bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-B04: Complex drug combinations can induce apoptotic killing in robust colorectal cancer cells
Authors: Horn Thomas , Ferretti Stéphane , Ebel Nicolas , Tam Angela , Ho Samuel , Harbinski Fred , Farsidjani Ali , Zubrowski Matthew , Halilovic Ensar , Morris Erick , Sellers William R. , Schlegel Robert , Wuerthner Jens , Garraway Levi A. , Jeay Sébastien , Greshock Joel , Caponigro Giordano , Lehár Joseph 
Published: May 2016

Abstract
Tumors are complex and robust biological systems that harbor the potential to proliferate against various drug treatments. Drug combinations provide a promising therapeutic strategy, but it is not clear which and how many drugs are required to overcome cancers.
Using image-based proliferation and apoptosis assays in colorectal cancer cells we systematically investigated complex treatments composed of two to six drugs targeting critical oncogenic pathways. Drug pairs targeting growth signaling resulted in synergies across a broad spectrum of genetic backgrounds, but often yielded cytostatic responses and failed to induce apoptosis. Enhanced, and sometimes genotype-specific cytotoxicity was seen after targeting additional mechanisms including apoptosis or cell cycle. Cells that resisted all tested drug pairs and drug triples were protected by a mechanism that prevented apoptosis. Targeted inhibition of this mechanism using combinations of up to four compounds induced cytotoxic responses in cells in vitro and in vivo.
Our results demonstrate that complex combinations of targeted drugs might be required to induce killing in cancers and show how the cells' genetic alterations and a molecular understanding of drug responses can guide their identification. The identification of resistance mechanisms that are pre-existing in subpopulations of tumor cells also opens the exciting avenue of sequenced treatments, with each drug or drug combination targeting and eradicating a specific cell population.
Citation Format: Thomas Horn, Stéphane Ferretti, Nicolas Ebel, Angela Tam, Samuel Ho, Fred Harbinski, Ali Farsidjani, Matthew Zubrowski, Ensar Halilovic, Erick Morris, William R. Sellers, Robert Schlegel, Jens Wuerthner, Levi A. Garraway, Sébastien Jeay, Joel Greshock, Giordano Caponigro, Joseph Lehár. Complex drug combinations can induce apoptotic killing in robust colorectal cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-B04.
Abstract LB-B06: Functionally defined therapeutic targets in diffuse intrinsic pontine glioma
Authors: Grasso Catherine S. 
Published: May 2016

Abstract
Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood cancer that has a limited response to treatment (median survival after diagnosis is only 9 months). Historically, DIPG research has been limited by a dearth of tumor tissue available for study and a lack of experimental model systems. Recently, both cell cultures derived from patients with DIPG and orthotopic xenograft models have been established. We performed a chemical screen in 16 patient-derived DIPG cultures using 83 drugs, selected by pediatric neurooncologists as either promising small-molecule compounds or traditional chemotherapeutic agents. Of these 83 drugs, 14 showed activities against three or more DIPG cultures. Notable ‘misses’ that highlight the resistance of this tumor to traditional chemotherapies included temozolomide, carboplatin, and vincristine, while DIPG cell cultures were reported to have substantial sensitivity to histone deacetylase inhibitors, consistent with the highly recurrent H3K27M driving mutations in ∼80% of DIPG. Panobinostat was one of the most effective drugs screened, with 12/16 DIPG cultures showing sensitivity to this drug. Compared to vorinostat, another HDAC inhibitor, panobinostat exhibited substantially greater potency against DIPG cells. Treatment of DIPG cultures with panobinostat yielded a time and dose-dependent decrease in viability (RNA-mediated knockdown of HDAC1 and HDAC2 confirmed the mechanism of action). Treatment of DIPG cultures with panobinostat also increased H3 acetylation and H3K27 trimethylation, and led to a partial rescue of the H3K27M induced global hypotrimethylation phenotype. Increased K27 trimethylation was an unexpected effect of the drug, but it is consistent with recent findings that acetylated H3K27 can ‘detoxify’ K27M-induced inhibition of PCR2. RNA-seq performed on panobinostat- or vehicle-treated DIPG cells revealed sweeping changes in gene expression, including normalization of the K27M gene expression signature and decrease of the oncogenic MYC target gene-expression signature. In addition, the multi-histone deacetylase inhibitor panobinostat demonstrated efficacy in DIPG orthotopic xenograft models administered using convection enhanced delivery. Combination testing of panobinostat and the histone demethylase inhibitor GSK-J4, recently shown to decrease viability of mutant DIPG cells, revealed that the two had synergistic effects. Together, these data suggest a promising FDA-approved therapeutic strategy for DIPG that could be rapidly translated for use in the clinic, further indicating that epigenetic modifying therapies are emerging as the most promising class of agents for the treatment of DIPG.
Citation Format: Catherine S. Grasso. Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-B06.
Abstract LB-B12: Using MiXeno Mouse Models as Robust Tool to Evaluate T Cell Dependent Immunotherapies
Authors: Zhang Juan , Qiao Meng , Shi Qian 
Published: May 2016

