tbuckley/cabot-search huggingface dataset:
Abstract 4801: Collection of lung cancer patient-derived xenograft (PDX) models to evaluate precision therapeutic strategies
Authors: Sonia Molina-Pinelo, Ricardo Melendez, Rocío Suarez, Laura García, Laura Ojeda, Nicolas Moreno, María V Guijarro, Luis Paz-Ares, Irene Ferrer
Journal: Cancer Research (2017)

Abstract Background: Translational cancer research needs appropriated preclinical models to discover predictive biomarkers and evaluate precision therapeutic strategies. Conventional available preclinical models have proven not been optimal to this end, since cell lines based xenografts do not reconstitute the complexity of human cancer and carry acquired mutations not found in the original tumor. For these reasons our aim was generate and completely characterize a collection of non-small cell lung cancer (NSCLC) PDX models useful for translational lung cancer research. Materials and methods: Resected primary tumors from NSCLC patients were subcutaneous xenografted in athymic nude mice and expanded in successive groups of mice to get a perpetual live bank of each tumor. Every tumor, which successfully grew in mice, was analyzed by histologic and molecular techniques (NGS gene panel, exome and RNA Seq). Furthermore, a bank of frozen pieces of tumor was expanded and stored in order to generate later cohorts of tumor-bearing mice suitable for preclinical drug evaluation. Results: Our collection consists on 42 PDX models (26 SCC, 12ADC, 3LCC). We have characterized all of them histologically and molecularly with a 22 genes NGS panel. Furthermore, we have analyzed the exome and transcriptome of 33 models (20 SCC, 10 ADC and 3 LCC). All PDX models mostly retain the principal histologic and molecular characteristics of their donors and recapitulate the heterogeneity of human lung tumors. In our PDX collection we have sufficiently represented all the NSCLC histology and the most relevant molecular alterations in lung cancer in order to perform precision medicine evaluation studies. Conclusions: We have generated a collection of 42 PDX models of NSCLC characterized at the histological, genomic and transcriptomic level, which represents the most frequent histological and molecular subtypes of this type of lung cancer. This collection will be really useful to integrate drug screening with biomarker discovery and to evaluate precision therapeutic strategies. Our future aim will be to use this collection for biomarkers identification and preclinical evaluation of new therapeutic strategies targeted to bad prognostic lung tumors with suboptimal therapeutic approaches. Citation Format: Sonia Molina-Pinelo, Ricardo Melendez, Rocío Suarez, Laura García, Laura Ojeda, Nicolas Moreno, María V Guijarro, Luis Paz-Ares, Irene Ferrer. Collection of lung cancer patient-derived xenograft (PDX) models to evaluate precision therapeutic strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4801. doi:10.1158/1538-7445.AM2017-4801
Abstract 4620: Signaling cascade of metastasis-associated macrophages determines breast cancer distal metastasis
Authors: Bin-Zhi Qian
Journal: Cancer Research (2017)

Abstract Macrophages are abundantly found in the tumor microenvironment and enhance malignancy. At distal metastatic sites, our previous studies identified a distinct population of metastasis-associated macrophages (MAMs) that promote tumor cell extravasation, seeding and persistent growth. These macrophages were derived from inflammatory monocytes recruited by CCL2/CCR2 chemokine signaling and directly promote tumour cell extravasation through VEGF production. Our recent studies identified two subsequent signaling pathways that mediate the retention and function of MAMs after recruitment that are critical for tumour cell survival and persistent growth. Specifically, activation of CCR2 signaling turns on CCL3 expression in MAMs. Genetic deletion of CCL3 or its receptor CCR1 in macrophages reduces lung metastasis, and MAM accumulation in tumor-challenged lung. Adoptive transfer of wild type monocytes restores lung metastasis in Ccl3 deficient mice. Mechanistically, Ccr1 deficiency prevents MAM retention in the lung by reducing direct MAM-tumour cell interactions. On the other hand, MAMs turn on cell surface expression of FMS-like tyrosine kinase 1 (FLT1) upon differentiation from monocytes. Using several genetic models of Flt1 deficiency, we show that macrophage specific FLT1 signaling is critical for breast tumor distal metastatic potential. FLT1 specific inhibitory antibody significantly inhibits the metastatic seeding and persistent growth but does not affect the recruitment or retention of MAMs. Furthermore, we identified that FLT1 signaling regulates a set of downstream inflammatory response genes including Colony Stimulating Factor 1 (CSF1) a central regulator of macrophage biology. Using a genetic gain-of-function approach we show that CSF1 mediated autocrine signaling in MAMs is downstream of FLT1 and can restore the tumor-promoting activity in MAMs even when FLT1 is inhibited. Together, our data indicates CCL3/CCR1 and FLT1 signaling pathways are critical in regulating MAMs and promoting breast cancer distal metastasis, and suggests the therapeutic potential of targeting these pathways in treating metastatic disease. Note: This abstract was not presented at the meeting. Citation Format: Bin-Zhi Qian. Signaling cascade of metastasis-associated macrophages determines breast cancer distal metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4620. doi:10.1158/1538-7445.AM2017-4620
Abstract 3082: Deficient NOXA in HER2-amplified breast cancer drives kinase inhibitor resistance
Authors: Konstantinos V. Floros, Kyung-A Song, Timothy L. Lochmann, Mark T. Hughes, Daniel A. Heisey, Hisashi Harada, Bin Hu, Jennifer Koblinski, Andrew J. Souers, Joel D. Leverson, Anthony C. Faber
Journal: Cancer Research (2017)

