bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 43: HBEGF cooperates with Cdkn2a and Pten loss to form malignant gliomas
Authors: Shin Clifford , Holmen Sheri 
Published: May 2016

Abstract
Malignant gliomas are aggressive brain tumors that carry a grim prognosis to over 10,000 patients a year in the United States. The highest grade tumor, glioblastoma, has an average survival of one year with the current standard of care, which includes surgical resection, radiotherapy, and temozolomide chemotherapy. Heparin-binding EGF-like growth factor (HBEGF), first discovered in macrophages as a mitogen for vascular smooth muscle cells, is a ligand for epidermal growth factor receptor, the most commonly amplified receptor-tyrosine kinase in glioblastoma. About 30% of glioblastomas express HBEGF, and it is also commonly upregulated in tumors that express the common EGFR mutant, EGFRvIII. To date, HBEGF has not been evaluated for its ability to promote the development of malignant gliomas in vivo. Using a method for somatic cell gene transfer, we show that HBEGF cooperates with loss of tumor suppressors Cdkn2a and Pten to form malignant gliomas in vivo. These tumors share many characteristics found in human glioblastoma such as necrosis and nuclear atypia. We also demonstrate using high-throughput sequencing that these tumors share a common gene signature to the human glioblastoma samples from The Cancer Genome Atlas study. No tumors were seen with loss of Cdkn2a and Pten alone, which are the two most common tumor suppressors altered in glioblastoma. Our findings demonstrate that HBEGF can drive the development of high grade gliomas in the context of Cdkn2a and Pten loss and that these tumors closely resemble the human disease.
Citation Format: Clifford Shin, Sheri Holmen. HBEGF cooperates with Cdkn2a and Pten loss to form malignant gliomas. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 43.
Abstract 46: Functional analysis of long noncoding RNAs in Bcr-Abl-mediated tumorigenesis
Authors: Guo Guijie , Wang Xuefei , Chen Jilong 
Published: May 2016

Abstract
Human genome is pervasively transcribed and the majority does not have apparent protein coding potential, which is defined as noncoding RNA (ncRNA). Long noncoding RNAs (lncRNAs) are greater than 200 nucleotides in length, transcribed by RNA polymerase II or III, and poorly conserved. Aberrant expression of numerous functional lncRNAs is associated with various human cancers. Chronic myeloid leukemia (CML) is a hematologic malignancy associated with a translocation between chromosome 9 and 22 that results in the formation of bcr-abl hybrid gene which occurs in over 90% of CML cases. However, the role of lncRNAs in Bcr-Abl-mediated chronic myeloid leukemia (CML) is not fully understood. In this study, we performed a comprehensive analysis of lncRNAs in human CML cells using a microarray of cDNAs encoding lncRNAs. The microarray analysis revealed 338 upregulated lncRNAs and 108 downregulated lncRNAs after silencing Bcr-Abl in human CML cells. To identify functional lncRNAs that are important in Bcr-Abl-mediated transformation, we selected the most significantly affected lncRNAs for further studies. These lncRNAs were examined by ORF finder from NCBI and protein-coding potential was determined. We identified several lncRNAs that acted as a key regulator of Bcr-Abl-mediated cellular transformation. Expression of these lncRNAs was further examined in response to disruption of Bcr-Abl expression or by inhibiting Bcr-Abl kinase activity in K562 cells and leukemic cells derived from CML patients. Experiments including ectopic overexpression or knockdown of these lncRNAs were performed to address the role and mechanism of how these lncRNAs function in the leukemic cells. Together, these results reveal that several lncRNAs are critically involved in Bcr-Abl-mediated cellular transformation and suggest a potential strategy for the treatment of Bcr-Abl-positive leukemia.
Note: This abstract was not presented at the conference.
Citation Format: Guijie Guo, Xuefei Wang, Jilong Chen. Functional analysis of long noncoding RNAs in Bcr-Abl-mediated tumorigenesis. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 46.
Abstract 49: Genomic analysis and simulation for understanding heterogenous cancer evolution
Authors: Niida Atsushi , Uchi Ryutaro , Takahashi Yusuke , Mimori Koshi , Miyano Satoru 
Published: May 2016

