bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA11: Functionalization the cancer genome
Authors: Mills Gordon B. , Lu Yiling , Cheung Wai Ting , Scott Kenneth , Liang Han 
Published: August 2014

Abstract
As we begin to implement next-generation sequencing into patient care, a central challenge will involve determining which aberrations in a given tumor represent “drivers” that determine tumor behavior versus “passengers” resultant from the inherent instability of cancer genomes. Critically even within cancer genes, many aberrations could still be passengers. Indeed, given the broad landscape of aberrations in human tumors, it is possible that genomic aberrations in a cancer gene could be hypomorphs (decreasing activity of a tumor suppressor gene), hypermorphs (increasing activity of an oncogene) or neomorphs (changing function of the protein). Neomorphs such as those engendered by mutations in IDH1 in glioma could be particularly challenging as their therapeutics liabilities are not likely to be predictable from known functions of the wild-type protein. Targeting driver aberrations should improve outcomes for patients, while targeting passenger aberrations would be without benefit and may instead result in unnecessary toxicity and delay implementation of effective therapies. It will also be critical to select the drug or drugs most likely to benefit each patient based on underlying aberrations in their own tumor. Unfortunately, there is a complete lack of practical high-throughput platforms able to identify and select optimal therapies targeting driver aberrations.
We have implemented a high-throughput pipeline that consists of generation of patient tumor mutations in open reading frames (ORF) and determining the effect of shRNA, wild-type ORFs and mutant ORFs in the BAF3 IL3 dependent sensor line. Aberrations that increase cell viability and proliferation are established as stable lines. Stable lines are then probed with a chemical genomic library of tool compounds targeting critical pathways as well as through a high-throughput reverse phase protein array (RPPA) functional proteomics platform. The intersection of functional effects in the platforms identifies potential drivers and elicits their mechanistic activity and potential therapeutic liabilities. This pipeline has the potential to elicit tumor drivers and identify individualized therapeutic approaches.
Citation Format: Gordon B. Mills, Yiling Lu, Wai Ting Cheung, Kenneth Scott, Han Liang. Functionalization the cancer genome [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr IA11.
Abstract IA6: Genetic strategies for next generation of breast cancer therapies
Authors: Silva Jose M. 
Published: August 2014

Abstract
One of the major challenges for modern cancer treatments is the ability to eliminate tumor cells without affecting normal cell homeostasis. We propose to identify the “Achilles' heel” of cancer cells using the novel concept of the “noncancer addition.” Additionally to alterations in bona-fide cancer genes, in a tumor cell, multiple normal regulatory networks have been rearranged in order to adapt to the tumorigenic state. As consequence of this divergence, survival of cancer cells also depends on noncancer genes that are essential to maintain the tumor homeostasis. Therefore, we postulate that interfering with these noncancer dependencies will result in system failure, that is, the cessation of the tumorigenic state. We are combining the power of interactome-prediction models with the state-of-the-art RNAi-genetic approaches to block the function of every gene in the entire genome to find genetic synthetic lethal interactions between noncancer genes and bona-fide cancer genes.
Recently, we have applied this strategy searching for novel therapeutic alternatives for ErbB2 positive breast cancer patients. ErbB2 is a receptor tyrosine kinase found overexpressed in 20-40% of breast tumors (ErbB2+ tumors) and correlates with poor prognosis. Different targeted therapies have been developed to specifically inhibit its activity. Unfortunately, the majority of these patient tumors eventually progress acquiring resistance. Thus, there is the need to find alternative tumor targets to develop specific, more efficient, treatments for these patients.
By combining genome-wide RNAi loss-of-function screens with system biology interactome models we have recently found that the JAK/STAT3 pathway is activated in ErbB2 overexpressing breast cancers through an autocrine loop mediated by the secretion of Interleukin-6 (IL-6). Importantly, blockage of this pathway strongly reduced the viability of ErbB2+ cancer cells. The identification of Stat3 as a tumor target in ErbB2+ tumors opens new avenues for patients which tumors have become refractory to standard protocols.
Citation Format: Jose M. Silva. Genetic strategies for next generation of breast cancer therapies [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr IA6.
Abstract PR3: Considering alternate signaling mechanisms models in extrinsic apoptosis using programmatic modeling approaches
Authors: Lopez Carlos F. , Muhlich Jeremy L. , Bachman John J. , Sorger Peter K. 
Published: August 2014

