava Reddy Kethiri, Purushottam M. Dewang, Ajith Vijayendra, Mohd Zainuddin, Ramesh Mullangi, Niranjan Rao, Aranapakam M. Venkatesan, Sanjeeva Reddy, Sandeep Gupta, Roger A. Smith. EN3356, a novel CYP17A inhibitor for the treatment of castration resistant prostate 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 C134.
Abstract C140: RIT1 mutations define a new genetic subset of lung adenocarcinoma.
Authors: Berger Alice , Imielinski Marcin , Duke Fujiko , Wala Jeremiah , Kaplan Nathan , Shi Geng-Xian , Andres Douglas , Meyerson Matthew 
Published: August 2014

Abstract
Lung adenocarcinoma is comprised of distinct mutational subtypes characterized by mutually exclusive oncogenic mutations in RTK/RAS pathway members KRAS, EGFR, BRAF, and ERBB2, and translocations involving ALK, RET, and ROS1. Identification of these oncogenic events has transformed therapy of lung adenocarcinoma via application of therapies targeted towards specific genetic lesions in stratified patient populations. However, such mutations have been identified in only ∼55% of lung adenocarcinoma cases in the United States, suggesting other mechanisms of malignancy may be involved in the remaining cases. We analyzed exome sequencing data from 413 lung adenocarcinomas and identified somatic mutations in the small GTPase gene RIT1 in ∼2% of samples. Mutations in RIT1 cluster in a hotspot near the switch II domain of the protein that is homologous to the Q61 region in RAS genes. RIT1 switch II domain mutations are mutually exclusive with all other known lung adenocarcinoma driver mutations. Ectopic expression of mutated RIT1 induces activation of AKT and ERK signaling pathways and transforms NIH3T3 cells in vitro and in vivo. These data identify RIT1 as a driver oncogene in a specific subset of lung adenocarcinomas.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C140.
Citation Format: Alice Berger, Marcin Imielinski, Fujiko Duke, Jeremiah Wala, Nathan Kaplan, Geng-Xian Shi, Douglas Andres, Matthew Meyerson. RIT1 mutations define a new genetic subset of lung adenocarcinoma. [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 C140.
Abstract C151: Contribution of serine, folate, and glycine metabolism to the ATP, NADPH, and purine requirements of cancer cells.
Authors: Tedeschi Philip M. , Markert Elke K. , Gounder Murugesan , Lin HongXia , Dolfi Sonia C. , Chan Leo Li-Ying , Qiu Jean , Hirshfield Kim M. , Boros Laszlo G. , Bertino Joseph R. , Oltvai Zoltan N. , Vazquez Alexei 
Published: August 2014

Abstract
Background: Recent observations on cancer cell metabolism indicate increased serine synthesis from glucose as a marker of poor prognosis. Expression of genes in this pathway also correlate with sensitivity to the antifolate methotrexate (Vazquez A, et al, Cancer Res. 2013 Jan 15;73(2):478-82). Using a large-scale model of human cell metabolism we have predicted that serine synthesis can be routed to a pathway for ATP production. The pathway is composed by reactions from the serine synthesis, one carbon (folate) metabolism and the glycine cleavage system (SOG pathway) and its flux is predicted to increase at high proliferation rates.
Results: Here we show that the SOG pathway is upregulated at the level of gene expression in a subset of human tumors and its level of expression correlates with gene signatures of cell proliferation and Myc targets activation. To investigate the activity of the SOG pathway at the level of metabolic fluxes we estimated the metabolic fluxes of the NCI60 panel of tumor derived cell lines, using previously reported exchange fluxes and a flux balance model of cell metabolism. We show that the estimated rates of reactions in the SOG pathway are highly correlated with the proliferation rates of these cell lines. We also find that the SOG pathway contributes significantly to the energy requirements of biosynthesis, the NADPH requirements of fatty acid synthesis and to the synthesis of purines. Finally, when the PC-3 prostate cancer cell line is subject to treatment with the antifolate methotrexate, we observe a decrease in the ATP levels, an inhibition of the proliferation rate and a decrease in the ribonucleotides and fatty acids synthesized from glucose.
Conclusions: Taken together our results indicate that the SOG pathway activity increases with the rate of cell proliferation and it contributes to the biosynthetic requirements of purines, ATP and NADPH.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C151.
Citation Format: Philip M. Tedeschi, Elke K. Markert, Murugesan Gounder, HongXia Lin, Sonia C. Dolfi, Leo Li-Ying Chan, Jean Qiu, Kim M. Hirshfield, Laszlo G. Boros, Joseph R. Bertino, Zoltan N. Oltvai, Alexei Vazquez. Contribution of serine, folate, and glycine metabolism to the ATP, NADPH, and purine requirements of 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 C151.
Abstract C152: Characterizing rhabdomyosarcoma and osteosarcoma cellular metabolism.
Authors: Issaq Sameer , Teicher Beverly , Monks Anne 
Published: August 2014

