bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA10: Kinase-impaired BRAF mutations as predictors of resistance and sensitivity
Authors: Johnson Faye , Sen Banibrata , Mazumdar Tuhina , Peng Shaohua , Kadara Humam , Diao Lixia , Byers Lauren 
Published: May 2015

Abstract
Non-small cell lung cancer (NSCLC) is a common and rapidly fatal cancer for which targeted therapies have been markedly effective in only about 15% of patients - specifically those with EGFR mutations or EML4-ALK translocations. During a clinical trial of the multi-targeted tyrosine kinase inhibitor dasatinib we identified a patient with stage IV NSCLC who harbored a novel BRAF mutation (Y472C), had a near complete radiographic response to the multitargeted kinase inhibitor dasatinib as sole therapy and remained without active cancer 7 years following treatment. We discovered that Y472CBRAF is a kinase-inactivating BRAF mutation (KIBRAF). BRAF mutations can result in increased or decreased BRAF kinase activity, as well as kinase-neutral mutations, and occur in 8% of NSCLC and many other tumor types. We found that NSCLC cells that harbor KIBRAF undergo senescence when exposed to the dasatinib whereas NSCLC patients and cell lines with wild type BRAF are resistant to dasatinib. Transfection of other NSCLC cells with KIBRAF mutations also increased their dasatinib sensitivity, whereas transfection with an activating BRAF mutation led to their increased dasatinib resistance. NSCLC cells transfected with Y472CBRAF exhibited CRAF, MEK, and ERK activation. Currently there are no well-defined, canonical pathways that explain the observed dasatinib-induced senescence in NSCLC cells with KIBRAF. Dasatinib inhibits the activity of 40 distinct kinase targets and can induce BRAF-CRAF dimerization and CRAF activation in cells with activated RAS or KIBRAF mutations. To investigate the mechanism leading to senescence we performed reverse phase protein arrays to simultaneously examine the expression of 137 proteins and phosphoproteins and gene expression arrays. This approach was limited by the existence of only two NSCLC cell lines with KIBRAF but nonetheless we determined that dasatinib induced DNA damage and subsequently activated DNA repair pathways and the HIPPO signaling pathway only in NSCLC cells with KIBRAF. We are currently conducting a clinical trial for NSCLC patients with KIBRAF mutations to determine the efficacy of dasatinib in these patients prospectively.
Citation Format: Faye Johnson, Banibrata Sen, Tuhina Mazumdar, Shaohua Peng, Humam Kadara, Lixia Diao, Lauren Byers. Kinase-impaired BRAF mutations as predictors of resistance and sensitivity. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr IA10.
Abstract IA12: Correlating cancer heterogeneity to treatment response and relapse
Authors: Papaemmanuil Elli 
Published: May 2015

Abstract
Systematic sequencing screens of hundreds of cancer genomes has delivered a near complete catalogue of somatic mutations in the coding genome that drive oncogenic transformation across a diverse range of tumor types. The picture that is emerging is one of extensive genomic diversity and clonal complexity.
Our recent work in MDS has shown that the underlying genomic architecture is predominantly characterized by infrequently mutated genes (&lt;5% of patient samples), specific gene-gene interactions and a structured order of mutation acquisition, implicating mutations in RNA splicing as early initiating events followed by secondary mutations in epigenetic modifiers and transcriptional regulators. The enrichment for infrequently mutated genes and complex secondary interactions impose significant challenges in defining prognostic and predictive biomarkers of patient outcome and therapeutic response. Single gene studies are not entirely representative of the disease pathophysiology and certainly do not account for the epistatic or modifying effects conferred by the composite underlying genetic architecture. Detailed investigations on well-annotated patient cohorts pre-, during and post- treatment support the definition of predictive signatures of response and studies investigating changes in clonal dynamics using sequential samples during therapy are offering important new avenues in understanding the underlying biology of chemo sensitivity as well as resistance.
Citation Format: Elli Papaemmanuil. Correlating cancer heterogeneity to treatment response and relapse. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr IA12.
Abstract IA18: ERK activity in mutant BRAF melanoma – A live report
Authors: Aplin Andrew E. 
Published: May 2015

