bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract SY24-02: Improving radio-sensitivity in cervical cancer by targeting tumor metabolism
Authors: Schwarz Julie K. 
Published: August 2018

Abstract
Our group has previously shown that cervical cancers that take up large quantities of glucose, as defined by pretreatment 18F-fluoro-deoxy-glucose positron emission tomography (FDG-PET) imaging, are resistant to standard-of-care treatment (cisplatin plus concurrent pelvic irradiation). In this session, we will review the clinical evidence that supports this finding, and translational studies that support a connection between aberrant PI3K/AKT signaling and increased glucose uptake in tumors. We will then detail recent preclinical evidence that supports simultaneous inhibition of glycolysis and redox metabolism as an effective and safe alternative treatment strategy for highly glycolytic, radiation-resistant cervical cancers. Ongoing efforts to identify, characterize, and validate biomarkers to guide this strategy will be discussed.
Citation Format: Julie K. Schwarz. Improving radio-sensitivity in cervical cancer by targeting tumor metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY24-02.
Abstract SY28-01: Management of MAP kinase and apoptosis signaling thresholds by microRNAs
Authors: Derry W. Brent 
Published: August 2018

Abstract
An important problem in cancer biology is concerned with how apoptotic thresholds are established. Defective regulation of apoptosis can cause resistance to chemotherapeutic agents and radiation therapy, which highlights the need to resensitize these tumors to therapy. The apoptosis pathway was first elucidated in the roundworm Caenorhabditis elegans, and studies in this organism continue to uncover regulatory mechanisms that are also conserved in humans. By taking advantage of the powerful genetics, cell biology, and proteomics tools of C. elegans, we seek to understand how apoptotic signaling is fine-tuned in response to ionizing radiation (IR). Our work has uncovered a network of regulatory mechanisms, such as ubiquitin proteolysis and microRNAs, that control the levels of apoptotic proteins. I will discuss our recent efforts to understand how microRNA 35 (mir-35) antagonizes translation of the BH3-only protein EGL-1 and the Ras/MAPK effector NDK-1 in response to IR. EGL-1 is homologous to human PUMA and NDK-1 is the worm orthologue of human NME1 (NME/NM23 nucleoside diphosphate kinase 1), which has been shown to regulate MAPK signaling in both worms and human cells. mir-35 normally functions to buffer IR-induced apoptosis through its combinatorial effects on EGL-1 and NDK-1 translation. Ablation of mir-35, or mutations in the mir-35 binding sites in the 3'-untranslated region (3'UTR) of egl-1 and ndk-1, increase the levels of these proteins and cause hypersensitivity to IR-induced apoptosis. By targeting both the core apoptosis pathway and the MAPK cascade, we propose that mir-35 plays a key role in fine-tuning apoptotic signaling in order to protect healthy cells and ensure a rapid response to DNA-damaging agents. Given the high conservation in the organization of these pathways from C. elegans to human, manipulating microRNAs might help resensitize tumors that have developed resistance to radiation and/or chemotherapy.
Citation Format: W. Brent Derry. Management of MAP kinase and apoptosis signaling thresholds by microRNAs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY28-01.
Abstract SY35-01: Systematic approaches to identify cancer dependencies
Authors: Hahn William C. 
Published: August 2018

Abstract
We now have a draft view of the genetic alterations that occur in human cancer, and molecular profiling of cancers provides the means to identify therapeutic agents for some patients. However, the number of mutations found at low frequency, the molecular heterogeneity of most cancers, and the lack of therapeutic agents specific for many cancer drivers limit the application of precision medicine in many patients. To complement genome characterization studies, we have used genome-scale gain- and loss-of-function approaches to identify genes required for cell survival and transformation. Specifically, we have performed systematic studies to interrogate rare alleles found altered in cancer genomes and used advances in synthetic gene synthesis to prospectively interrogate all possible alleles of known cancer genes. In parallel, we have performed both genome-scale RNAi and CRISRP-Cas9 screens in more than 800 cancer cell lines to identify differentially essential genes and the context that specifies gene dependency. These studies allow us to define a global cancer dependencies map, which will help further operationalize precision cancer medicine.
Citation Format: William C. Hahn. Systematic approaches to identify cancer dependencies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY35-01.
Abstract SY37-03: Mitochondrial genetic contributions to metastatic efficiency
Authors: Welch Danny R. 
Published: August 2018

