bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A09: Induced aggravation of oxidative DNA damage as a targeted synthetic lethal approach in mismatch repair-deficient tumors
Authors: Fontebasso Yari , Lord Christopher J. , Ashworth Alan 
Published: August 2014

Abstract
The post-replicative DNA mismatch repair (MMR) pathway plays a key role in the maintenance of genomic stability. MMR corrects mismatches within the DNA helix that arise due to errors in nucleotide incorporation during either semi-conservative replication or synthesis associated with DNA repair. The importance of this system is testified by the fact that mutations affecting components of this repair pathway cause a “mutator” phenotype and predisposition to a wide variety of malignancies including colorectal, gastric, endometrial, and urothelial cancers. For example, the hereditable disorder Lynch syndrome (hereditary nonpolyposis colon cancer) is associated with germline loss of function mutations in the MMR tumor suppressor genes MLH1, MSH2, PMS2 and MSH6. In addition to this familial syndrome, MMR deficiency is present in 15% to 17% of all colorectal cancer cases and a common cause of nonfamilial MMR deficiency is biallelic hypermethylation of the MLH1 promoter that results in a reduction of MLH1 expression.
Synthetic lethal relationships have been identified that involve specific MMR genes, suggesting that the synthetic lethal paradigm could be applied to MMR deficiency. Previously, efforts to functionally identify genetic DNA mismatch repair synthetic lethalities and potential therapeutic targets have focused on the analysis of either candidate genes or relatively small gene subsets such as protein kinases. In order to define additional SL targets in MMR-deficient genetic backgrounds, we describe here the application of an shRNA screen in matched isogenic dMMR/pMMR (MMR-deficient/MMR-proficient) model cell lines. Using this screening approach, we identify new synthetic lethal interactions between MMR deficiency and components of the base excision repair and of the nucleotide sanitization systems. We propose that selective aggravation of oxidative damage constitutes a promising therapeutic approach in mismatch repair - deficient cancer cells.
Citation Format: Yari Fontebasso, Christopher J. Lord, Alan Ashworth. Induced aggravation of oxidative DNA damage as a targeted synthetic lethal approach in mismatch repair-deficient tumors. [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 A09.
Abstract A13: Identification of evolutionarily conserved genetic interactions in DNA mismatch repair
Authors: Tosti Elena , Katakowski Joseph A. , Schaetzlein Sonja , Kim Hyun-Soo , Ryan Colm J. , Shales Michael , Roguev Assen , Krogan Nevan J. , Palliser Deborah , Keogh Michael-Christopher , Edelmann Winfried 
Published: August 2014

Abstract
The DNA mismatch repair (MMR) system is responsible for correcting base substitution and insertion-deletion mutations (IDLs) generated during erroneous replication in bacteria, yeast and mammals. MMR complexes also recognize damaged-base mispairs resulting from environmental exposure to DNA damaging agents. The loss of MMR causes a “mutator” phenotype, resulting in the genome-wide accumulation of mutations, and is the underlying cause for Hereditary Non-polyposis Colorectal Cancer / Lynch Syndrome (HNPCC/LS) and a significant proportion of sporadic colorectal cancer (CRC). MMR-deficient tumors also display resistance to DNA damaging agents and, as a consequence, are resistant to a variety of commonly chemotherapeutic agents. Thus, the development of novel therapeutic strategies that more efficiently target MMR-deficient cancer cells would be highly desirable. A promising new direction to identify potential targets for anticancer treatment is the harnessing of synthetic lethality. Here, we have identified conserved synthetic lethal / sick genetic interactions (GIs) for MMR factors between two distant yeast species, S. pombe and S. cerevisiae. We have confirmed several of these negative GIs in mammalian cells, indicating that they are evolutionarily conserved. Specifically, we have identified a negative genetic relationship between Msh2, a major MMR component mutated in colorectal cancer, and Senp6 protease, which regulates the SUMOylation of a range of genome maintenance proteins. Our findings suggest that Senp6 is a promising new target for the treatment of MMR-deficient CRCs.
Citation Format: Elena Tosti, Joseph A. Katakowski, Sonja Schaetzlein, Hyun-Soo Kim, Colm J. Ryan, Michael Shales, Assen Roguev, Nevan J. Krogan, Deborah Palliser, Michael-Christopher Keogh, Winfried Edelmann. Identification of evolutionarily conserved genetic interactions in DNA mismatch repair. [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 A13.
Abstract A26: Cross-species analysis of genome-wide regulatory models elucidates master regulators of prostate cancer progression and treatment response
Authors: Mitrofanova Antonina , Aytes Alvaro , Lefebvre Celine , Shen Michael , Abate-Shen Cory , Califano Andrea 
Published: August 2014