Abstract
The response of BRAF V600E/K melanoma patients to either RAF inhibitors or the RAF/MEK inhibitor combination is heterogeneous and short-term responses are associated with acquired resistance. Our previous studies have implicated compensatory FOXD3-ERBB3-AKT signaling as an adaptive response to targeted inhibition of the ERK1/2 pathway. While adaptive responses likely modulate the initial tumor response to targeted inhibitors, stable changes drive acquired resistance leading to the re-growth of tumors that initially responded to RAF inhibitors. Outgrowth of resistant cells may be due to the acquisition of a secondary mutation and/or selection of pre-existing cells harboring genetic alterations that negate the effect of RAF inhibitors. To model acquired resistance to RAF inhibitors, we developed mutant BRAF melanoma ERK1/2 activity reporter xenograft models. This system enables quantitative analysis of ERK1/2 activity in response to pathway inhibitors across the whole tumor in a temporal manner. We have utilized this system to analyze the initial response to RAF inhibitors in vivo, as well as re-activation of the ERK1/2 pathway associated with acquired resistance. Furthermore, we are utilizing this model to analyze response and resistance to RAF/MEK inhibitor combinations and next-generation RAF inhibitors.
Citation Format: Andrew E. Aplin. ERK activity in mutant BRAF melanoma – A live report. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr IA18.
Abstract PR02: Identification of ERK1/2 mutations that confer resistance to MAPK pathway inhibitors
Authors: Goetz Eva M. , Ghandi Mahmoud , Treacy Daniel , Wagle Nikhil , Garraway Levi A. 
Published: May 2015

Abstract
Recent treatment advances in metastatic BRAF mutant melanoma using targeted therapy have increased progression free survival by many months. However, resistance to these targeted agents is a common occurrence, with relapse occurring in almost every case. Many of the alterations that confer clinical resistance to RAF and MEK inhibitors in BRAF mutant melanoma reactivate the MAPK pathway, but remain sensitive to ERK inhibition in vitro. Prospectively determining mechanisms of resistance to MAPK pathway inhibitors, such as an ERK inhibitor, before clinical trials begin may inform which patients will respond to therapy, potential markers of resistance, or best therapy combinations. Previous studies have shown that in vitro random mutagenesis screens can select specific alleles seen in resistant patient populations. Since ERK inhibitors are entering clinical trials, we wanted to determine mutations in ERK1 and ERK2 that could confer resistance to ERK or RAF/MEK inhibition. Therefore, we expressed dox-inducible ERK1 or ERK2 mutant libraries in A375 cells, which were then treated with MAPK inhibitor(s) and doxycycline until resistant cells emerged. Exogenous ERK1 or ERK2 was analyzed in resistant cells by massively parallel DNA sequencing. We validated 15 alleles that conferred resistance to the ERK inhibitor, VX-11e, and 11 alleles that conferred resistance to RAF, MEK, or RAF+MEK inhibition (dabrafenib and trametinib). Some resistance alleles were analogous between ERK1 and ERK2, while others were specific to ERK1 or ERK2. ERK inhibitor resistant alleles were localized to areas surrounding the ATP/drug binding site, including the glycine-rich loop, c-helix, and activation loop. These alleles were also cross-resistant to another ERK inhibitor, SCH-772984, albeit some only at lower concentrations. The RAF/MEK inhibitor resistant residues were located in the c-helix, activation loop, and common docking domain. Only a single ERK1 allele was found to confer resistance to RAF + MEK and ERK inhibition, suggesting that resistance mutations in ERK might be suppressed if RAF, MEK, and ERK inhibitors are given in combination. In addition, an ERK mutation arising in a patient treated with an ERK inhibitor would still be sensitive to RAF/MEK inhibition and vice versa. Screening for these alleles before administering therapy or after relapse may help inform patient treatment.
Citation Format: Eva M. Goetz, Mahmoud Ghandi, Daniel Treacy, Nikhil Wagle, Levi A. Garraway. Identification of ERK1/2 mutations that confer resistance to MAPK pathway inhibitors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr PR02.
Abstract PR03: Identifying biomarkers of drug response and resistance using personalized Drosophila models of colorectal cancer
Authors: Bangi Erdem , Murgia Claudio , Teague Alexander , Sansom Owen , Cagan Ross 
Published: May 2015