Abstract
Experiments often result in observations that suggest conflicting biochemical mechanisms in signaling networks. Mathematical modeling of biological systems is a method used to probe such experimental observations and provide a consensus among seemingly discordant observations. However, probing multiple mechanistic hypotheses in biological modeling often involves the instantiation of complex systems of equations, which despite their usefulness, makes model revision, extension, and sharing extremely challenging. To address these modeling barriers, we have developed a modeling framework that brings a process-based approach to biological modeling. In our approach, biological models are written as programs that encode biological functions as needed. Our modeling framework, developed in the Python language, offers access to a large set of existing numerical and programming methods to biological systems modeling. Given our choice of programming language, the resulting models are easier to share, distribute, extend, and revise, adding transparency to the model-creation and execution process. We demonstrate our approach by exploring three competing mechanisms that describe the interactions among the Bcl-2 family of proteins and their contributions to mitochondrial outer membrane permeabilization in extrinsic apoptosis. We used our modeling framework to systematically explore these three proposed mechanisms resulting in the instantiation of sixteen biochemical model topologies for numerical exploration. Our preliminary results, based on simulations calibrated to experimental data, suggest that the so-called indirect mechanism does not accurately reproduce experimental observations. Results from simulations suggest that the so-called embedded model more seems to better align with existing experimental data. Despite these observations, further topology- and numerical-based characterization of the model topology and parameter-space is being carried out to more accurately understand the role of these Bcl-2 proteins in apoptosis. We aim to formulate hypotheses, testable through experiments, about the interaction among these proteins and their role in Bcl-2 cancer biology.
This proffered talk is also presented as Poster A9.
Citation Format: Carlos F. Lopez, Jeremy L. Muhlich, John J. Bachman, Peter K. Sorger. Considering alternate signaling mechanisms models in extrinsic apoptosis using programmatic modeling approaches [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr PR3.
Abstract PR9: Investigating combinatorial ligand addiction provides insights into rational drug combinations in cancer therapy
Authors: Pace Emily A. , Nielsen Ulrik B. , Schoeberl Birgit , Chai Diana H. , Parikh Anand , Kalra Ashish , Oyama Shinji , Johnson Bryan , Tan Gege , Fulgham Aaron , Bukhalid Raghida 
Published: August 2014

Abstract
Cancer, the second most common cause of death in the United States, is a collection of diseases caused by uncontrolled cell growth and metastasis. The main treatment for cancer is chemotherapy, which generally kills fast growing cells nonspecifically and has many side effects. A different type of cancer treatment, called targeted therapy, aims to avoid general toxicity by using drugs that block the activity of specific gene products, usually encoded by oncogenes, which have been shown to drive tumor growth. To date, targeted therapies, alone or in combination with chemotherapies, have mainly been successful in rare subsets of patients with tumors addicted to single oncogenes. This has created a rationale to mainly treat patients with an oncogene-addiction (such as those carrying mutated or overexpressed kinases) with targeted therapies like erlotinib and trastuzumab, which inhibit human epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2/ErbB2), respectively. Here, evidence is provided that targeted therapies are also effective in tumors that are dependent on multiple growth factors – a phenomenon that is called combinatorial ligand addiction. Specifically, it is shown that ligands that bind the EGFR family and the hepatocyte growth factor receptor (HGFR/MET) can activate protein kinase B (PKB/AKT) across a broad set of cancer cell lines, suggesting that ligand signaling is redundant and widespread. It is also shown that ErbB ligands have distinct signaling dynamics and strengths, which provides a rationale for investigating each component of the ErbB signaling network. Using a systematic approach, we found that ErbB3 is an important therapeutic target even though it is not overexpressed and lacks kinase activity. Furthermore, it is shown that cell lines with and without known oncogene-addiction express autocrine ligands and have improved growth inhibition with drug combinations that include autocrine ligand-blocking antibodies. This research demonstrates that combinatorial ligand addiction creates a new rationale for therapeutic combinations to improve efficacy and prevent resistance in cancer cells that are treated with current targeted drugs.
This proffered talk is also presented as Poster A22.
Citation Format: Emily A. Pace, Ulrik B. Nielsen, Birgit Schoeberl, Diana H. Chai, Anand Parikh, Ashish Kalra, Shinji Oyama, Bryan Johnson, Gege Tan, Aaron Fulgham, Raghida Bukhalid. Investigating combinatorial ligand addiction provides insights into rational drug combinations in cancer therapy [abstract]. In: Proceedings of the AACR Special Conference on Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations; 2012 Jun 27-30; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2012;72(13 Suppl):Abstract nr PR9.
Abstract A05: Phosphoinositide-3-kinase pathway promotes colon cancer stem cell proliferation
Authors: Chen Sugong , Fisher Robert C. , Shenoy Anitha K. , Lopez Maria Cecilia , Moldawer Lyle L. , Baker Henry V. , Huang Emina H. 
Published: August 2014