Abstract
The study of cancer therapeutics in mouse models is impaired by our limited understanding of whether the regulatory mechanisms that mediate their activity are conserved in human patients. To address this limitation, we have constructed a mouse prostate cancer regulatory model (interactome) based on in vivo drug-based perturbations of 15 transgenic models of prostate cancer as well as a human interactome from a large-scale set of molecular profiles of patient derived tissue. For the mouse interactome, we performed molecular perturbations by treatment with small molecules, including inhibitors of the androgen receptor, tyrosine kinase receptors, MAPK, Akt/mTOR, JAK/STAT, and NF-KB signaling pathways as well as several chemotherapeutic agents. We then used a cross-species analysis to independently identify and match master regulators of cancer progression with the therapeutic compounds that optimally abrogate their activity both in the human and in the mouse regulatory models. Cross-species interactome interrogation represents a new paradigm for ‘human to mouse to human’ (H2M2H) analyses, aimed at maximizing translational potential. By interrogating our regulatory models using molecular profiles of cancer progression, we identified two genes, FOXM1 and CENP-F, that are synergistically required for the maintenance of aggressive, metastatic prostate tumors and are predictive of clinical outcome. Indeed, lentivirus mediated shRNA co-silencing of these master regulators dramatically decreases tumorigenesis in vivo. Interrogation of these interactomes using small molecule signatures further identified candidate combinations that successfully abrogate the activity of the FOXM1/CENPF axis in metastatic prostate cancer GEM models, and significantly reduce tumor and metastatic burden in vivo, thus improving survival significantly over standard of care chemotherapy. Our findings suggest that simultaneous targeting of FOXM1 and CENPF may be especially beneficial in patients who have failed conventional chemotherapy.
Citation Format: Antonina Mitrofanova, Alvaro Aytes, Celine Lefebvre, Michael Shen, Cory Abate-Shen, Andrea Califano. Cross-species analysis of genome-wide regulatory models elucidates master regulators of prostate cancer progression and treatment response. [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 A26.
Abstract A39: Quantitative FRET technology for SUMOylation cascade and high-throughput screening assay for SUMOylation inhibitor in cancer drug discovery
Authors: Liao Jiayu , Wiryawan Hilda , Song Yang , Liu Yan , Jiang Ling , Malik Harbani Kaur , Saaredra Amanda N. 
Published: August 2014

Abstract
The ubiquitin—proteasome system and ubiquitin-like protein pathways, such as SUMOylation, are critical in protein homeostasis and activities in vivo and are emerging as a new strategy to treat many acute and chronic human diseases, such as cancers. Although various kinase inhibitors have been developed as target-based therapy, solid tumors are still challenges in clinical therapy because various resistant are developed after kinase inhibitor treatments, and therapeutic agents with novel mechanisms are urgently needed. SUMO has been shown to modify various critical proteins, such as p53, MDM2, Estrogen receptor and androgen receptors. More recently, a genome-wide siRNA screening shown that inhibition of SUMO E1 ligases can lead to synergistically lethality of c-Myc overexpressed breast cancer cells. However, so far, specific inhibitor of SUMOylation is still not available for the scientific or pharmaceutical communities.
We developed a novel quantitative Förster resonance energy transfer (FRET) technology platform for both basic kinetics parameter determinations and high-through screening (HTS) assays for SUMOylation cascade. The novel theoretical and experimental procedures for protein interactions affinity (Kd) determinations in the SUMOylation cascade, including the interaction between SUMO1 and its E2 ligase, Ubc9, E1 heterodimers(Aos1 and Uba2), E1 and E2 interactions(Uba2 and Ubc9), and E2 and substrate interactions(Ubc9 and RanGap1c) and protease kinetics, Kcat/KM of SENP1 endopeptidase activity have been developed in a systems biology manner. The data are in good agreement with traditional methods. Multiple FRET-based HTS assays have also been developed and HTS campaigns have led to very promising hit that can preferentially kill Non-small cell lung cancer cells. The novel SUMOylation inhibitor can be used for cancer treatments by synergistically lethality strategy.
Note: This abstract was not presented at the conference.
Citation Format: Jiayu Liao, Hilda Wiryawan, Yang Song, Yan Liu, Ling Jiang, Harbani Kaur Malik, Amanda N. Saaredra. Quantitative FRET technology for SUMOylation cascade and high-throughput screening assay for SUMOylation inhibitor in cancer drug discovery. [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 A39.
Abstract B10: ER stress protein GRP78 as a therapeutic target combined with antiangiogenic therapy in renal cell carcinoma
Authors: Han Kyung Seok , Li Na , Li Estelle , Ladan Fazli , Martin Gleave , So Alan 
Published: August 2014