Abstract
Backgrounds: Fighting cancer by taking advantage of a patient's own immune system is showing considerable success in oncology research. Using therapeutic antibodies against tumor-associated antigens or modulating the host immune system, has been shown to prolong survival of patients with certain solid tumors or leukemia, particularly when combined with conventional treatments. Recent fast-track designations and regulatory approvals (including the first FDA approvals of anti-PD-1 agents in advanced melanoma) have signified the coming of age of cancer immunotherapy as a treatment paradigm, creating both potential patient benefits and commercial success for the pharmaceutical industry. A lack of experimental immunotherapy models is a major obstacle toward answering these questions and developing better treatments, and there is a high unmet need for new preclinical models to help drive forward immune therapy research and to recapitulate clinical treatments.
Results: Crown Bioscience has created transient human immunity in mice (MiXeno) for testing human immunotherapeutics, particularly T cell engaged immunotherapies by mixing human peripheral blood mononucleated cells (PBMC) with xenograft models. Our data showed that anti-human PD-1 or PD-L1 antibodies demonstrated significant anti-tumor activities in several Mixeno models, including A375 melanoma model and KARPAS-299 lymphoma model. The emergence of the efficacy coincided with the T cell reconstitution in mouse blood. T cells are also recruited to the tumor microenvironment. The number of T cells in the tumor microenvironment varies significant and is largely dependent on tumor cells itself.
Conclusion: The MiXeno model provides an alternative to the full stem cell reconstitution approach, and may allow T cell engaged immunotherapies (monotherapies or combinational therapies) to be evaluated in xenograft models.
Citation Format: Juan Zhang, Meng Qiao, Qian Shi. Using MiXeno Mouse Models as Robust Tool to Evaluate T Cell Dependent Immunotherapies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-B12.
Abstract LB-C10: Identification of Therapeutic Targets for Chemotherapy-Resistant Colon Cancer Stem Cells
Authors: Francipane Maria Giovanna , Bulanin Denis , Lagasse Eric 
Published: May 2016

