bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA27: A novel cancer-testis antigen protein microarray for autoimmune profiling in cancers: Diagnosis, stratification, and treatment monitoring
Authors: Blackburn Jonathan 
Published: December 2017

Abstract
The cancer-testis antigens are a group of unrelated proteins aberrantly expressed in various cancers in adult somatic tissues. This aberrant expression can trigger spontaneous immune responses, a phenomenon exploited for the development of disease markers and therapeutic vaccines. However, expression levels often vary amongst patients presenting the same cancer type, and these antigens are therefore unlikely to be individually viable as diagnostic or prognostic markers. Nevertheless, patterns of antigen expression may provide correlates of specific cancer types and disease progression. This paper will describe the development and application of a novel, readily customizable cancer-testis antigen microarray platform, together with robust bioinformatics tools, which enable quantification of anti-cancer-testis antigen autoantibody profiles in patient sera. By exploiting the high affinity between autoantibodies and tumor antigens, our highly multiplexed protein microarray platform gives linearity of response over 4 orders of magnitude and an autoantibody quantitation limit in the pg/mL range.
By using oriented attachment of folded, recombinant antigens and a polyethylene glycol microarray surface coating, our platform gives minimal non-specific antibody binding. Unlike other proteomics methods, which typically use lower affinity interactions between monoclonal antibodies and tumor antigens for detection, the high sensitivity and specificity realized using our autoantibody-based approach may facilitate the development of better cancer biomarkers, as well as potentially enabling pre-symptomatic diagnosis. We will illustrate the usage of our platform by monitoring the time-dependent response of melanoma patient cohorts to an experimental therapeutic NY-ESO-1-based cancer vaccine, to combination BRAF and MEK inhibitor treatment, and to anti-CTLA4/anti-PD1 vaccination.
Citation Format: Jonathan Blackburn. A novel cancer-testis antigen protein microarray for autoimmune profiling in cancers: Diagnosis, stratification, and treatment monitoring [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA27.
Abstract IA38: Viral cancers: The forgotten culprits in the African cancer problem
Authors: Moore Patrick S. 
Published: December 2017

Abstract
Infection is responsible for approximately one-fifth of cancer cases worldwide. Causes and rates of cancer vary dramatically throughout the world. While infection is often overlooked as a cancer cause in the United States and Europe, it is often the main driving force for cancer in other parts of the world. The first human cancer virus discovered, Epstein-Barr virus (EBV), was isolated from a Ugandan Burkitt lymphoma in 1964. Infectious cancers including hepatocellular carcinoma, cervical carcinoma, Kaposi's sarcoma and gastric carcinoma represent the majority of cancer cases among men and women in some world regions, particularly in Africa. This lecture will focus on how new cancer viruses can be discovered, using Kaposi sarcoma herpesvirus and Merkel cell polyomavirus found in our lab as examples. The common characteristics--as well as the diverse nature--of viral cancers will be described. The extraordinary public health success of vaccines in preventing cancers of particular importance in Africa will be highlighted, and missed opportunities for low-cost, effective prevention and treatment of infectious cancers will be discussed. As with discovery of EBV, it is quite possible that the next cancer agent will be discovered in cancers unique to African countries but will have important implications to public health throughout the world.
Citation Format: Patrick S. Moore. Viral cancers: The forgotten culprits in the African cancer problem [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA38.
Abstract IA6: Lgr5 stem cell-based organoids in human disease
Authors: Clevers Hans 
Published: December 2017