Abstract
Cancer results from accumulation of mutations in the genome and evolutionary selection for growth advantage. In the evolutionary process, it is assumed that multiple clones appear, and this phenomenon called intratumor heterogeneity could cause therapeutic failures by fostering evolutionary adaptation. To study intratumor heterogeneity in colorectal cancer, we performed whole exome sequencing of samples from multiple regions within a single tumor. our genomic analysis revealed high intratumor heterogeneity; however, principles underlying it remained unclear. To explore the principles , we built a cellular automaton model, termed the BEP model, which can reproduce the branching cancer evolution in silico. We then extensively searched for conditions leading to high intratumor heterogeneity as observed in the experimental data, by performing simulations with various parameter settings on a supercomputer. The simulation result suggests that a high mutation rate leads to high intratumor heterogeneity, which is generated by neutral evolution. Collectively, this study provides provide novel insights into heterogenous cancer evolution.
Citation Format: Atsushi Niida, Ryutaro Uchi, Yusuke Takahashi, Koshi Mimori, Satoru Miyano. Genomic analysis and simulation for understanding heterogenous cancer evolution. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 49.
Abstract 51: Molecular profiling of relapsed childhood cancer
Authors: Wadham Carol , Saletta Federica , Byrne Jennifer A. , Trahair Toby , Ziegler David S. , McCowage Geoffrey , Marshall Glenn , Haber Michelle , Norris Murray 
Published: May 2016

Abstract
Background: Despite the overall success achieved in treating childhood cancers, a major challenge is to find alternative treatment options for those children who suffer relapse. This requires more detailed understanding of the molecular pathways responsible for maintaining and promoting an aggressive drug resistant phenotype, as well as the successful targeting of these pathways.
Materials and methods: We are implementing a molecular profiling approach to individual tumours, which includes Fluidigm Biomark qRT-PCR analysis (a panel of 96 marker genes), next-generation sequencing (Ion Proton custom AmpliSeq panel of 480 genes) and automated immunohistochemistry (IHC, 30 antibodies to 25 proteins/ phosphoproteins).
Results: Preliminary testing of a subset of these genes has been conducted on 12 cell lines representing the major childhood cancer subtypes, as well as 8 patient-derived primary cultures including 4 inflammatory myofibroblastic tumours, 2 diffuse intrinsic pontine gliomas and 2 acute lymphoblastic leukemia (ALL). The potential for molecular profiling to assist in drug selection was subsequently tested in high throughput in vitro drug sensitivity assays using a drug library based on the profiling data. Gene expression has also been analysed in forty five cell lines from mice bearing patient-derived ALL xenografts. The individualised mouse xenografts will allow in vivo testing of the efficacy of molecularly targeted drugs. We are now undertaking a retrospective study of diagnostic frozen and formalin fixed paraffin embedded samples from 55 paediatric cancer patients who subsequently experienced relapse.
Conclusion: We have implemented a screening approach to identify molecular targets in paediatric cancer patients who have failed the best current treatments available, and for whom treatment options following relapse are extremely limited. The ultimate goal is to undertake a multicentre prospective clinical trial in paediatric patients with recurrent or refractory solid tumours or leukemias for whom targeted drug therapy will be identified using molecular profiling.
Citation Format: Carol Wadham, Federica Saletta, Jennifer A. Byrne, Toby Trahair, David S. Ziegler, Geoffrey McCowage, Glenn Marshall, Michelle Haber, Murray Norris. Molecular profiling of relapsed childhood cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 51.
Abstract IA03: The evolutionary landscape of CLL: Therapeutic implications
Authors: Wu Catherine J. 
Published: May 2016

Abstract
Clonal evolution is a key feature of cancer progression and relapse. Recent studies across cancers have demonstrated the extensive degree of intratumoral heterogeneity present within individual cancers. We hypothesized that evolutionary dynamics contribute to the variations in disease tempo and response to therapy that are highly characteristic of chronic lymphocytic leukemia (CLL). We have recently investigated this phenomenon by developing a pipeline that estimates the fraction of cancer cells harboring each somatic mutation within a tumor through integration of whole-exome sequence (WES) and local copy number data (Landau et al., Cell 2013). By applying this analysis approach to 149 CLL cases, we discovered earlier and later cancer drivers, uncovered patterns of clonal evolution in CLL and linked the presence of subclones harboring driver mutations with adverse clinical outcome. Thus, our study, generated from a heterogeneous sample cohort, strongly supports the concept that CLL clonal evolution arises from mass extinction and therapeutic bottlenecks which lead to the emergence of highly fit (and treatment resistant) subclones. We further hypothesized that epigenetic heterogeneity also shapes CLL clonal evolution through interrelation with genetic heterogeneity. Indeed, in recent work, we have uncovered stochastic methylation disorder as the primary cause of methylation changes in CLL and cancer in general, and that this phenomena impacts gene transcription, genetic evolution and clinical outcome. Thus, integrated studies of genetic and epigenetic heterogeneity in CLL have revealed the complex and diverse evolutionary trajectories of these cancer cells.
Immunotherapy is exquisitely suited for specifically and simultaneously targeting multiple lesions. We have developed an approach that leverages whole-exome sequencing to systematically identify personal tumor mutations with immunogenic potential, which can be incorporated as antigen targets in multi-epitope personalized therapeutic vaccines. We are pioneering this approach in an ongoing trial in melanoma and will now expand this concept to address diverse malignancies. Our expectation is that the choice of tumor neoantigens for a vaccine bypasses thymic tolerance and thus generates highly specific and potent high-affinity T cell responses to eliminate tumors in any cancer, including both trunk and branch lesions.
Citation Format: Catherine J. Wu. The evolutionary landscape of CLL: Therapeutic implications. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr IA03.
Abstract IA07: The application of integrative sequencing for precision oncology
Authors: Chinnaiyan Arul 
Published: May 2016

