bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B32: Patient-derived tissue slice grafts of high-risk primary prostate cancer: An authentic preclinical model for synthetic lethality-based therapy
Authors: Zhao Hongjuan , Thong Alan , Nolley Rosie , Reese Stephen , Santos Jennifer , Ingels Alexandre , Peehl Donna 
Published: August 2014

Abstract
Background: Effective eradication of high-risk primary prostate cancer (HRPCa) could significantly decrease mortality from prostate cancer. Drugs exploiting synthetic lethality have gained attention as novel anticancer agents. However, the discovery of such therapies for HRPCa is hampered by the lack of authentic preclinical models.
Methods: We improved upon tumorgraft models that have been shown to predict drug response in other cancer types by implanting thin, precision-cut slices of HRPCa under the renal capsule of immunodeficient mice. Tissue slice grafts (TSGs) from 6 cases of HRPCa were established in mice. Following androgen deprivation by castration, TSGs were recovered and the presence and phenotype of cancer cells were evaluated.
Results: High-grade cancer in TSGs generated from HRPCa displayed characteristic Gleason patterns and biomarker expression. Response to androgen deprivation therapy (ADT) was as in humans, with some cases exhibiting complete pathologic regression and others showing resistance to castration. As in humans, ADT decreased cell proliferation and prostate-specific antigen expression in TSGs. Adverse pathological features of parent HRPCa were associated with lack of regression of cancer in corresponding TSGs after ADT. Castration-resistant cancer cells remaining in TSGs showed upregulated expression of androgen receptor target genes, as occurs in castration-resistant prostate cancer (CRPC) in humans. Finally, a rare subset of castration-resistant cancer cells in TSGs underwent epithelial-mesenchymal transition, a process also observed in CRPC in humans.
Conclusions: Our study demonstrates the feasibility of generating TSGs from multiple patients and of generating a relatively large number of TSGs from the same HRPCa specimen with similar cell composition and histology among control and experimental samples in an in vivo setting. The authentic response of TSGs to ADT, which has been extensively characterized in humans, suggests that TSGs can serve as a surrogate model for clinical trials to achieve rapid and less expensive screening of synthetic lethality based therapeutics for HRPCa and primary CRPC.
Citation Format: Hongjuan Zhao, Alan Thong, Rosie Nolley, Stephen Reese, Jennifer Santos, Alexandre Ingels, Donna Peehl. Patient-derived tissue slice grafts of high-risk primary prostate cancer: An authentic preclinical model for synthetic lethality-based therapy. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B32.
Abstract IA13: Targeting the dependence of N-Myc on interaction with Aurora-A with small molecules
Authors: Brockmann Markus , Poon Evon , Chesler Louis , Eilers Martin 
Published: August 2014

Abstract
Multiple proof-of-principle experiments suggest that targeting members of the Myc family of oncoproteins will have significant therapeutic benefit in human tumors. Deregulated expression of MYCN, one of the three family members implicated in human tumors, is prevalent in both pediatric and adult neuroendocrine tumors. We have shown previously that MYCN-amplified neuroblastoma cells depend on high levels of Aurora-A expression for maintaining N-Myc function. Similarly, Aurora-A and N-Myc bind each other and together drive an oncogenic gene expression program in neuroendocrine prostate tumors. Although stabilization of N-Myc does not require the catalytic activity of Aurora-A, we found that two inhibitors of Aurora-A disrupt the Aurora-A/N-Myc complex and promote degradation of N-Myc via the Fbxw7 ubiquitin ligase. Disruption of the Aurora-A/N-Myc complex inhibits N-Myc-dependent transcription, correlating with tumor regression and prolonged survival in a mouse model of MYCN-driven neuroblastoma, suggesting that Aurora-A is an accessible target that makes destabilization of N-Myc a viable therapeutic strategy.
Citation Format: Markus Brockmann, Evon Poon, Louis Chesler, Martin Eilers. Targeting the dependence of N-Myc on interaction with Aurora-A with small molecules. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr IA13.
Abstract IA7: Chromosome instability and synthetic lethality in yeast and cancer
Authors: Hieter Philip , Bailey Melanie , O'Neil Nigel , Pel Derek van , Stirling Peter 
Published: August 2014