Abstract
The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We originally defined Lgr5 as a Wnt target gene, transcribed in colon cancer cells. Two knock-in alleles revealed exclusive expression of Lgr5 in cycling, columnar cells at the crypt base. Using lineage tracing experiments in adult mice, we found that these Lgr5+ve crypt base columnar cells (CBC) generated all epithelial lineages throughout life, implying that they represent the stem cell of the small intestine and colon. Lgr5 was subsequently found to represent an exquisitely specific and almost ‘generic’ marker for stem cells, including in hair follicles, kidney, liver, mammary gland, inner ear tongue and stomach epithelium.
Single sorted Lgr5+ve stem cells can initiate ever-expanding crypt-villus organoids, or so called ‘mini-guts’ in 3D culture. The technology is based on the observation that Lgr5 is the receptor for a potent stem cell growth factor, R-spondin. Similar 3D cultures systems have been developed for the Lgr5+ve stem cells of human stomach, liver, pancreas, prostate and kidney. Using CRISPR/Cas9 technology, genes can be efficiently modified in organoids of various origins.
Citation Format: Hans Clevers. Lgr5 stem cell-based organoids in human disease [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA6.
Abstract A20: Depletion of replication factor MCM7 is synthetically lethal to oncogenic KRAS expression
Authors: Gastl Bastian , Klotz-Noack Kathleen , Klinger Bertram , Zuber Johannes , Blüthgen Nils , Schäfer Reinhold , Sers Christine 
Published: December 2017

Abstract
Colorectal cancer (CRC) is a substantial cause of death in the western world. With KRAS being one of the most frequently altered oncogenes in CRC, it is an obvious target for cancer therapy. But despite enormous efforts over the past three decades to target mutated RAS, not a single drug has made it to the clinic.
In order to find vulnerabilities of KRAS mutant cells, we performed a shRNA-based screen. We used CaCo2 cells (wild type for KRAS/BRAF/PIK3CA) with doxycycline (DOX) inducible expression of the oncogenic KRASG12V as a model system. The custom-designed shRNA library comprised 121 selected genes encoding signaling proteins and transcription factors, which we have previously identified to be strongly up- or downregulated after treatment with MEK inhibitors.
We found that CaCo2 cells expressing KRASG12V are highly sensitive to the depletion of the DNA replication licensing factor Minichromosome Maintenance Complex Component 7 (MCM7), whereas wild-type CaCo2 cells are resistant to MCM7 depletion. The screening result was verified with 3 independent shRNAs under anchorage dependent and independent conditions. Similar results were obtained with NRASG12D and in DLD1 (KRASwt/KRASG13D) and DLD1 (KRASwt/-) cells.
The proposed molecular mechanism is RAS-induced genotoxic stress that cannot be resolved after MCM7 reduction. MCM7-containing complexes prime DNA for replication by binding to replication origins. However, only a few of the licensed origins are later used for DNA replication, while most origins stay dormant. The dormant origins are essential for resolving stalled replication forks after replicative stress. Unresolved stalled forks lead to DNA damage, which drives the cell into apoptosis. Further experiments will show the extent of DNA damage upon RAS induction and knock down of MCM7.
Since DNA replication licensing is only required in actively dividing cells and cells with physiological RAS signaling seem to be resistant to partial depletion of MCM7, it might be an ideal target for treating RAS mutated cancers.
Citation Format: Bastian Gastl, Kathleen Klotz-Noack, Bertram Klinger, Johannes Zuber, Nils Blüthgen, Reinhold Schäfer, Christine Sers. Depletion of replication factor MCM7 is synthetically lethal to oncogenic KRAS expression [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A20.
Abstract A30: Identifying microenvironment-dependent vulnerabilities in multiple myeloma using CRISPRi
Authors: Ramkumar Poornima , Tawney Jaime , Acosta-Alvear Diego , Kampmann Martin 
Published: December 2017