Abstract
Introduction. The cancer stem cell (CSC) model posits that a select cell-subpopulation exists in solid tumors that sustain tumorigenesis. Previously, we have shown that aldehyde-dehydrogenase (ALDH) enriches colon CSCs (CCSC) from sporadic colon cancer. In this study, Affymetrix microarray was used to screen for differences between ALDHhi and ALDHlo cells isolated from sporadic human colon adenocarcinoma. As a result, the phosphoinositide-3-kinase (PI3K) pathway was identified as a potential regulator of CCSC growth and differentiation. Functional assays demonstrate that inhibition of PI3K results in significant reduction in proliferation and colony formation of by CCSCs.
Experimental Procedures. Unbiased Expression-Profile Analysis: We implanted human CCSCs into flanks of NOD-SCID mice. Flow assisted cell sorting discriminated resulting tumor epithelia into ALDHhi and ALDHlo groups from 6 individual sporadic human adenocarcinomas, which were analyzed using Affymetrix GeneChip Human Genome U133 Plus 2.0 Array. Proliferation Assay: Bromodeoxyuridine (BrdU) incorporation measured the effect of LY294002 (Calbiochem) (1-100 μM) on proliferation. Colony Assay: Methylcellulose colony assays were used to assess the effect of LY294002 on colony formation.
Summary of Data. Expression Profile Analysis revealed 136 genes that were significantly up or down-regulated in the ALDHhi cell groups (&gt;3-fold; p&lt;0.001). The beta regulatory subunit of phosphoinositide-3 kinase demonstrated a 5.2 fold up-regulation in the ALDHhi vs. ALDHlo CCSCs. Cell Proliferation Assay: LY294002 significantly inhibits CCSC proliferation with IC50 ~ 50 μM and near complete inhibition at the dose of 100 μM (p&lt;0.001). Colony Assay: LY294002 significantly reduces total colony area formed by CCSCs, with a similar trend as shown in BrdU proliferation assays (p&lt;0.001).
Conclusions. We have previously shown that ALDH enriches colon cancer epithelia. Here we show that the PI3K signaling pathway is differentially expressed between ALDHhi and ALDHlo CCSCs derived from primary tumor xenografts. We demonstrate in vitro functional differences in CCSCs with drug-inhibition assays.
Citation Format: Sugong Chen, Robert C. Fisher, Anitha K. Shenoy, Maria Cecilia Lopez, Lyle L. Moldawer, Henry V. Baker, Emina H. Huang. Phosphoinositide-3-kinase pathway promotes colon cancer stem cell proliferation. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A05.
Abstract A14: Transforming growth factor beta signaling regulates the fate of intestinal stem cells
Authors: Fischer Jared M. , Miller Ashleigh , Calabrese Peter P. , Shibata Darryl , Liskay R Michael 
Published: August 2014

Abstract
Transforming growth factor beta signaling has important roles in stem cell behavior, differentiation, cell motility, cell cycle and apoptosis. Here, we have utilized a novel mouse model that facilitates the sporadic inactivation of TgfβR2 via frameshift reversion of Cre in single, isolated cells and concomitant lineage tracing with a Cre-reporter. Short-term lineage tracing of TgfβR2-deficient crypts revealed reduced expansion suggesting a growth disadvantage among crypts. In contrast, long-term lineage tracing of TgfβR2-deficient crypts revealed an increased number suggesting a growth advantage within the crypt. To reconcile these apparently contradictory findings, we studied the dynamics of proliferative, Lgr5+ stem cells following TgfβR2 loss. We found that TgfβR2-deficient stem cell lineages required more time to reach monoclonality within the crypt. Using mathematical modeling of stem cell neutral drift, we found that increased “stemness” or a greater probability of a self-renewing asymmetrical outcome for TgfβR2-deficient stem cells was more consistent with our experimental results. Further analysis of TgfβR2-deficient stem cells in vivo revealed a decreased production of Paneth cells, a finding we corroborated in cultured intestinal organoids by treating with either a TgfβR1/2 inhibitor or low levels of the Tgfβ1 ligand. Recent studies by others suggested that quiescent stem cells are intermediaries between proliferative Lgr5+ stem cells and Paneth cells and that Tgfβ signaling is important in the formation of quiescent stem cells in other tissues. Therefore, we are currently asking whether Tgfβ signaling is important in the formation of quiescent stem cells in the intestine.
Citation Format: Jared M. Fischer, Ashleigh Miller, Peter P. Calabrese, Darryl Shibata, R Michael Liskay. Transforming growth factor beta signaling regulates the fate of intestinal stem cells. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A14.
Abstract A15: A reciprocal feedback loop between grainyhead-like-2 and ZEB1 controls EMT and tumor suppression
Authors: Cieply Benjamin , Ford Heide L. , Farris Joshua , Frisch Steven 
Published: August 2014