Abstract
A fundamental difficulty in cancer research is the complex, multigenic and genetically diverse nature of human tumors, recently emphasized by cancer genome sequencing efforts. To capture this genetic complexity and diversity, we identified the most frequently observed double, triple and quadruple combinations of mutations in human colon cancer genomes and generated the corresponding combinations in Drosophila. We then investigated the tumorigenic and metastatic potential of 30 multigenic combinations we established by targeting them specifically to the adult Drosophila colon. These models recapitulate key features of human cancer, many of which arise as emergent properties of multigenic combinations. Importantly, we show that multigenic models are more resistant to compound effects than single-hit models and that combinatorial therapy is more effective against multigenic combinations. Specifically, we tested 16 clinically relevant targeted agents against our models using dissemination into the abdominal cavity as a quantitative read-out to monitor drug response. We found that 12 of these 16 compounds were effective against rasG12V alone while the four-hit model rasG12V p53RNAi ptenRNAi apcRNAi was resistant to all. We then uncovered a potential mechanism for resistance to PI3K pathway inhibitors as well as biomarkers for single agent response and resistance. We also developed a combination therapy that overcomes resistance of our four-hit model to single agent PI3K pathway inhibitors. We have validated our findings in human colorectal cancer cell lines, xenograft models as well as 3D colospheres and allografts derived from genetically engineered mouse models of colorectal cancer. We are currently investigating mechanisms mediating resistance of our four-hit model to the remaining compounds. We hope to use this information to devise additional rational combination therapies effective against genetically complex tumors. Overall, these models provide an excellent opportunity to study tumorigenesis and metastasis in the context of the whole animal and explore compound effects on a genetically diverse set of models. The emergent properties we identified in our multigenic combinations and interesting correlations we observed between tumor genotype and drug response also represent important steps towards personalized medicine.
Citation Format: Erdem Bangi, Claudio Murgia, Alexander Teague, Owen Sansom, Ross Cagan. Identifying biomarkers of drug response and resistance using personalized Drosophila models of colorectal cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr PR03.
Tumor Twitter: Cellular Communication in the Breast Cancer Stem Cell Niche
Authors: Brooks Michael D. , Wicha Max S. 
Published: May 2015

Abstract
Summary: Communication between the diverse assortment of cells that constitute the tumor microenvironment plays an important role in tumor development. Using a p53-null mouse model, Zhang and colleagues describe a novel feedback loop involving breast cancer stem cells and their progeny mediated by WNT2, CXCL12, and IL6. Cancer Discov; 5(5); 469–71. ©2015 AACR.
See related article by Zhang et al., p. 520
The Interplay of Immunotherapy and Chemotherapy: Harnessing Potential Synergies
Authors: Emens Leisha A. , Middleton Gary 
Published: May 2015