Abstract
Acquired drug resistance is a major clinical problem in a variety of cancer types and our understanding of the underlying mechanisms is insufficient. We lack a complete understanding of the interplay of factors between the tumor and its microenvironment controlling drug sensitivity. Several published studies and our preliminary results show that bone marrow microenvironment reduce the sensitivity of multiple myeloma cells to clinically approved proteasome inhibitor, carfilzomib, making it an ideal model system.
Here we employ innovative CRISPR-interference (CRISPRi) based functional genomics platform to identify cell-intrinsic and microenvironment-dependent vulnerabilities in multiple myeloma. This platform utilizes a catalytically dead Cas9 (dCas9) fused to a transcriptional repressor domain to target and silence specific genes using single guide-RNAs (sgRNA). We have engineered the myeloma cells to express components of the CRISPRi system enabling us to perform genome-wide screens to identify factors that modulate sensitivity to carfilzomib. To identify microenvironment-dependent factors that alter carfilzomib sensitivity, we established a co-culture system where the CRISPRi expressing myeloma cells are grown in the presence of bone marrow stromal cells and subject to treatment with carfilzomib. We performed a pilot-screen using a library of sgRNAs targeted towards genes involved in the human proteostasis network and known cancer drug targets. The library expressing CRISPRi-myeloma cells were grown as mono- and co-culture in the presence or absence of carfilzomib. Through this screen we were able to identify several factors knockdown of which had differential effects in mono- and co-culture conditions on the growth of the cells and/or their drug response. Currently we are validating the identified factors using various biochemical assays and available pharmacological tools. This study will pave the way to better understand the crosstalk between the tumor and its microenvironment and enable rational design of combination therapies to overcome drug resistance.
Citation Format: Poornima Ramkumar, Jaime Tawney, Diego Acosta-Alvear, Martin Kampmann. Identifying microenvironment-dependent vulnerabilities in multiple myeloma using CRISPRi [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A30.
Abstract B14: Precision functional genomics for glioblastoma: Identifying molecular therapeutic targets using CRISPR-Cas9 and RNAi technologies in patient isolates
Authors: Hoellerbauer Pia , Feldman Heather , Arora Sonali , Carter Lucas , Girard Emily J. , Corrin Philip , Olson James M. , Holland Eric C. , Paddison Patrick J. 
Published: December 2017

Abstract
Glioblastoma (GBM) is the most aggressive and common form of adult brain cancer and is among the deadliest cancers, with a median survival of 15 months using standard-of-care therapies. Thus, improved treatments for GBM are desperately needed. To identify new GBM molecular therapeutic targets, our group has performed multiple functional genetic screens in patient-derived GBM stem-like cells (GSCs) and non-transformed human neural stem and progenitor cells (NPCs), which represent non-neoplastic controls. These screens, which have used both RNAi and CRISPR-Cas9 platforms, have led to the identification of several key molecular vulnerabilities in GSCs, including GBM-specific defects in: 3' splice site recognition, kinetochore function, and loss of redundancy between the kinase activities of PKMYT1 and WEE1. At this meeting we will present an overview of these studies, as well as our current efforts to: comprehensively retest all GBM-specific vulnerabilities scoring in these screens; address whether vulnerabilities arise from specific genetic alterations in patient samples (e.g. NF1 loss or PTEN loss); determine whether inhibition of specific molecular targets blocks tumor growth and/or maintenance; and demonstrate the mode of GBM-specific death for particular targets (e.g., cell cycle arrest, apoptosis, etc). In addition, we will highlight both strengths and limitations of applications of CRISPR-Cas9 technologies in patient samples. Collectively, our work illustrates the power of combining functional genetic technologies with the use of patient isolates to identify novel, patient-specific therapeutic strategies for GBM.
Citation Format: Pia Hoellerbauer, Heather Feldman, Sonali Arora, Lucas Carter, Emily J. Girard, Philip Corrin, James M. Olson, Eric C. Holland, Patrick J. Paddison. Precision functional genomics for glioblastoma: Identifying molecular therapeutic targets using CRISPR-Cas9 and RNAi technologies in patient isolates [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B14.
Abstract B32: Restoration of beta cell mass as a synthetic lethal strategy to overcome oncogenic Kras-driven pancreatic ductal adenocarcinoma
Authors: Nguyen Thienly , Parajuli Parash , Ahmad Asrar , Singh Purba , Eragameddy Sailaja , Ramakrishnan Gopalakrishnan , Levy Laurence , Ferrigno Oliver , Mo Yin-Yuan , Pochampally Radhika , Razzaque Mohammed S , Prunier Celine , Atfi Azeddine 
Published: December 2017