Abstract
Complex phenotypes, like tumorigenicity or metastasis, require coordinated expression of multiple genes. Additionally, the contributions of some of those genes can be affected by polymorphisms in the protein coding or regulatory sequences (PMID: 22257951). The pathobiology of metastasis remains poorly understood because both intrinsic (i.e., genetic) and extrinsic (i.e., tumor-microenvironment interactions) are involved. A growing body of data indicates demonstrate that there are underlying genetic components that govern the processes involved in cancer spread and colonization. To assess the contributions of mitochondrial genetics in metastasis, we created Mitochondrial Nuclear Exchange (MNX) mice by transferring an oocyte nucleus from strainx into an enucleated oocyte from strainy, and showed that mammary tumor formation and metastasis are regulated by inherited mitochondrial polymorphisms in an oncogenic driver-dependent manner (PMID: 26471915; PMID: 29070615). Since stromal compartments also possess changed mitochondria in the MNX mice, we hypothesized that mitochondrial polymorphisms in non-cancer cell compartments could exert effects on tumor formation and/or metastasis in addition to genetic (cell autonomous) changes. Syngeneic tumor cells were injected into MNX mice with the same nuclear, and therefore same MHC, background. Experimental metastasis was compared between wild-type and MNX mice (i.e., with same or different mtDNA backgrounds, respectively). E0771 mammary carcinoma and B16-F10 melanoma cells (both syngeneic to C57BL/6J), formed significantly (P&lt;0.01) more lung metastases in C57BL/6J-mtMNX(C3H/HeN). K1735-M2 melanoma cells (syngeneic to C3H/HeN) formed significantly (P&lt;0.05) fewer lung metastases in C3H/HeNmtMNXC57BL/6J. These results have been replicated ≥3 times using &gt;10 mice per experiment. C57BL/6J mitochondria confer resistance to metastasis in both cell autonomous and non-cell autonomous experiments. Basal metabolic and ROS differences comparing mouse embryonic fibroblasts isolated from wild-type and MNX mice are among mechanisms being explored. Differential gene expression occurred in tissues isolated from wild-type and MNX mice (PMID: 28663334). Additionally, altered immune and microbiota profiles have been observed. Together, our findings highlight striking influences that mitochondrial haplotypes can exert on tumorigenicity and metastasis via both intrinsic and extrinsic mechanisms.
Support: Susan G. Komen for the Cure (SAC11037), Natl Fndn Cancer Res. and CA168524.
Citation Format: Danny R. Welch. Mitochondrial genetic contributions to metastatic efficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY37-03.
Abstract SY40-01: In vivo genetic screens for genes that modulate tumor immunity
Authors: Haining W Nicholas 
Published: August 2018

Abstract
Despite the dramatic clinical success of cancer immunotherapy with PD-1 checkpoint blockade, most patients do not experience sustained clinical benefit from treatment, suggesting that additional therapeutic strategies are needed. To discover new immunotherapy targets, we developed a pooled, loss-of-function in vivo genetic screening approach using CRISPR/Cas9 genome editing in mouse transplantable tumors treated with vaccination and PD-1 checkpoint blockade. We tested 2,400 genes expressed by melanoma cells for those that synergize with or cause resistance to checkpoint blockade, and recovered the known immune evasion molecules, PD-L1 and CD47. Loss of function of genes required to sense interferon-γ caused resistance to immunotherapy. Deletion of Ptpn2, a pleotropic protein tyrosine phosphatase, improved response to immunotherapy. Cellular, biochemical, transcriptional, and genetic epistasis experiments demonstrated that loss of function of Ptpn2 sensitizes tumors to immunotherapy by enhancing interferon-γ-mediated effects on antigen presentation and growth suppression. Thus, strategies that increase interferon-γ sensing by tumor cells could improve the efficacy of immunotherapy. More generally, in vivo genetic screens in tumor models can identify new immunotherapy targets, model resistance mechanisms, and may accelerate the rational selection of combination immunotherapy.
Citation Format: W Nicholas Haining. In vivo genetic screens for genes that modulate tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY40-01.
Abstract SY43-01: Coordinated gene expression mediated by RNA modifications
Authors: Agami Reuven 
Published: August 2018