Abstract
Genes that maintain chromosome stability (CIN genes) are conserved in eukaryotes and are often somatically mutated in cancer. We have been identifying synthetic lethal partner genes, in yeast synthetic lethal (SL) interaction networks, that are highly connected with sets of CIN genes somatically mutated in cancer. This identifies hub proteins and processes that are candidate targets for synthetic lethal killing of cancer cells with defined CIN gene somatic mutations. One hub process in these networks is DNA replication. The protein product of FEN1 (encoding flap endonuclease) was used as a target for small-molecule inhibitor screening using a fluorescence-based assay for enzyme activity. Inhibitors of FEN1 activity in vitro were shown to selectively inhibit the proliferation of cultured cancer cells carrying inactivating mutations in CDC4, or knockdown or inhibition of MRE11A, two genes frequently mutated in a variety of cancers. Analysis of synthetic lethal interactions with cohesin gene mutations, a class of somatic mutation found in several tumor types, found that cohesin mutants require the function of genes that mediate replication fork progression. PARP1 has roles in the DNA damage response but also the restart of stalled replication forks. We found that cohesin mutants exhibited synthetic lethal interactions with PARP mutants in C. elegans, and demonstrated that this interaction is conserved in human cells by showing that PARP inhibitors reduce the viability of cultured human cells depleted for cohesin components. Solomon, Waldman et al (Science 333:1039-43, 2011) have shown that the cohesin subunit gene, STAG2, is recurrently mutated in glioblastoma, Ewing's sarcoma, and melanoma tumors. Using matched glioblastoma cell lines containing either a truncated STAG2 or wild-type STAG2 knock-in, we found that STAG2 mutants undergo significantly decreased proliferation in the presence of PARP inhibition, suggesting that PARP inhibitors may be effective in treating cancers carrying somatic mutations in cohesin genes.
Citation Format: Philip Hieter, Melanie Bailey, Nigel O'Neil, Derek van Pel, Peter Stirling. Chromosome instability and synthetic lethality in yeast and cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr IA7.
Abstract PR10: A cyclic AMP-regulated melanocyte lineage program confers resistance to MAP kinase pathway inhibition
Authors: Johannessen Cory M. , Johnson Laura A. , Piccioni Federica , Townes Aisha , Frederick Dennie T. , Flaherty Keith T. , Wargo Jennifer A. , Root David E. , Garraway Levi A. 
Published: August 2014

Abstract
BRAFV600E-mutant malignant melanomas depend on RAF/MEK/ERK (MAP kinase) signaling for tumor cell growth. RAF and MEK inhibitors show remarkable clinical efficacy in BRAFV600E melanoma; however, resistance to these agents remains a formidable challenge. Systematic characterization of resistance mechanisms may inform the development of more effective therapeutic combinations. To chart the landscape of potential resistance mechanisms, we performed systematic gain-of-function resistance studies by expressing &gt;15,500 genes individually in a BRAFV600E melanoma cell line treated with RAF, MEK, ERK, or combined RAF/MEK inhibitors. These studies revealed a cyclic AMP-dependent melanocytic signaling network not previously associated with drug resistance, including G-protein coupled receptors, adenyl cyclase, protein kinase A and cAMP response element binding protein (CREB). In biopsies from BRAFV600E melanoma patients, phosphorylated (active) CREB was suppressed by RAF/MEK-inhibition but restored in relapsing tumors. Expression of transcription factors activated downstream of MAP kinase and cAMP pathways also conferred resistance, including c-FOS, NR4A1, NR4A2 and MITF. While direct small-molecule inhibition of transcription factors is a current challenge, MITF expression can be suppressed with histone deacetylase (HDAC) inhibitors. Combined treatment with MAP kinase pathway and a panel of HDAC inhibitors suppressed MITF expression and cAMP-mediated resistance. Collectively, these data suggest that oncogenic dysregulation of a melanocyte lineage dependency can cause resistance to RAF/MEK/ERK inhibition, which may be overcome by combining signaling- and chromatin-directed therapeutics.
This abstract is also presented as Poster B23.
Citation Format: Cory M. Johannessen, Laura A. Johnson, Federica Piccioni, Aisha Townes, Dennie T. Frederick, Keith T. Flaherty, Jennifer A. Wargo, David E. Root, Levi A. Garraway. A cyclic AMP-regulated melanocyte lineage program confers resistance to MAP kinase pathway inhibition. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr PR10.
Abstract A11: Modeling drug response and resistance using patient-derived xenograft models.
Authors: Yang Guizhi , Green John , Kowal Colleen , Cogan Shawn , Velazquez Roberto , Monahan John , Korn Joshua , Keen Nicholas , Williams Juliet , Gao Hui 
Published: August 2014