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a disease that remains incurable due to diagnosis at advanced stages, which renders any therapeutic intervention impracticable. The vast majority of PDAC patients develop new-onset diabetes, which often culminates in dysfunction of vital organs, leading to severe morbidity and high mortality. How PDAC development leads to diabetes is still unfolding. More than 90% of PDAC cases have an oncogenic mutation that affects the proto-oncogene Kras, mostly G12D. Using several mouse models of KrasG12D-driven PDAC, which faithfully recapitulate the human disease, we observed a massive depletion of beta cell mass, occurring even at early stages of pancreatic intraepithelial neoplasia (PanIN). This phenomenon was selective for beta cells, as PanIN or PDAC formation did not affect any other type of islet cells, including alpha and delta cells, which produce Glucagon and Somatostatin, respectively. Intriguingly, both alpha and delta cells retained their localization at the periphery of islets that are devoid of beta cells, giving rise to PanIN-like structures. Such pattern was observed when KrasG12D expression was combined with genetic inactivation of other tumor suppressor genes frequently inactivated in human PDAC, including TP53 and p16Ink4a. Lastly, we also detected depletion of beta cells and presence of remnant islets resembling PanIN in human PDAC, attesting to the clinical relevance of our findings, and further rise the attractive question of whether restoration of beta cell mass could be utilized to curb PDAC driven by oncogenic Kras.
Citation Format: Thienly Nguyen, Parash Parajuli, Asrar Ahmad, Purba Singh, Sailaja Eragameddy, Gopalakrishnan Ramakrishnan, Laurence Levy, Oliver Ferrigno, Yin-Yuan Mo, Radhika Pochampally, Mohammed S Razzaque, Celine Prunier, Azeddine Atfi. Restoration of beta cell mass as a synthetic lethal strategy to overcome oncogenic Kras-driven pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B32.
Abstract B36: A 1,5-diheteroarylpenta-1,4-dien-3-one inhibits TNBC cell growth by blocking AKT/mTOR/P70S6K pathway
Authors: Atefi Mohammad , Patanapongpibul Manee , Ma Lynn , Chen Qiao-Hong , Wang Guangdi , Wu Yong , Vadgama Jay 
Published: December 2017

Abstract
One in 8 women will develop breast cancer during the course of her life. Recent developments in the field of drug development have provided a significant increase in progression free survival and decrease in mortality of this disease. However, one of the main problems in breast cancer remains the development of resistance to current treatments and relapse of the disease. Moreover, there is no known target for the treatment of the triple negative breast cancers (TNBC) subset, which is more aggressive than the other types of the disease. Therefore, it is imperative to develop new drugs that can block the activity of pro-survival signaling within the cancer cells and inhibit their growth, particularly in the TNBC subset. In an attempt to identify such drugs, we screened a panel of 13 compounds, containing the general structure of 1,5-diheteroarylpenta-1,4-dien-3-one (compounds 34 to 46), for their effectiveness in inhibiting the growth of both TNBC and ER+ breast cancers. The IC50s for these compounds were in the range of 63 to 8346 nM against various breast cancer cell lines. Interestingly, the most potent compound (# 34), (1E,4E)-1,5-bis(1-pentan-2-yl)-1H-imidazol-2-yl)penta-1,4-dien-3-one, showed its highest growth inhibitory activity in the TNBC cell line, MDA-MB-231, while also being effective in inhibiting the growth of ER+ cell lines to a lesser extent. Further investigations were then focused on this TNBC cell line. The mechanism of action of compound 34 was investigated by using a Human Phospho-Kinase Array, which revealed a significant decrease in p-P70S6K and p-mTOR. Additional assays confirmed the same results and also showed significant reductions in total mTOR and Total AKT as well as significant decreases in p-P70S6K and p-mTOR. Moreover, compound 34 treatment induced higher levels of p-c-JUN and p-P38, which may be indications of cell stress upon treatment. Overall our data indicate that compound 34 induces profound decreases in the activity of pro-survival pathways such as AKT/mTOR, which significantly inhibited growth of the TNBC cell line.
Citation Format: Mohammad Atefi, Manee Patanapongpibul, Lynn Ma, Qiao-Hong Chen, Guangdi Wang, Yong Wu, Jay Vadgama. A 1,5-diheteroarylpenta-1,4-dien-3-one inhibits TNBC cell growth by blocking AKT/mTOR/P70S6K pathway [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B36.
Abstract IA10: Finding vulnerabilities of drug resistant cancers
Authors: Bernards René 
Published: December 2017