Abstract
Current first-line chemotherapy generally consists of cytotoxic agents. While these agents may initially control disease by effectively debulking tumors, the tumors invariably recur due to the ability of cancer stem cells (CSCs) to survive and repopulate the tumor mass.
To identify potential molecular targets in 5-fluorouracil (5-FU) refractory CSCs, we developed 5-FU resistant cell lines over a period of a year.
Here we show that 5-FU maintains colon CSCs in an undifferentiated state in vitro. While untreated control cells passaged in parallel progressively acquired a differentiated morphology comprising crypt-villus structures, cells treated with an IC50 dose or escalating doses of 5-FU organized in round colonies with defined edges. Cells from these chemoresistant colonies exhibited a high nucleus-to-cytoplasm ratio and prominent nucleoli, features of pluripotent stem cells. Chemoresistant cells showed a reduced proliferation rate with respect to their counterparts. While immunofluorescent analysis revealed chemoresistant cells expressed a panel of pluripotency markers, flow cytometric analysis indicated a change in CD antigens associated with tumorigenicity and pluripotency in chemoresistant cells as compared to untreated cells. These results suggest colon CSCs, while under the selective pressure of chemotherapy in vitro, are likely to display an adaptive plasticity resembling fate reprogramming.
Three-dimensional growth in Matrigel revealed untreated cells were able to arrange themselves in a ring around a well-defined central lumen. Conversely, chemoresistant cell-derived organoids had poorly defined or no central lumens. While untreated cells generated fast-growing, well-differentiated tumors, resistant cells generated slow-growing, moderately differentiated tumors in vivo.
Finally, a large number of genes were screened in cell/tissue from both groups using Real-Time PCR arrays. Through this analysis, we identified molecular targets that might assist in the development of therapeutic strategies which will counteract the mechanisms of chemoresistance.
Citation Format: Maria Giovanna Francipane, Denis Bulanin, Eric Lagasse. Identification of Therapeutic Targets for Chemotherapy-Resistant Colon Cancer Stem Cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C10.
Abstract PL02-02: Progress in lung cancer treatment with immunotherapy
Authors: Garon Edward B. 
Published: May 2016

Abstract
As recently as a few years ago, non-small cell lung cancer (NSCLC) was not considered particularly amenable to therapeutic approaches that manipulated immune responses. The rapid transition to inhibition of the programmed cell death 1 (PD-1) immune checkpoint in routine management of NSCLC patients has been remarkable. Although the duration of response to this class of drugs is impressive, particularly in light of comparator therapies, the restriction of responses to a minority of those treated limits the benefit to select patients. During the development of inhibitors of the PD-1 immune checkpoint in NSCLC, biospecimens including tissue and blood have been collected to evaluate predictors of response to this class of agents. Despite extensive evaluation though, controversy exists. The role of various factors in identifying patients likely to respond to inhibition of the PD-1 immune checkpoint is an area of intensive investigation. The relative importance of factors 1) intrinsic to the tumor such as staining for biomarkers including the PD-1 ligand PD-L1 and tumor mutational load, 2) factors seen in the infiltrating immune cells, including the presence and types of immune cell and staining for PD-L1, and 3) factors specific to the patient and the process of carcinogenesis (such as prior smoking history) are being defined.
Citation Format: Edward B. Garon. Progress in lung cancer treatment with immunotherapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL02-02.
Abstract PL03-01: Targeting K-RAS driven cancer
Authors: Barbacid Mariano 
Published: May 2016

Abstract
K-RAS oncogenes have been implicated in about one fifth of all human cancers including lung adenocarcinoma and pancreatic ductal adenocarcinoma, two tumor types with some of the worse prognosis. In order to identify effective therapeutic strategies to treat these tumors, we have developed genetically engineered mouse (GEM) models that closely recapitulate their natural history. We are using these mice to validate targets of potential therapeutic value with the ultimate goal to translate these findings to the clinic. In previous studies, we have crossed these GEM models with mice that carried either germ line or lox-Cre conditional knock out loci encoding each of the downstream kinases of the Raf/Mek/Erk pathway as well as the cell cycle interphase Cdks to interrogate their role in the development of K-Ras driven lung adenocarcinomas. These studies have led us to validate the c-Raf and Cdk4 kinases as essential targets for these tumors (Puyol et al., Cancer Cell 2010; Blasco et al., Cancer Cell 2011). Following a similar strategy, we have demonstrated that the EGF Receptor and c-Raf were also absolutely essential for the development of pancreatic ductal adenocarcinomas (Navas et al., Cancer Cell 2012). Importantly, systemic ablation of either c-Raf or Cdk4 has no significant effect on normal homeostasis. Now, we have decided to interrogate the role of these targets in advanced tumors. To this end, we have generated new GEM models in which expression of the resident K-Ras oncogene, as well as ablation of the p53 tumor suppressor is mediated by the frt-FLp(o) targeting system, a strategy that allows temporal separation of tumor development from target ablation. In addition, we have generated lox-Cre based conditional knock-in strains that upon recombination direct the expression of kinase dead isoforms instead of inducing protein ablation. We feel that these strains should serve as better models to mimic drug intervention in the clinic. Finally, we are now combining ablation (or inactivation) of these targets in order to identify combinations that may eventually eradicate advanced tumors. We hope that these studies will serve to guide the design of future clinical trails to treat patients carrying K-RAS mutant tumors.
Citation Format: Mariano Barbacid. Targeting K-RAS driven cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL03-01.
Abstract PL05-01: ERCC1 alternative readouts
Authors: Kuo Mei-Shiue , Olaussen Ken A. , Soria Jean-Charles 
Published: May 2016