Abstract
Metastatic melanoma is a highly lethal type of cancer and is often refractory to all traditional chemotherapeutic agents. Melanoma is associated with a high burden of genetic alteration, e.g. BRAF, NRAS or NF1 mutation. In the clinic, BRAF inhibitors are used as a targeted therapy to treat melanoma patients, but thus far a single-agent approach is not capable of achieving a durable response for this lethal disease. Very often, patients rapidly develop resistance to BRAF inhibitors. In the current study, we propose a large scale in vivo screening using patient-derived xenograft models (PDXs) for compound profiling. Since these PDX melanoma models are derived from individual patient tumors and therefore represent the genetic heterogeneity of patient tumors, we propose a “one animal per model per compound” approach (mouse clinical trial) to understand the genetic factors that contribute to drug response. In addition, we use this approach to model drug resistance after long-term compound treatment. We find that the mouse clinical trial approach accurately predicts response of both cytotoxic chemotherapeutics as well as targeted therapies. In addition, this approach successfully recapitulates the resistance profile of a novel BRAF inhibitor LGX818 in melanoma. We also find that combination of LGX818 with other targeted therapy agents including PI3K and MEK inhibitors significantly increases the response rates and delays the development of resistance. Taken together, our findings suggest that the mouse clinical trial is a valid approach to model drug response and resistance, and can be used to predict patient response in the clinic.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A11.
Citation Format: Guizhi Yang, John Green, Colleen Kowal, Shawn Cogan, Roberto Velazquez, John Monahan, Joshua Korn, Nicholas Keen, Juliet Williams, Hui Gao. Modeling drug response and resistance using patient-derived xenograft models. [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 A11.
Abstract A171: Antitumor effects of intervenolin, a novel natural compound with anti-Helicobacter pylori activity, and its synthetic derivatives on gastric and colorectal cancer cells.
Authors: Kawada Manabu , Inoue Hiroyuki , Ohba Shun-ichi , Abe Hikaru , Hatano Masaki , Amemiya Masahide , Hayashi Chigusa , Usami Ihomi , Watanabe Takumi , Igarashi Masayuki , Masuda Tohru , Shibasaki Masakatsu , Nomoto Akio 
Published: August 2014

Abstract
Tumor tissues are composed of not only tumor cells but also the surrounding stroma. While the stroma consists of various kinds of cells, among them fibroblasts-like stromal cells can regulate the growth and metastasis of tumor cells positively or negatively. Thus, the modulation of the tumor-stromal cell interactions can be a new antitumor strategy. We have been searching compounds that modulate the interactions using coculture system of tumor cells and stromal cells. In the course of our screening, we have isolated a novel compound, intervenolin, from the culture broth of Nocardia sp. ML96-86F2. Intervenolin inhibits the growth of human gastric and colorectal cancer cell lines when cocultured with the respective organ-derived stromal cells more strongly than that of the cancer cells cultured alone. To improve low yield of intervenolin from the bacterial culture and to create more potent compounds, we have synthesized intervenolin and its derivatives. Some of the derivatives also show the same effect as intervenolin in vitro. Furthermore, intervenolin and its derivatives show antitumor effects against xenograft models of human gastric cancer cells and also MDR-expressing colorectal cancer cells in vivo. Furthermore, intervenolin and its derivatives exert selective anti-Helicobacter pylori activity. We are now investigating the mechanism of its action and trying to synthesize more potent its derivatives.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A171.
Citation Format: Manabu Kawada, Hiroyuki Inoue, Shun-ichi Ohba, Hikaru Abe, Masaki Hatano, Masahide Amemiya, Chigusa Hayashi, Ihomi Usami, Takumi Watanabe, Masayuki Igarashi, Tohru Masuda, Masakatsu Shibasaki, Akio Nomoto. Antitumor effects of intervenolin, a novel natural compound with anti-Helicobacter pylori activity, and its synthetic derivatives on gastric and colorectal 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 A171.
Abstract A177: Mode of action of PM060184, a new interfacial microtubule inhibitor of marine origin.
Authors: Martínez-Diez Marta , Martínez-Leal Juan Fernando , Garcia-Fernandez Luis F. , Galmarini Carlos M. 
Published: August 2014