Abstract
Gene transcription and mRNA translation are two main pillars of gene expression. Due to the different timings, spots of action, and mechanisms of regulation, these processes are mainly regarded as distinct and generally uncoupled, despite serving a common purpose. We identified that the rate of transcription regulates the efficacy of translation. We show that RNA modification, in the form of N6-adenosine methylation (m6A), is co-transcriptional and depends on the dynamics of RNA transcription. Altogether, our study uncovered a general and widespread link between transcription and translation that is governed by epigenetic modification of mRNAs. We postulate that this mechanism will play a role in cancer-related processes.
Citation Format: Reuven Agami. Coordinated gene expression mediated by RNA modifications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY43-01.
Abstract A57: Antisense oligonucleotide therapeutics with receptor-targeted delivery in triple-negative breast cancer cells via microRNA blockade without passenger strand side effects
Authors: Jin Yuan-Yuan , Wickstrom Eric 
Published: August 2018

Abstract
Triple-negative breast cancer (TNBC) attacks &gt;40,000 young women annually in the US, and has no molecular targeted therapies. MicroRNAs drive many forms of cancer, and they modulate multiple gene pathways simultaneously. Highly expressed microRNA miR-17-5p is distinctive in TNBC and contributes to cancer cell survival. We hypothesized that reduction of miR-17-5p activity by delivering oligonucleotide-based antagomiRs specifically to breast cancer cells via receptor-mediated endocytosis would inhibit metastatic behavior of TNBC cells.
Using a luciferase reporter system harboring a miR-17-5p binding site in the 3′ untranslated region of the luciferase gene, we assessed the efficacy of various antagomiRs. Contrary to conventional wisdom, that only one of the two strands in a pre-miRNA duplex is active, such as miR-17-5p, we previously observed that a full-length miR-17-5p DNA-LNA blocker created additional off-target effects by mimicking miR-17-3p, implying that therapeutic microRNA blockers should be designed to avoid resemblance to the opposing strands. We designed guide strand specific blockers of miR-17-5p composed of gapmers with anionic backbone derivatives 2′-fluoro-arabino nucleic acid (FANA), and 2′-aminomethyl-bridged nucleic acid (NC-BNA). Since most breast cancer cells overexpress insulin-like growth factor receptor (IGF1R), a peptide derivative of the IGF1 was conjugated to anti-miR-17-5p antagomiRs to achieve breast cancer cell-specific delivery.
Our results showed that in multiple TNBC cell lines, the NC-BNA 15mers displayed high efficacy with sub-nM activity for miR-17-5p blockade and significant inhibition of cell growth. Anti-miR-17-5p-IGF1 peptide conjugate successfully inhibited miR-17-5p activity in the luciferase reporter system. We are further examining the effects of NC-BNA-peptides in multiple TNBC cell lines. Our study provides a good basis for the development of a new TNBC targeted therapy. Supported by Bound Therapeutics LLC. Conflict of interest: pending TJU PCT/US2015/015681 patent application licensed to Bound Therapeutics LLC.
Citation Format: Yuan-Yuan Jin, Eric Wickstrom. Antisense oligonucleotide therapeutics with receptor-targeted delivery in triple-negative breast cancer cells via microRNA blockade without passenger strand side effects [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A57.
Abstract B02: Intratumoral bidirectional transitions between epithelial and mesenchymal cells in triple-negative breast cancer
Authors: Yamamoto Mizuki , Inoue Jun-ichiro 
Published: August 2018