Abstract
Studies of the genomic landscape of human cancers have demonstrated that most solid cancers have a multitude of mutations, a subset of which may be “actionable” with current drugs. Thus, the personalization of therapy for cancer will require molecular characterization of unique and shared genetic aberrations. Patients who have advanced/refractory cancer and are candidates for clinical trials could potentially benefit by identifying eligibility for “targeted” drugs based on the “actionable” genes in their specific tumor. Growing technological advances in genomic sequencing has now made it possible to consider the use of sequence data in a clinical setting. MI-ONCOSEQ initiative brings together expertise at the University of Michigan including clinical oncology, cancer genetics, bioinformatics, clinical pathology, social and behavioral sciences, and bioethics in order to implement clinical cancer sequencing. Our study identifies patients with advanced or refractory cancers that are eligible for clinical trials, consent them to the study, obtain biospecimens (tumor tissue, germline tissue) and store clinical data. The clinical sequencing team processes biospecimens, performs comprehensive sequencing and analysis of tumors to identify point mutations, copy number changes, rearrangements/gene fusions, and aberrant gene expression. Finally, a multi-disciplinary Precision Medicine Tumor Board deliberates on return of actionable or incidental genomic results.
Citation Format: Arul Chinnaiyan. The application of integrative sequencing for precision oncology. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr IA07.
Abstract IA11: Clinical application of next-generation sequencing as a guide to treatment selection
Authors: Solit David B. 
Published: May 2016

Abstract
Profound and durable responses are often observed in early stage clinical trials of novel cancer agents in only a small minority of patients. It has long been postulated that these responses have a definable genetic basis but until now it was not feasible to perform a comprehensive genomic analysis of such patients. Rather, at best a few candidate genes were examined. Technical feasibility thus ensured that oncology trials were designed to identify agents that have a statistically significant benefit in a genetically unselected population, a paradigm that has led to the development of many agents that have modest or no benefit in the vast majority of patients. Agents with profound activity in only a small number of patients were on the other had deemed inactive and abandoned. Our preliminary experience shows that next generation sequencing methodology can now be feasibly applied in the clinical setting to identify previously unrecognized biomarkers of response for agents that show profound responses in only a minority of patients. As an example, we explored the molecular basis of an outlier phenotype, an apparent disease cure of a 51-year old woman with recurrent metastatic small cell carcinoma. The patient was treated on a phase 1 clinical trial that combined topoisomerase I inhibition with an ATP-competitive inhibitor of checkpoint kinase 1 (Chk1). Whole genome sequencing revealed a complex but highly clonal tumor genome with a somatic, missense mutation in the Mre11 complex gene RAD50, which functions to initiate double stranded break (DSB) repair by homologous recombination or non- homologous end joining. Through modeling in yeast, we confirmed that this heterozygous RAD50 mutation, which affects a highly conserved residue and whose wild type copy was focally deleted, conferred sensitivity to topoisomerase I inhibition. Drug sensitivity was markedly enhanced upon genetic ablation of the DNA damage checkpoint pathway, suggesting a synthetic lethal interaction between checkpoint kinase inhibition and clastogenic chemotherapy. These results and additional examples to be presented demonstrate the feasibility of using whole-genome sequencing in the clinical setting to identify previously occult biomarkers of drug sensitivity that can aid in the identification of patients most likely to respond to targeted anticancer drugs. The use of novel clinical trial designs to confirm genotype-phenotype associations will also be discussed.
Citation Format: David B. Solit. Clinical application of next-generation sequencing as a guide to treatment selection. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr IA11.
Abstract IA20: Moving CAR T cell therapy forward: CARs and armored CARs
Authors: Brentjens Renier J. 
Published: May 2016