Abstract
Sarcomas represent a diverse group of malignancies with distinct molecular and pathological features. A better understanding of the alterations associated with specific sarcoma subtypes is critically important to improve sarcoma treatment. A renewed interest in the metabolic properties of cancer cells, as well as the recognition of altered cellular metabolism as a critical hallmark of cancer, has led to an exploration of targeting metabolic dependencies of cancer cells as a therapeutic strategy. In this study, we have characterized key bioenergetic properties of human rhabdomyosarcoma and osteosarcoma cell lines in order to identify potential differences in sarcoma subtypes. We have also investigated the effects of compounds that inhibit glycolysis or mitochondrial respiration, either alone or in combination, and examined relationships between bioenergetic parameters and sensitivity to metabolic inhibitors. Glycolytic and mitochondrial bioenergetic profiles were generated using Seahorse extracellular flux analysis to measure extracellular acidification rates and oxygen consumption rates, and significant differences in glycolytic and respiratory bioenergetics between rhabdomyosarcoma and osteosarcoma cell lines were identified. Using 2-deoxy-D-glucose (2-DG), a competitive inhibitor of glycolysis, oligomycin, an inhibitor of mitochondrial ATP synthase, and metformin, a widely-used diabetes drug and inhibitor of complex I of the mitochondrial respiratory chain, we evaluated the effects of metabolic inhibition on sarcoma cell growth and bioenergetic function. Inhibition of glycolysis by 2-DG effectively reduced the viability of alveolar rhabdomyosarcoma cells versus embryonal rhabdomyosarcoma, osteosarcoma, and normal cells, whereas inhibition of mitochondrial respiration by oligomycin or metformin did not significantly affect viability. Combined inhibition of glycolysis and respiration decreased cell growth more effectively than either treatment alone in all sarcoma lines tested. Additionally, inhibition of glycolysis significantly reduced intracellular ATP levels in all sarcoma lines tested, and sensitivity to 2-DG-induced growth inhibition was related to respiratory rates and glycolytic dependency. Our findings suggest that inhibition of metabolic pathways in sarcomas should be further investigated as a potential therapeutic strategy. Funded by NCI Contract No. HHSN261200800001E.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C152.
Citation Format: Sameer Issaq, Beverly Teicher, Anne Monks. Characterizing rhabdomyosarcoma and osteosarcoma cellular metabolism. [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 C152.
Abstract C171: Novel therapeutic strategies targeting the hedgehog signaling pathway and mTOR pathway in biliary tract cancer (BTC).
Authors: Zuo Mingxin , Rashid Asif , Churi Chaitanya , Hung Mien-Chie , Javle Milind 
Published: August 2014

Abstract
Background: BTC represents the second most common primary cancer of the hepatobiliary system and is associated with a poor prognosis. Activation of PI3K/mTOR and hedgehog pathways has been demonstrated in biliary cancer. Activated mTOR/S6K1 pathway promotes Gli1 transcriptional activity and oncogenesis through S6K1-mediated Gli phosphorylation. Recently, synergistic antitumor efficacy was demonstrated with the combination of hedgehog and mTOR inhibitors, particularly in cases with mTOR/S6K pathway in esophageal cancer (Cancer Cell 2012; 21(3):374-87).
Methods: Gene expression profiling was performed on 10 human biliary tract cancer cell lines (MMNK-1, Mz-ChA-1, Sk-ChA-1, KKU-M213, KKU-M214, KKU-M055, KKU-M139, M213L5H, and M213LOH) by real-time qRT-PCR. CellTiter-Glo® luminescent cell viability assay, colony formation, and stem cells morphology spheres were conducted to examine the effects of the combination of Rapamycin and Vismodegib on cell proliferation. Western-blot assay was used to examine the related protein expression. Fluorescence-activated cell sorting (FACS) was used to examine the effects of the combination on BTC stem cells.
Results: Based on Gli1 and S6K gene expression, the Mz-ChA-1 and Sk-ChA-1 cell lines were chosen to investigate the effects of the combination of Rapamycin and Vismodegib on BTC (Table 1). Combination of Rapamycin and Vismodegib exhibited the synergistic antiproliferative effect on Mz-ChA-1 cells. The combination of Rapamycin and Vismodegib inhibited the Mz-ChA-1 cell proliferation, colony formation and stem cell sphere formation. This combination therapy decreases the NANOG, OTC3/4, and E-Cadherin gene expression in Mz-ChA-1 stem cells. Furthermore, the drug combination can decrease the phospho-p70S6K and Gli1 protein and increase cleaved caspase-3 expression in Mz-ChA-1 cells. No such effect was observed in Sk-ChA-1 cells.Conclusions: Crosstalk between the mTOR pathway and HH pathway provides a new avenue for combination therapy in BTC with hedgehog and mTOR inhibitors.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C171.
Citation Format: Mingxin Zuo, Asif Rashid, Chaitanya Churi, Mien-Chie Hung, Milind Javle. Novel therapeutic strategies targeting the hedgehog signaling pathway and mTOR pathway in biliary tract cancer (BTC). [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 C171.
Abstract C18: Antitumor activity of xanthohumol, an inhibitor of valosin-containing protein.
Authors: Shikata Yuki , Kanagaki Shuhei , Sasazawa Yukiko , Tashiro Etsu , Yoshimaru Tetsuro , Komatsu Masato , Katagiri Toyomasa , Imoto Masaya 
Published: August 2014