Abstract
Epithelial-mesenchymal transition (EMT) and its reverse process, MET, are crucial in cancer metastasis. EMT allows cancer cells to move to proximal blood vessels for intravasation. However, because EMT and MET processes are dynamic, mesenchymal cancer cells are likely to undergo MET to form metastatic foci and subsequently re-undergo EMT to restart the metastatic process. To elucidate such regulation, we chose HCC38, a human triple-negative breast cancer (TNBC) cell line, because HCC38 is composed of epithelial and mesenchymal populations. We purified epithelial and mesenchymal cells from Venus-labeled and unlabeled HCC38 and mixed them at various ratios to follow EMT and MET. Using this system, we demonstrate that the two populations significantly enhance the transition of cells from the other population to their own. In addition, knockdown of ZEB1 or SLUG significantly suppressed EMT but promoted partial MET. We also demonstrate that primary breast cancer cells underwent EMT. These changes were very similar to those observed in EMT in HCC38. Consequently, we propose HCC38 as a suitable model to analyze EMT-MET dynamics that could affect development of TNBC.
Citation Format: Mizuki Yamamoto, Jun-ichiro Inoue. Intratumoral bidirectional transitions between epithelial and mesenchymal cells in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B02.
Abstract B17: Activating AMPK signaling by SCT-1015 to suppress tumor growth on triple negative breast cancer cells
Authors: Su Jung-Chen , Huang Jui-Wen , Shiau Chung-Wai 
Published: August 2018

Abstract
AMPK (AMP-activated protein kinase) is one of the central regulators of cellular and organismal metabolism that has been linked to the regulation of tumor progression; however, its biologic functions and signaling cascades remain unclear. Recently, many AMPK activators, including metformin, phenformin, and nilotinib, have shown anticancer efficacy. Nilotinib is a small-molecule tyrosine kinase inhibitor approved for the treatment of imatinib-resistant chronic myelogenous leukemia (CML).
In our previous study, we found that nilotinib increased AMPK phosphorylation and led to autophagic cell death in human hepatocellular carcinoma (HCC) cells. To dissect the involvement of Bcr-Abl kinases in nilotinib-mediated cell death in human TNBC cells, we designed a series of new compounds, with structure similar to nilotinib but without hinge-binding activity in the ATP binding pocket of kinases.
In this work, we found one of the nilotinib analogues, SCT-1015, showed better efficacy on AMPK activation and cell death induction compared to nilotinib without inhibiting Bcr-Abl kinase in human TNBC cells. Moreover, we demonstrate that SCT-1015 increased AMPK phosphorylation and inhibited cell proliferation in TNBC. Importantly, SCT-1015 suppressed tumor growth in HCC1806 orthotopic mice model. Our study indicates that targeting AMPK signaling pathway may be a useful approach for the development of targeted agents for anti-breast cancer.
Citation Format: Jung-Chen Su, Jui-Wen Huang, Chung-Wai Shiau. Activating AMPK signaling by SCT-1015 to suppress tumor growth on triple negative breast cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B17.
Abstract B22: Inducing cell state transitions in triple-negative breast cancer (TNBC)
Authors: Loo Ser Yue , Toh Liping , Pathak Elina , Tan Wilson , Ma Siming , Yuan Ju , Periyasamy Giridharan , Torta Federico , Chan Jack , Tan Tira , Sim Yi Rong , Tan Veronique , Tan Benita , Madhukumar Preetha , Yong Wei Sean , Ong Kong Wee , Wong Chow Yin , Wenk Markus R. , Foo Roger , Yap Yoon-Sim , Lim Elaine , Tam Wai Leong 
Published: August 2018