Abstract
PM060184 belongs to a new family of tubulin-binding agents originally isolated from the marine sponge Lithoplocamia lithistoides. This compound is currently produced by total chemical synthesis and is under evaluation in Phase I clinical studies in patients with advanced cancer diseases. Recently published results indicate that members of the PM060184 family are interfacial microtubule inhibitors that bind with nanomolar affinity to unassembled αβ-tubulin dimers at the beta tubulin plus end (Pera et al. 2013, ACS Chem. Biol.) In an attempt to shed light into the mechanism responsible of its antitumor activity, we have studied the effects of PM060184 in tumor cells including microtubule network structure, centrosome modifications and type of cell death induced by this compound. PM060184 rapidly internalizes into the tumor cells and shows a high intracellular retention rate, reflecting the high avidity for its cellular target. In addition, the antitumor activity of the compound seems to be rather irreversible after short (30 min) exposure times. At the cellular level, PM060184 inhibits tubulin polymerization. Interestingly, PM060184 affects interphase cells, where the compound induces disorganisation and fragmentation of the microtubule network and disturbing cell migration. PM060184 also affects mitotic cells, inducing the appearance of multipolar mitosis and lagging chromosomes at the metaphase plate. All these effects correlate with prometaphase arrest and induction of caspase-dependent apoptosis or appearance of cells in a multinucleated interphase-like state unrelated to classical apoptosis pathways. In summary, these results indicate that PM060184 represents a new tubulin binding agent with promising potential as an anticancer agent.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A177.
Citation Format: Marta Martínez-Diez, Juan Fernando Martínez-Leal, Luis F. Garcia-Fernandez, Carlos M. Galmarini. Mode of action of PM060184, a new interfacial microtubule inhibitor of marine origin. [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 A177.
Abstract A193: Transmembrane protein TMEM92 as a novel target in prostate cancer.
Authors: Morgan Richard , Feng Gui , Pandha Hardev S. 
Published: August 2014

Abstract
TMEM92 is a previously uncharacterized gene predicted to encode a 159 amino acid peptide with a single transmembrane domain and sequence homology to the SHISA group of proteins, some of which have a role in early development. In this study we evaluated the expression and function of TMEM92 in prostate cancer. This gene is expressed in primary prostate tumors and the prostate cancer derived cell lines PC3, DU145 and LNCaP, both at the RNA and protein level. TMEM92 expression appears to be cancer specific, as it is not expressed in normal prostate tissue or in normal adult organs. It is also absent from the WPMY-1 cell line, which is derived from normal prostate epithelium. siRNA-mediated knockdown of TMEM92 in PC3 cells induces apoptosis, as does the treatment of these cells with an anti-TMEM92 antibody, whilst neither treatment is cytotoxic for WPMY-1 cells. Taken together these findings suggest that TMEM92 is a potential therapeutic target in prostate cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A193.
Citation Format: Richard Morgan, Gui Feng, Hardev S. Pandha. Transmembrane protein TMEM92 as a novel target in 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 A193.
Abstract A203: An in vitro tumor model to characterize tumor cell metabolism in heterogeneous complex microenvironments.
Authors: Rodenhizer Darren , Cojocari Dan , Wouters Bradley G. , McGuigan Alison P. 
Published: August 2014