Abstract
Intrinsic and acquired drug resistance represent major obstacles to effective cures for cancer. Understanding these mechanisms is instrumental for the design of strategies to counter these resistance mechanisms.
In my presentation, I will focus on an example of intrinsic drug resistance and one of acquired drug resistance. As an example of intrinsic drug resistance, I will discuss the lack of response to MEK inhibitors seen in KRAS mutant tumors of various. The consistently poor response of KRAS mutant tumors to inhibition of its downstream kinases is unexpected, as it defies the concept of oncogene addiction. Nevertheless, a subset of tumors responds well to MEK inhibition, but it remains unclear which biomarkers can be used to identify MEK inhibitor sensitive cancer cells. I will demonstrate that inactivating mutations in both MAP3K1 and MAP2K4 will confer strong sensitivity to MEK inhibition in cancers of any tissue origin. Given that most major cancers have a mutation rate in these two genes of around 10%, the use of these mutations may help select patient subgroups that benefit from MEK inhibitor therapy.
As an example of acquired drug resistance, I will discuss resistance of BRAF(V600E) mutant melanomas to drugs that target the BRAF and/or MEK kinases. This acquired resistance is almost always caused by reactivation of signaling through this pathway in the presence of drug. Drug withdrawal in such patients leads to a further hyper-activation of MAPK pathway, leading to a cellular state that has hallmarks of oncogene-induced senescence. I will show that drugs can be identified that maintain high levels of MAPK pathway signaling in BRAF inhibitor resistant melanomas upon cessation of BRAF inhibitor treatment. These drugs are only active in melanoma cells that have acquired resistance to BRAF inhibitors and not in parental melanoma cells, because they require MAPK hyper-activation that is induced by the gained resistance to BRAF inhibitors to be effective. In general, second line treatment of tumors that have acquired resistance to first line therapy is less effective. The unique aspect of the second line therapy identified here is that it exploits a vulnerability that is only gained upon acquisition of resistance to BRAFi therapy. The proposed therapy also takes advantage of the fact that acquisition of resistance to BRAFi follows a predictable path in the clinic making their responses to second line also more predictable.
Citation Format: René Bernards. Finding vulnerabilities of drug resistant cancers [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA10.
Abstract IA15: Genetic screens to study cancer
Authors: Sabatini David M. 
Published: December 2017

Abstract
We will describe our efforts to use the CRISPR/Cas9 system to systematically identify the genetic liabilities of cancer cells and the synthetic lethal relationships of common oncogenes.
Citation Format: David M. Sabatini. Genetic screens to study cancer [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA15.
Abstract IA17: Synthetic-lethal strategies for MYC-driven cancers
Authors: Goga Andrei 
Published: December 2017

Abstract
MYC is an essential, pleiotropic transcription factor whose amplification or deregulated expression is one of the most commonly occurring events in cancer. Despite the importance of MYC as a therapeutic target, no available drugs directly inhibit MYC transcriptional activity. Our group has undertaken several orthogonal approaches to identify MYC-pathway directed synthetic-lethal interactions. Using cell-based and transgenic animal models we have identified new potential therapeutic targets. These include metabolic, cell cycle and novel kinase vulnerabilities of MYC-driven cancers that will be discussed.
Citation Format: Andrei Goga. Synthetic-lethal strategies for MYC-driven cancers [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA17.