Abstract
Although cancer chemotherapy has historically been considered immune suppressive, it is now accepted that certain chemotherapies can augment tumor immunity. The recent success of immune checkpoint inhibitors has renewed interest in immunotherapies, and in combining them with chemotherapy to achieve additive or synergistic clinical activity. Two major ways that chemotherapy promotes tumor immunity are by inducing immunogenic cell death as part of its intended therapeutic effect and by disrupting strategies that tumors use to evade immune recognition. This second strategy, in particular, is dependent on the drug, its dose, and the schedule of chemotherapy administration in relation to antigen exposure or release. In this Cancer Immunology at the Crossroads article, we focus on cancer vaccines and immune checkpoint blockade as a forum for reviewing preclinical and clinical data demonstrating the interplay between immunotherapy and chemotherapy. Cancer Immunol Res; 3(5); 436–43. ©2015 AACR.
240 human tumor cell line profiling to evaluate relationships between tumor genotypes and cancer cell sensitivity
Authors: O'Day Christine , Ovechkina Yulia , Marcoe Karen , Keyser Robert , Yoshino Karen , Nguyen Phuong , Bernards Karen , Chesnut-Speelman Jessica 
Published: May 2015

Abstract
Multiple targeted therapies have been shown to be effective for treating cancer such as imatinib for treating chronic myelogenous leukemia, erlotinib for non-small-cell lung cancers and trastuzumab for HER2 positive breast cancer. The sporadic sensitivity to these reagents has precipitated many inquiries into the relationship between phenotype and genotype. We have developed an in vitro cellular system to evaluate the relationship between tumor genotypes and cancer cell sensitivity over 240 human tumor cell lines. We used a panel of targeted therapeutics (such as erlotinib, CL-1040, and dasatinib) to demonstrate the prognostic value of this in vitro approach for developing anticancer drugs. This is a novel approach for a drug testing strategy for targeted anticancer therapeutics of interest to those in personalized medicine. This approach would help to match the drugs to a more efficacious patient population.
Early cancer therapy response assessment by quantitative F-18 FDG PET/CT
Authors: Mountz James M. , Laymon Charles , Deeb Erin , Chen Yin Jie 
Published: May 2015

Abstract
Purpose: Reliable noninvasive quantitative methods for assessing early response to chemotherapy are vital for development of more personalized cancer therapy management, by allowing earlier decisions regarding therapy changes. The CT RECIST method is widely used; however, CT does not provide information on the physiologic properties of the tumor. In this study, F-18 FDG (FDG) PET is compared to CT in predicting response to chemotherapy using changes in imaging biomarkers of tumor metabolism and size early after initiation of therapy compared to baseline (BL) and follow-up.
Materials and Methods: Nine patients with malignant cancer (lung, colorectal, or lymphoma) entered this early therapy response study. All patients received a BL scan before the initiation of chemotherapy, an early therapy assessment (ETA) scan between 2 to 7 weeks after initiation of therapy, and a study end point (FTA) scan between 3 to 9 months. The average length of time between ETA and FTA scans was 4 months. All PET/CT scans were performed on GE ST PET/CT scanner, approximately 60 min after patients received IV injection of approximately 15 mCi of F-18 FDG. All PET/CT images were registered and analyzed on MIMvista workstation to calculate FDG SUV values and CT RECIST measurements. By comparing BL and FTA scans, patients were classified as responders or non-responders based on RECIST. To compare FDG PET and CT data, the largest tumor was identified on CT at BL and its area and SUV were measured at ETA and FTA in each patient.
Results: At FTA, responders had an average (FTA CT area)/(BL CT area) of 0.40 and average (FTA SUV)/(BL SUV) of 0.25. For non-responders, these values were 1.55 and 1.27 respectively. At ETA, for responders, (ETA CT area)/(BL CT area) averaged 0.65 and (ETA SUV)/(BL SUV) averaged 0.26. For non-responders, these values were 1.19 and 1.15 respectively.
Conclusion: FDG uptake reduction at ETA compared to BL can be used to distinguish responders from non-responders, classified based upon RECIST at FTA. This early change in FDG uptake is more sensitive than early CT changes in predicting response to chemotherapy at FTA.
Research Support: This research was supported in part by grant U01 CA140230 from the National Cancer Institute to Dr. Mountz.
Imaging end-points to predict response to IGF1R/IR inhibition in CRC models
Authors: Serkova Natalie J. , Bradshaw-Pierce Erica L. , Hasebroock Kendra M. , Merz Andrea L. , Pitts Todd M. , Eckhardt Gail S. 
Published: May 2015