Abstract
T cells may be genetically modified to express chimeric antigen receptors (CAR) targeted to antigens expressed by tumor cells. We have developed this technology in the laboratory and translated this adoptive T cell approach in the clinic. Treatment of patients with CD19 targeted CAR T cells has resulted remarkable remission rates in relapsed B cell acute lymphoblastic leukemia (B-ALL). Specifically, based on currently updated clinical outcomes, we have achieved &gt;85% CR rates in adult patients with relapsed B-ALL treated with CD19 targeted CAR T cells which far exceed historical expectations. Further, by deep sequencing analysis, most treated patients were MRD- after CAR T cell therapy. Significantly, remissions were observed in both patients with overt morphological residual disease at the time of therapy as well as in patients with only residual MRD+ disease. Clinical trials form other centers which confirm the presented clinical trial outcomes from our center will be reviewed. While overall generally well tolerated, we found that patients treated with CAR T cells in the setting of overt disease experienced a cytokine release syndrome (CRS) with associated fevers, hypotension, and mental status changes including overt seizures. In contrast, far more modest responses were seen in patients with relapsed chronic lymphocytic leukemia (CLL). The discordant clinical outcomes between B-ALL and CLL patients treated with CD19 targeted CAR T cells remains a subject of conjecture although the tumor microenvironment is a strong focus of further investigation. To this end, we will present novel data on a next generation of CAR T cells, termed “armored CARs” further genetically designed to overcome an immune suppressive tumor microenvironment through further genetic modification of CAR T cells. Promising preclinical studies utilizing these “armored CAR” T cell approaches and their role in future clinical trials will be discussed.
Citation Format: Renier J. Brentjens. Moving CAR T cell therapy forward: CARs and armored CARs. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr IA20.
Abstract A004: Upregulation of soluble programmed death ligands in patients with colorectal cancer
Authors: Du Jipei , Cheng Yao , Mao Zhigang , Liao Shiping , Zheng Yanjiang , Zhang Ji , Wang Yufang 
Published: May 2016

Abstract
Objective: The programmed death-1/programmed death-1 ligands (PD-1/PD-Ls) pathway is critical for attenuating autoimmunity and maintaining T cell homeostasis. It has been suggested that PD-1/PD-Ls plays an important role in tumor evasion from host immunity. Although strong evidence supports the concept of immunosurveillance and immunoediting in colorectal cancer, the immune regulatory role of PD-1/PD-Ls pathway is not clear in colorectal cancer (CRC) patients. Here we investigated the expression of PD-1 and the soluble ligands (sPD-Ls) in blood plasma of patients with inflammatory Bowel Disease (IBD) and CRC.
Methods: Age-matched 107 health controls, 109 patients with colorectal cancer and 109 patients with IBD from West China Hospital (Chengdu, Sichuan, China.) were enrolled in the present study. The levels of PD-1 and sPD-Ls in blood plasma were analyzed by enzyme linked immunosorbent assay (ELISA). Expression of PD-L1 and PD-L2 were investigated in colorectal tissue by immunohistochemical (IHC) staining.
Results: The level of PD-1 in the plasma of the CRC patients was significantly up-regulated compared with healthy people (P=0.004), but there was no significant difference between IBD patient and healthy people. The levels of PD-1 were higher in CRC patients than in IBD patients. The levels of PD-L1 and soluble PD-L2 in peripheral blood were significantly increased in CRC patients comparing to health patients (P=0.0028 and p=0.0264, respectively). sPD-Ls were correlated with circulatory PD-1 expression in the CRC patients. These results indicated that the PD-1/PD-Ls pathway is activated in the CRC patients. However, we didn't observe significant differences either between IBD patients and healthy people or between CRC patients and IBD patients. We further confirmed that PD-L1 and PD-L2 were localized in colorectal cancer cells by IHC. In 67 CRC patients, the positive rates of PD-L1 and PD-L2 were 35.3% and 65%, respectively. In addition, expression of PD-1, PD-L1 and PD-L2 were higher in the patients with metastatic CRC compared to the patients with primary CRC.
Conclusion: The higher levels of plasma sPD-Ls may be associated with CRC and may predict CRC metastatic progression. The existence of immunosuppressive PD-1 and sPD-Ls in the circulation of CRC patients may indicate that PD-Ls suppress immune responses against CRC not only locally, but also systemically. This information will provide a novel insight into the role of PD-1/PDLs in CRC-mediated immunosuppression.
Citation Format: Jipei Du, Yao Cheng, Zhigang Mao, Shiping Liao, Yanjiang Zheng, Ji Zhang, Yufang Wang. Upregulation of soluble programmed death ligands in patients with colorectal cancer. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A004.