Abstract
Autophagy is a bulk, nonspecific protein degradation pathway that is involved in the pathogenesis of cancer and neurodegenerative disease. Here, we observed that xanthohumol (XN), a prenylated chalcone present in hops (Humulus lupus L.) and beer, modulates autophagy. By using XN-immobilized beads, valosin-containing protein (VCP) was identified as a XN-binding protein. VCP has been reported to be an essential protein for autophagosome maturation. Using an in vitro pull down assay, we showed that XN bound directly to the N domain, which is known to mediate co-factor and substrate binding to VCP. These data indicated that XN inhibited the function of VCP, thereby allowing the impairment of autophagosome maturation, and resulting in the accumulation of microtubule-associated protein 1 light chain 3-II (LC3-II).On the other hand, it has been reported that the expression level of VCP is correlated with progression of cancer, and VCP-overexpressing cell lines showed the resistance to apoptosis. Therefore, in this study, we examined the antitumor effects of XN on several types of human tumor cells. First we tested the sensitivity to XN in 15 human tumor cell lines. Each cell was treated with XN for 48 hrs, and XN-induced apoptosis was quantitatively analyzed by flow cytometry. As a result, XN potently induced apoptosis in 6 cell lines (SW480, SW620, HCT116, A2058, A375 and SW48 cells) as judged from subG1 population, and another 9 tumor cell lines were resistant to XN. Next, we examined whether VCP is involved in XN-induced apoptosis. Although, these 15 cell lines showed similar expression levels of VCP, another VCP inhibitor, Eeyarestatin I, also induced apoptosis in XN-sensitive tumor cells (SW480 cells and HCT116 cells) but not in VCP-insensitive tumor cells (A431 cells and EC17 cells). These findings suggest that the several human tumor cell lines require VCP function for their survival, and VCP would be a potential chemotherapeutic target molecule for subset of tumor cells.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C18.
Citation Format: Yuki Shikata, Shuhei Kanagaki, Yukiko Sasazawa, Etsu Tashiro, Tetsuro Yoshimaru, Masato Komatsu, Toyomasa Katagiri, Masaya Imoto. Antitumor activity of xanthohumol, an inhibitor of valosin-containing protein. [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 C18.
Abstract C183: Targeted disruption of the BCL9/b-catenin complex inhibits oncogenic WNT signaling.
Authors: Carrasco Ruben D. , Walensky Loren 
Published: August 2014

Abstract
Deregulated Wnt/β-catenin signaling underlies the pathogenesis of a broad range of human cancers yet the development of targeted therapies to disrupt the pathway has remained a formidable challenge due to the toxicities associated with disrupting the pathway's homeostatic functions and the large protein interaction surfaces involved. BCL9 is an important co-activator for β-catenin-mediated transcription and is highly expressed in tumors but not in the cells of origin, presenting an opportunity to selectively block pathologic β-catenin activity. BCL9 drives β-catenin signaling through a direct binding interaction mediated by its α-helical homology domain-2. We report the development of a Stabilized Alpha-Helix of BCL9 (SAH-BCL9) that targets β-catenin, dissociates native β-catenin/BCL9 complexes, selectively suppresses Wnt transcription, and elicits mechanism-based anti-tumor responses. The clinical translation potential of this approach is underscored by the capacity of SAH-BCL9 to effectively suppress the growth, angiogenesis, invasion, and metastasis of Wnt-dependent colorectal cancer and multiple myeloma in vivo.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C183.
Citation Format: Ruben D. Carrasco, Loren Walensky. Targeted disruption of the BCL9/b-catenin complex inhibits oncogenic WNT signaling. [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 C183.