Abstract
Background: Antiangiogenic therapy deprives oxygen and nutrition from the tumor. These stress conditions cause unfolded or misfolded proteins in tumor cells. Glucose regulated protein 78 (GRP78) binds to unfolded proteins and dissociates from the membrane-bound ER stress sensors. Dissociation of GRP78 from these stress sensors allows their subsequent activation which suppresses global mRNA translation to protect cells from excessive unfolded proteins. We investigated a potential role of GRP78 as a combined therapeutic target in renal cell carcinoma treated with antiangiogenic therapy.
Methods: Renal cell carcinoma cells (Caki-1, Caki-2, UMRC-3 and UMRC-6) were used to investigate the effect of GRP78 knockdown, which was performed by small interfering RNA. Caki-1 xenografts were developed and treated with sunitinib 40mg/kg/day to evaluate in vivo expression of GRP78 during antiangiogenic therapy. Caki-1 cells stably overexpressing GRP78 were developed to investigate the role of GRP78 in cancer cell. Hypoxic stress was induced by 1% hypoxia chamber and hypoglycaemic stress was induced by glucose-free media. Downstream signalling pathways of GRP78 were evaluated by Western blots.
Results: In vitro hypoxia and/or glucose deprivation induced GRP78 upregulation in Caki-1 cells. GRP78 was also induced in Caki-1 xenografts treated by sunitinib. Overexpression of GRP78 increased tumor proliferation in hypoxic and/or hypoglycemic stresses by activating PERK/eIF2α pathway and protected tumor cells from stress-induced apoptosis. Knockdown of GRP78 using small interference RNA inhibited cancer cell survival and induced apoptosis in renal cell carcinoma cells in vitro. GRP78 knockdown also sensitized renal cell carcinoma cells to ER stress-induced apoptosis and hypoxic and hypoplycemic stress-induces apoptosis.
Conclusions: Antiangiogenic therapy induces ER stress by depriving oxygen and glucose from renal cell carcinoma. ER protein GRP78 has a critical role in protecting renal cell carcinoma cells from hypoxic and hypoglycemic stress induced by antiangiogenic therapy. Knockdown of GRP78 sensitizes RCC cells to apoptotic cell death from anti-angiogenic stresses. Our results suggest that GRP78 is a novel therapeutic target in renal cell carcinoma management.
Citation Format: Kyung Seok Han, Na Li, Estelle Li, Fazli Ladan, Gleave Martin, Alan So. ER stress protein GRP78 as a therapeutic target combined with antiangiogenic therapy in renal cell carcinoma. [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 B10.
Abstract B28: Screening for kinase dependencies in HPV-associated cancer
Authors: Fenton Tim , Brough Rachel , Williams Luke , Bajrami Ilirjana , Ashworth Alan , Lord Chris , Boshoff Chris 
Published: August 2014

Abstract
Human papillomavirus (HPV) is the primary causative agent in cervical cancer, a number of other anogenital cancers and a growing subset of head and neck squamous cell carcinomas (HNSCC). HPV-driven tumour cells exhibit a dependence upon the continued expression of two viral oncogenes, E6 and E7, which act primarily by promoting degradation of the p53 and pRb tumour suppressors. While pharmacological targeting of E6 and E7 has proven difficult, we hypothesized that tumour cells expressing these oncogenes may in turn become dependent upon the activity of specific cellular proteins. Since protein kinases have proven readily targetable using small molecule drugs, we screened a kinome-wide siRNA library against a panel of HPV-negative and HPV-positive HNSCC and cervical cancer cell lines to identify kinases specifically required in HPV-positive cancer cells.
Citation Format: Tim Fenton, Rachel Brough, Luke Williams, Ilirjana Bajrami, Alan Ashworth, Chris Lord, Chris Boshoff. Screening for kinase dependencies in HPV-associated 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 B28.
Abstract B38: Targeting FOXM1 in multiple myeloma
Authors: Tompkins Van S. , Gu Zhimin , Xu Hongwei , Tricot Guido , Zhan Fenghuang , Janz Siegfried 
Published: August 2014