Abstract
Triple-negative breast cancer (TNBC), as immunohistochemically defined by its estrogen receptor (ER)-negative, progesterone receptor (PR)-negative and human epidermal growth factor receptor-2 (HER2)-negative status, is an important subtype due to its biologically aggressive behavior and limited treatment options available. TNBC is associated with an overall poorer prognosis, with higher risk of disease recurrence/progression and shorter duration of treatment response, i.e., treatment resistance. Treatment resistance may be largely attributed to cancer stem cells (CSCs), which are intrinsically treatment resistant and continually self-renew, proliferate, and differentiate into different phenotypes. Activation of the cell biologic program, epithelial-mesenchymal transition (EMT), has been demonstrated to promote the dedifferentiation of heterogeneous subpopulations of cancer cells towards CSC phenotypes. We hypothesized that induction of the mesenchymal-epithelial transition (MET) program might disrupt CSC function, drive differentiation, and render greater susceptibility to conventional chemotherapy. In this study, we utilized high-throughput chemical-genetic screens to uncover a potent class of MET mediators. With the use of in vitro and in vivo models of TNBC, we showed that changing the malignant cell state to a differentiated phenotype by inducing MET reduced mammosphere formation, increased chemosensitivity, and decreased the tumor burden in NSG mice. Delving into the mechanisms of tumor differentiation via ChIP-seq, RNA-seq, and Gene Ontology analysis revealed differences in metabolic status between cell states, which might be exploited in the treatment of TNBC. We also assessed combinations of MET mediators, in order to increase the potency and durability of differentiation. Hence, this study assessed the role of differentiation in the treatment of TNBC and the efficacy of various MET mediators, singly and in combination, in inducing differentiation.
Citation Format: Ser Yue Loo, Liping Toh, Elina Pathak, Wilson Tan, Siming Ma, Ju Yuan, Giridharan Periyasamy, Federico Torta, Jack Chan, Tira Tan, Yi Rong Sim, Veronique Tan, Benita Tan, Preetha Madhukumar, Wei Sean Yong, Kong Wee Ong, Chow Yin Wong, Markus R. Wenk, Roger Foo, Yoon-Sim Yap, Elaine Lim, Wai Leong Tam. Inducing cell state transitions in triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B22.
Abstract B34: Novel synergistic combination therapies with BET bromodomain inhibitors in triple-negative breast cancer
Authors: Bevill Samantha M. , Sciaky Noah , Golitz Brian T. , Rashid Naim U. , Zawistowski Jon S. , Johnson Gary L. 
Published: August 2018

Abstract
Adaptive resistance to targeted cancer therapies is a universal problem in cancer treatment where tumor cells circumvent targeted pathway inhibition to reactivate growth signaling. In our previous work, we observed genome-wide enhancer remodeling following MEK inhibition (MEKi) capable of driving adaptive gene transcription in triple-negative breast cancer (TNBC). Adaptive enhancers were enriched for the BET bromodomain protein BRD4 and cotreatment with MEKi and BET inhibitor (JQ1) could durably suppress TNBC growth in multiple cell lines and preclinical mouse models. There are currently 10 BET inhibitors in clinical trials being tested as single agents across multiple tumor types including TNBC. There is also a growing body of preclinical literature using epigenetic inhibitors to block the adaptive ability of tumor cells in combination with multiple targeted therapies. This led us to screen for inhibitors that synergize with JQ1 to suppress growth of TNBC using a 176-compound library enriched for epigenetic and kinase inhibitors. We performed synergy screens in 6 TNBC cell lines across 6 doses of JQ1 and each library compound. Using the Bliss Independence model to assess synergy, we found that inhibition of MEK, CDK9, Aurora Kinase, CREBBP/P300, and BAZ2A/B was strongly synergistic with JQ1. BRD4, CDK9, and the acetyltransferase CREBBP/P300 are all members of the P-TEFb transcriptional elongation complex. When we performed additional synergy screens against the P300 bromodomain inhibitor CPI-637, we found a significant overlap in synergistic targets with the JQ1 screen including MEK, BET bromodomain proteins, ERK, Aurora Kinase, and CDK9. BAZ2A/B inhibition using the small-molecule inhibitor GSK2801, which targets the bromodomain of BAZ2A/B, synergized significantly stronger with JQ1 across all cell lines compared to CPI637. BAZ2A/B proteins are members of nucleosome remodeling complexes that mediate DNA silencing by aiding in recruitment of histone modifying enzymes. Ongoing studies seek to understand the role of BAZ2A/B and the mechanism of GSK2801 synergy with BET bromodomain inhibition using RNA sequencing and ChIP sequencing experiments. These results define novel targets that synergize with JQ1 to suppress tumor cell growth and illuminate additional mechanisms of transcriptional regulation driven by BET bromodomain proteins in TNBC.
Citation Format: Samantha M. Bevill, Noah Sciaky, Brian T. Golitz, Naim U. Rashid, Jon S. Zawistowski, Gary L. Johnson. Novel synergistic combination therapies with BET bromodomain inhibitors in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B34.