Abstract
Tumor cells often exhibit altered metabolic behaviors that are influenced by the heterogeneity of the tumor microenvironment. This heterogeneity arises from the presence of multiple cell types, variable ECM compositions, and variable protein expression due to the presence of oxygen and nutrient gradients. Conventional methods of identifying tumor therapies fail to account for these metabolic variations in the context of a heterogeneous microenvironment. To address this shortfall, we have developed a layered, three-dimensional, heterogeneous tumor model that allows spatiotemporal metabolite collection on a timescale relevant for metabolomics profiling. SKOV-3 ovarian cancer cells were mixed with collagen and infiltrated into a scaffolding material to create a thin layer. Multiple layers were then stacked to make a thick section of tumor tissue which is then combined with a customized oxygen impermeable bioreactor. EF5 immunofluorescence was used to confirm the presence of an oxygen gradient and to quantify the spatial PO2 values, which mimic those found in solid tumors. Cell viability and nutrient, and drug distribution profiles were also characterized and profiles were found to resemble those found in spheroid culture and in vivo. Cellular response to hypoxia was confirmed through qPCR analysis of mRNA of hypoxia-inducible genes such as CA9 and CHOP, and with HIF1α staining. Our technology allows for the creation of complex, yet controlled tumor microenvironments while facilitating “snap shot” data acquisition, and will allow researchers to decouple the influence of heterogeneity on metabolic response in cancerous solid tumors.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A203.
Citation Format: Darren Rodenhizer, Dan Cojocari, Bradley G. Wouters, Alison P. McGuigan. An in vitro tumor model to characterize tumor cell metabolism in heterogeneous complex microenvironments. [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 A203.
Abstract A235: Anti-CSF-1R antibodies reduce tumor-associated macrophages and inhibit tumor growth in preclinical models.
Authors: Li Yanxia , Mathew Sneha , Wu Lan , Wang Ying , Persaud Kris , Burtrum Douglas , Balderes Paul , Surguladze David , Haurum John , Ludwig Dale , Doody Jacqueline 
Published: August 2014

Abstract
In cancer, increased infiltration of macrophages within and surrounding the tumor mass correlates with increased tumor invasiveness and growth. In addition, presence of tumor-associated macrophages (TAMs) has been shown to correlate with poor prognosis, particularly in breast, prostate, ovarian, and cervical cancer. TAM proliferation, differentiation, and survival is dependent on CSF-1R activation, a type III integral membrane tyrosine kinase receptor selectively expressed on cells of the mononuclear phagocyte lineage. Given that TAMs enhance tumor growth and that activation of the CSF-1R pathway is required for TAM function, an antibody against mouse CSF-1R was generated for proof-of-principle studies. CS7, a monoclonal anti-mouse CSF-1R antibody inhibited both CSF-1 and IL-34 binding to mouse CSF-1R, leading to inactivation of the receptor and downstream signaling molecules. In addition, CS7 prevented monocyte proliferation and macrophage differentiation with IC50s of 0.1 nM and 0.75 nM, respectively. In murine models of breast cancer using CSF-1-secreting MDA-MB-231, Hcc1954, 4T1 or EMT6 tumor cells, CS7 treatment led to a marked reduction in TAMs and an associated decrease in tumor growth. In contrast, breast tumor xenografts with CSF-1 non-secreting breast tumor cell lines JimT1 and MCF-7 had limited or no decrease in tumor volume following CS7 treatment. In prostate models, DU145 tumor cell line xenografts (CSF-1-secreting) but not PC3 (CSF-1 non-secreting) tumor growth was inhibited by CS7, recaptitulating the results seen with breast xenografts. Thus, in breast and prostate preclinical models, CSF-1 secretion by tumor cells is a prerequisite for sensitivity to anti-CSF-1R treatment. Taken together, targeting CSF-1R with a monoclonal antibody inhibits CSF-1R signaling via CSF-1 and IL-34, prevents monocytic to macrophage differentiation, and reduces tumor volume in preclinical models, validating CSF-1R as a target for therapeutic application in cancer.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A235.
Citation Format: Yanxia Li, Sneha Mathew, Lan Wu, Ying Wang, Kris Persaud, Douglas Burtrum, Paul Balderes, David Surguladze, John Haurum, Dale Ludwig, Jacqueline Doody. Anti-CSF-1R antibodies reduce tumor-associated macrophages and inhibit tumor growth in preclinical models. [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 A235.