Abstract
Platinum-based compounds, including cisplatin and oxaliplatin, trigger cell death by distorting the helix structure and subsequently affecting DNA replication and transcription. The therapeutic efficacy of platinum-based chemotherapy varies among patients and only a portion of them have real benefits. Precision medicine searches for the optimal therapy for each patient. The proteins involved in DNA repair are thus potential biomarkers to select patients more prone to respond to platinum-based chemotherapy.
The ERCC1 (excision repair cross-complementation group 1) protein is essential in nucleotide excision repair (NER) and other repair pathways involved in the repair of platinum-induced DNA damages. ERCC1 with its partner XPF (xeroderma pigmentosum complementation group F) form a structure-specific endonuclease that is responsible for 5' incision during DNA repair. ERCC1 has been reported to be a prognostic and predictive biomarker for cisplatin treatments in various cancers. Many studies have shown that the ERCC1 status, including ERCC1 polymorphisms, ERCC1 RNA expression and ERCC1 protein expression, are associated with platinum-based therapy efficacy. However, this correlation between ERCC1 status and the clinical outcome has not always reached a consensus, probably due to inadequate methods to determine ERCC1 expression and unreliability of the current commercial ERCC1 antibodies.
Alternative splicing leads to several isoforms of ERCC1. We have reported that only ERCC1-202 mediates highly efficient removal of platinum-GG intrastrand adducts and should therefore be considered as the only functional isoform. Putative roles of the other isoforms remain unknown. The expression of ERCC1 is mostly determined by qRT-PCR or IHC. However, these two methods are not able to discriminate the functional ERCC1-202 isoform from other isoforms. We will present the design of a tailor-made antibody directed against the interacting complex ERCC1/XPF. This new ERCC1/XPF heterodimer-specific antibody permits the detection of the functional ERCC1-202 isoform when it is used in combination with other antibodies in proximity ligation assays (PLA). The applicability of this alternative read out for ERCC1 expression on clinical samples will be discussed.
Citation Format: Mei-Shiue Kuo, Ken A. Olaussen, Jean-Charles Soria. ERCC1 alternative readouts. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL05-01.
Abstract PL08-04: High-throughput drug screens in cancer cell models to enable precision cancer medicine
Authors: Garnett Mathew 
Published: May 2016

Abstract
Alterations in cancer genomes strongly influence clinical responses to therapy and can be used as molecular biomarkers of response to targeted agents. However, the identification of biomarkers for effective patient stratification remains a considerable challenge for the development of effective therapies.
We are performing large-scale drug sensitivity screens using genetically characterised in vitro cellular models of human cancer. Cancer cells are profiled for differential sensitivity to clinical, pre-clinical and experimental anti-cancer compounds and drug response is linked with genomic features. We aim to identify the molecular features of cancer cells which impact on drug sensitivity and resistance, and investigate the molecular rationale for the observed sensitivity. This provides insights into mechanism of drug action, identifies opportunities for re-purposing existing drugs for new indications, and enables the identification of biomarkers to facilitate the development of targeted cancer therapies.
I will describe results from our recent analysis of how cancer-driving alterations identified from the analysis of 11,000 patient tumours correlate with response to 265 compounds profiled in a panel of 1,000 human cancer cell-lines. This comprehensive analysis provides an initial glimpse of the landscape of pharmacogenomic interactions operative in human cancer, and is a resource to identify novel therapeutic possibilities for selected cancer sub-populations.
Citation Format: Mathew Garnett. High-throughput drug screens in cancer cell models to enable precision cancer medicine. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL08-04.
Abstract PR03: Novel ceritinib resistance mechanisms: new resistant mutation, fibroblast growth factor receptor 3 overexpression and cMET amplification-mediated ceritinib resistance
Authors: Katayama Ryohei , Sakashita Takuya , Yanagitani Noriko , Takeuchi Kengo , Nishio Makoto , Fujita Naoya 
Published: May 2016