Abstract
Unprecedented progress in our understanding of the biologic and molecular genetic underpinnings of multiple myeloma (MM) has recently led to the development of novel targeted therapeutic agents, including proteasome inhibitors, immunomodulatory drugs, CS1-binging antibody, and histone deacetylase inhibitors, which have produced tangible, evidence-based benefits for patients with MM. Nonetheless, the overall outcome remains grim, due in large part to limitations in treating high-risk MM. We recently determined that the level of FOXM1 mRNA expression is of prognostic significance for myeloma patients, as both event-free survival and overall survival were reduced in cases exhibiting high FOXM1 expression. Forty-six of 351 myeloma patients (13.1%) had elevated FOXM1 message, with the majority (29/46, 63%) residing in the MAF/MAFB and proliferation high-risk molecular subgroups. Upregulation of FOXM1 was also observed in patients deemed high-risk using the 70-gene signature as a metric. These results suggest that upregulation of FOXM1 is a feature of high-risk MM, leading to the hypothesis that up-regulation of FOXM1 contributes to increased MM aggressiveness. To evaluate whether targeting FOXM1 results in reduced growth and survival of myeloma cells, MM cell lines exhibiting high levels of FOXM1 were found to have low micromolar sensitivity to treatment with thiostrepton or siomycin A — two thiazole antibiotics known to inhibit FOXM1 activity. Because of known off-target effects of these inhibitors, we are confirming the results using short-hairpin RNA. Our data suggest that developing effective therapeutic strategies against high-risk MM should include consideration of FOXM1 as a new target.
Citation Format: Van S. Tompkins, Zhimin Gu, Hongwei Xu, Guido Tricot, Fenghuang Zhan, Siegfried Janz. Targeting FOXM1 in multiple myeloma. [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 B38.
Abstract IA21: Oncogenomic-dependent vulnerabilities in lung adenocarcinoma
Authors: White Michael A. 
Published: August 2014

Abstract
Diversity in the genetic lesions that drive cancer initiation and progression is extreme. This diversity exists not only among tumors from different patients, but also among cancer cells within the same patient. This nefarious complexity is, in large measure, responsible for the capacity of this disease to evade current best efforts for effective therapy. “Personalized medicine” has been proposed in response to this conundrum as a mechanism to tailor cancer treatment to a specific tumor's genetic and epigenetic characteristics. However, selection of appropriate treatment is dramatically limited by the paucity of appropriate drugs and by the difficulty of linking treatment options to the appropriate patients. The challenge is to identify authentic intervention targets for development of an appropriately diverse cohort of therapies to contend with disease heterogeneity. We are addressing this challenge by a focused investigation of common vulnerabilities that arise as a consequence of oncogene expression and tumor evolution. Here we will describe a cancer intervention discovery pipeline using parallel genetic and chemical perturbations within an extensive panel of cell lines representative of the molecular lesions detected in lung cancer by national and international cancer genome sequencing efforts. We have found that current first line targeted therapies are discoverable within this panel together with the enrollment biomarkers required to stratify patient treatment regimens. Further, we have found that new genetic and chemical vulnerabilities can be revealed that are linked to recurrent mutations in lung cancer patients that are not currently “actionable.” We are leveraging this approach to stratify lung cancer subtypes and elaborate intervention targets that are linked to those subtypes by robust molecular discriminators.
Citation Format: Michael A. White. Oncogenomic-dependent vulnerabilities in lung adenocarcinoma. [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 IA21.
Abstract IA4: Synthetic lethal screens in Drosophila
Authors: Perrimon Norbert 
Published: August 2014

Abstract
During development and homeostasis, cells integrate numerous signals that are either systemic or produced by neighboring cells, informing them of the state of the organism, tissues, and neighboring cells. How cells integrate and interpret these various signals is one of the major focuses of our laboratory. We are particularly interested in identifying nodes of signaling networks that allow the crosstalk between canonical pathways and to study the dynamics of signal integration. I will discuss our current studies on the crosstalk between Insulin and Hippo networks and present our approach using mutant cell lines generated with TALENs to perform synthetic lethal screens. Further, I will present both cell lines and in vivo studies in Drosophila gut stem cells aimed to study the dynamics of signaling pathways activation.
Citation Format: Norbert Perrimon. Synthetic lethal screens in Drosophila. [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 IA4.
Abstract IA5: Functional genomics and synthetic lethality
Authors: Hahn William C. 
Published: August 2014

Abstract
Recent advances in genomics now make it possible to consider enumerating all of the genetic lesions in specific cancers. While these approaches will yield critical information regarding the identify, number, and types of alterations found in human tumors, a complementary approach to decipher the molecular basis of malignant transformation depends upon the application of genome scale tools to annotate the function of genes involved in cancer initiation and progression. The integration of such functional approaches with on-going efforts to identify and enumerate genetic alterations in human tumors will provide a path to discover and validate cancer vulnerabilities. Many commonly occurring and well-validated oncogenes and tumor suppressor genes remain refractory to molecularly targeted therapies. We have used systematic loss and gain of function approaches to identify cancer vulnerabilities in the context of oncogenes and tumor suppressor genes. Specifically, we have launched Project Achilles to systematically identify essential genes in more than 500 cancer cell lines that have been characterized genomically. These studies have provided new insights into genes dependent in cancers that express specific oncogenes, loss of genetic elements and in cancers in which particular signaling pathways are activated. Taken together, these studies suggest that combining forward and reverse genetic approaches with information derived from the cancer genome characterization projects provides a path toward a comprehensive understanding of genes involved in cancer.
Citation Format: William C. Hahn. Functional genomics and synthetic lethality. [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 IA5.