Abstract
This abstract is being presented as a short talk in Plenary Session 6. A full abstract is printed in the Proffered Abstracts section (PR9) of the Conference Proceedings.
The Imaging Probe Development Center at NIH: A central core facility for the production and dissemination of molecular imaging probes
Authors: Griffiths Gary L. 
Published: May 2015

Abstract
The Imaging Probe Development Center (IPDC, Rockville, MD), founded as part of the 2003 trans-NIH Roadmap for Medical Research initiative, provides synthetic chemistry support needed by interdisciplinary researchers for the supply of molecular imaging probes. Such research projects run from basic through translational to clinical in nature. The IPDC has state-of-the-art equipment and is staffed by scientists drawn from diverse backgrounds encompassing expertise in synthetic, inorganic, radiochemical, and conjugation chemistries. The IPDC has worked with principal investigators from over a dozen different NIH Institutes, along with some extramural collaborators, with a preponderance of projects related to cancer imaging, and has supplied literature-reported and novel agents used in all types of imaging modalities, including MRI, optical fluorescence and PET/SPECT. Examples of probes used for cancer imaging studies will be discussed including several radiolabeled low molecular weight drugs synthesized from first principles and radiolabeled monoclonal antibodies and other proteins. Several agents are undergoing further studies in clinical and process development. Recently made probes will be used to illustrate the scope and capabilities of the Center. The Center is able to work with other interested parties in order to develop useful imaging agents, particularly those that also have therapeutic implications. For more information, or to make enquiries about probe availability or potential collaborations you may visit our website at: http://www.ipdc.nih.gov.
Evaluation of c-FLIP(long), c-FLIP(short), and caspase 8 expression in primary tumors using a semiquantitative multiplex LSC-based assay
Authors: Wall Jason A. , Thor Christopher , Cottrell Susan , Rand Hugh , Branstetter Daniel , Pan Yang 
Published: May 2015

Abstract
Recent studies have demonstrated the value in quantification of tumor expression and mutational status of growth factor signaling components as potential predictors of clinical response. Quantification of elements in the apoptosis pathways may provide a similar value in predicting clinical response to new therapies based on induction of apoptosis through death-receptor-mediated signaling. To that end, we have qualified a 5-color multiplexed immune histofluorescent tissue-based assay to provide semiquantitative measurement of expression of death-inducing signaling complex (DISC) components. The DISC components we measured in FFPE archival samples from human solid tumors are caspase 8, c-FLIP(long) and c-FLIP(short). Additional components of the multiplex were a pan-keratin reagent for identification of cytokeratin expressing epithelial tumor cells, and a histone H3 reagent for staining quality control. Image collection was accomplished via laser scanning cytometry (LSC) with a data pipeline which generates FCS3.0 (flow cytometry standard 3.0) files. This allowed intensity analysis of gated tumor enriched regions via standard flow cytometry analysis software. Antibodies were identified via in vitro screens using high/low target expressing cell lines, and further tested using xenografts of the cell lines of interest. The assay was qualified by examining day-to-day, slide-to-slide, and inter-operator variability using xenograft TMA (tissue micro-array) controls. The intensity of stained samples over 24 hours was stable. Total experimental %CV was demonstrated to be less than 25%. We analyzed 6 commercially available cancer TMA slides containing 387 tumor cores representing colon, lung, pancreas, breast, sarcoma, and non-Hodgkin's lymphoma, along with 43 corresponding normal cores. We found a wide range of expression of caspase 8, c-FLIP(l), and c-FLIP(s) within each tumor type, as well as clear differences between normal and tumor tissues. These findings indicate a potential for stratification of clinical response by DISC protein expression in therapeutics that act via death receptor mediated apoptosis.