Abstract
Anaplastic lymphoma kinase (ALK) rearrangement, which was first identified in non-small cell lung cancer (NSCLC) in 2007, is observed in 3%-5% of non-small-cell lung cancer (NSCLC) patients. For the treatment of ALK-rearranged non-small-cell lung cancer (NSCLC) patient, crizotinib, cMET/ALK/ROS1-TKI was tested and has shown remarkable tumor shrinkage in clinical trials for the treatment of advanced ALK-rearranged NSCLC patients. However, these tumors inevitably develop resistance to crizotinib due to various secondary mutations, ALK fusion gene amplification, or bypass pathway activation mediated by other receptor tyrosine kinases. To overcome crizotinib resistance, multiple ALK-TKIs have been developed. Ceritinib, a next-generation ALK-TKI, showed great efficacy in crizotinib-refractory, ALK-rearranged NSCLC patients in a clinical trial. However, the emergence of resistance to ALK-TKI is a major limitation for the effective therapy. Although various secondary mutations or bypass pathway activation-mediated resistance have been identified, large part of the resistance mechanism is still unknown.
In this study, we explored ceritinib-resistant mechanisms using ceritinib-resistant, echinoderm microtubule-associated protein-like 4-ALK-positive H3122 cells and ceritinib-resistant patient-derived cells. Genetic alteration was examined by sequencing of cancer related genes. Protein expression related to ceritinib was examined by receptor-tyrosine kinase (RTK) array, immunoblotting and IHC. To overcome the identified resistance, single or combination treatment of the kinase inhibitors was testes in vitro and in vivo.
We identified three novel ceritinib resistance mechanisms: a resistance mutation (L1198F), fibroblast growth factor receptor 3 (FGFR3) activation, and cMET gene amplification. L1198F-mutated ALK was the most sensitive to crizotinib. Molecular dynamic structure simulation successfully predicted the affinity of ceritinib or crizotinib to wild type and L1198F-mutated ALK. The patient-derived cMET-amplified ceritinib-resistant cells were sensitive to crizotinib, and the FGFR3-upregulated, ceritinib-resistant H3122 cells were re-sensitized to ALK-TKIs by FGFR inhibitor co-treatment.
Our study revealed multiple ceritinib resistance mechanisms and suggest that some of the ceritinib resistance can be overcome by crizotinib.
Citation Format: Ryohei Katayama, Takuya Sakashita, Noriko Yanagitani, Kengo Takeuchi, Makoto Nishio, Naoya Fujita. Novel ceritinib resistance mechanisms: new resistant mutation, fibroblast growth factor receptor 3 overexpression and cMET amplification-mediated ceritinib resistance. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PR03.
Abstract PR07: AZD9291 activity in patients with leptomeningeal disease from non-small cell lung cancer: a Phase I study
Authors: Lee Dae Ho , Kim Dong-Wan , Ahn Myung-Ju , Cho Byoung Chul , Lee Jong Seok , Ye Xin , Yang Pamela , Jiang Haiyi , Yang James Chih-Hsin 
Published: May 2016

Abstract
This abstract has been withheld from publication due to its inclusion in the AACR-NCI-EORTC Molecular Targets Conference 2015 Official Press Program. It will be posted online at the time of its presentation in a press conference or in a session.
Citation Format: Dae Ho Lee, Dong-Wan Kim, Myung-Ju Ahn, Byoung Chul Cho, Jong Seok Lee, Xin Ye, Pamela Yang, Haiyi Jiang, James Chih-Hsin Yang. AZD9291 activity in patients with leptomeningeal disease from non-small cell lung cancer: a Phase I study. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PR07.