Abstract
The oncogenic Epithelial-Mesenchymal Transition (EMT) enhances malignant progression by promoting invasion and survival of tumor cells. EMT is induced by microenvironmental factors including TGF-β and Wnt agonists, and transcription factors including the E-box binding factors Twist, Snail and ZEB. Previously, we reported that a member of the mammalian Grainyhead family of wound healing-regulatory transcription factors, Grainyhead-like-2 (GRHL2), suppresses EMT and restores sensitivity to anoikis by repressing ZEB1 expression and inhibiting TGF-β signaling. Here, we elucidate the functional relationship between GRHL2 and ZEB1 in EMT/MET and tumor biology. At least three homeodomain proteins, Six1, LBX1, and HoxA5, transactivated the ZEB1 promoter; for Six1, this occurred through direct protein-promoter interaction. GRHL2 altered the Six1-DNA complex, inhibiting this transactivation. Correspondingly, GRHL2 expression prevented tumor initiation in xenograft assays, sensitized breast cancer cells to paclitaxel, and suppressed the emergence of CD44highCD24low cells in a cell line where this marker set correlates with cancer stem cell phenotype. GRHL2 was down-regulated in recurrent mouse tumors that had evolved to an oncogene-independent, EMT-like state, supporting a role for GRHL2 down-regulation in this tumor phenotype transition modeling disease recurrence. The combination of TGF-β and Wnt activation repressed GRHL2 expression through direct interaction of ZEB1 with the GRHL2 promoter, inducing EMT. These observations indicate that a reciprocal feedback loop between GRHL2 and ZEB1 controls epithelial vs. mesenchymal phenotypes and EMT-driven tumor progression.
Citation Format: Benjamin Cieply, Heide L. Ford, Joshua Farris, Steven Frisch. A reciprocal feedback loop between grainyhead-like-2 and ZEB1 controls EMT and tumor suppression. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A15.
Abstract A33: Aneuploidy due to inhibition of Aurora B induces p21 through activation of p38 by proteotoxic stress and ROS
Authors: Kumari Geeta , Ulrich Tanja , Gaubatz Stefan 
Published: August 2014

Abstract
Faithful transmission of genomic information to the two daughter cells requires highly coordinated cell cycle regulation. Aurora kinases have been implicated in mediating critical events during mitosis and cytokinesis. Aurora B is the enzymatic component of the chromosome passenger complex (CPC) which shows a characteristic localization during various phases of mitosis. Both the expression level and kinase activity of Aurora B is upregulated in several primary tumors including breast cancer and colon cancer and is associated with poor prognosis. Therefore, Aurora B is an attractive anti-cancer target and several chemical inhibitors of Aurora B are already in clinical trials. Inhibition of Aurora B results in cell cycle arrest. However, the signaling pathways responsible for the phenotypes observed after Aurora B inhibition have not yet been fully explored. We have recently shown that the p53 target gene p21 (CDKN1A) is activated both at protein and mRNA levels after pharmacological inhibition of Aurora B and that p21-activation is dependent on p53 and on the p38 MAP kinase. While the stabilization of p53 and its recruitment to the p21 promoter occur independently of p38, transcriptional elongation of p21 depends on active p38 after Aurora B is inhibited. We further show that partial inhibition of Aurora B is sufficient to induce p21. FISH (Fluorescence in-situ hybridization) assays indicate increased aneuploidy without inhibition of cytokinesis when Aurora B is partially inhibited. Increased aneuploidy is correlated with generation of reactive oxygen species (ROS) and proteotoxic stress, but not with DNA damage. In summary, our data suggest that aneuploidy due to partial inhibition of Aurora B results in proteotoxic stress and in the production of ROS, which contributes to the induction of p21 through activation of p38 MAPK. Significantly, Aurora B inhibitors and drugs that act on aneuploid cells (AICAR and 17AAG) synergize in the inhibition of cell proliferation and in inhibition of transformation. Thus, combining Aurora B inhibitors with drugs that act on aneuploid cells may result in a more effective cancer therapy than Aurora B inhibitors alone.
Note: This abstract was not presented at the conference.
Citation Format: Geeta Kumari, Tanja Ulrich, Stefan Gaubatz. Aneuploidy due to inhibition of Aurora B induces p21 through activation of p38 by proteotoxic stress and ROS. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A33.