Abstract The purpose of this study is the development of a novel combination therapy that targets HER2-amplified breast cancer. About one quarter of breast cancers harbor amplification of HER2. HER2 is a transmembrane receptor tyrosine kinase (RTK) belonging to the ERBB family of receptors (ERBB1-4). Upon hetero- and homo-dimerization, HER2 activates several key intracellular pathways, regulating many cellular functions including proliferation and survival. HER2 inhibitors (HER2i) (e.g. the receptor tyrosine kinase (RTK) inhibitor, lapatinib) are now part of standard care for treating HER2-amplified breast cancers. However, despite their anti-cancer benefit, these drugs have limited efficacy as monotherapies, which contrasts to other RTK inhibitors in other RTK-driven cancers. To better understand this apparent dichotomy, in the present study, we evaluated potential modifiers of HER2i therapy. Here, we found that the pro-apoptotic NOXA, a member of the B-cell CLL/lymphoma 2 (BCL2) family which acts mainly via inhibitory binding of the pro-survival MCL-1, was markedly down-regulated in breast cancers compared to other cancers, and this was largely attributed to the HER2-amplified subset. Experimentally, overexpressing NOXA or silencing MCL-1 dramatically sensitizes HER2 amplified breast cancer cell lines to lapatinib via apoptosis. Consistently, pharmaceutical inhibition of MCL-1 sensitizes HER2-amplified breast cancers to lapatinib in vitro and in vivo. Mechanistically, disruption of MCL-1:BIM complexes and MCL-1:BAK underlie dual HER2i/MCL-1i therapy. Therefore, deficient NOXA expression constitutes a bonafide apoptotic block in HER2 amplified breast cancers, contributes to mitigated HER2i responses, and presents a rational combination therapy that may improve HER2i responses. Citation Format: Konstantinos V. Floros, Kyung-A Song, Timothy L. Lochmann, Mark T. Hughes, Daniel A. Heisey, Hisashi Harada, Bin Hu, Jennifer Koblinski, Andrew J. Souers, Joel D. Leverson, Anthony C. Faber. Deficient NOXA in HER2-amplified breast cancer drives kinase inhibitor resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3082. doi:10.1158/1538-7445.AM2017-3082
Abstract 1024: Genome-wide examination of topological variability reveals cell type-specific mechanisms of oncogene activation
Authors: Caleb Lareau, Martin Aryee
Journal: Cancer Research (2017)

Abstract INTRODUCTION: The organization of chromatin within the nucleus into hierarchical three-dimensional (3D) structures plays a key role in the regulation of gene expression. Differences in 3D architecture, such as the presence or absence of “loops” between specific enhancers and their target genes, are a major driver of transcriptional and phenotypic variation. By determining the accessibility of genes to transcriptional machinery and distal regulatory regions, mechanisms mediating oncogene activation can be discerned. Recent studies have implicated pathogenic alterations in genome topology with the activation of proto-oncogenes in a multitude of cancers. METHODS: To characterize the topological changes associated with different cancer states, we developed a computational suite of tools that facilitates the systematic discovery, annotation, and visualization of features in chromatin topology and assigns statistical confidence estimates to regions with variability between cellular phenotypes. Our framework facilitates the integration of heterogeneous genomic data, including gene expression, histone modification, DNA methylation, open chromatin, and genetic variation, to further characterize changes in 3D genome. Ultimately, we propose a joint model that functionalizes the effect of epigenetic modifications on transcription as mediated through hierarchical chromatin structure. RESULTS: We identify regions of topological variation unique to breast cancer, cervical cancer, glioblastomas with and without an IDH1 mutation, melanoma, and leukemia. Patterns of disrupted insulation and subsequent localization of enhancers to proto-oncogenes can be attributed to variation in the epigenome, including variation in DNA methylation and open chromatin, at distal regulatory regions. These 3D alterations provide a mechanism for activation of specific oncogenic pathways, including signaling mediated by p38, PLK3, and BRCA. CONCLUSIONS: Variable patterns of chromatin topology provide a unique signature and mechanism of oncogenes for the cancer phenotypes considered. Additionally, our framework provides a novel means for interpreting epigenetic variability, particularly at distal regulatory regions, and explaining transcriptional variation associated with cancer phenotypes as mediated through structural changes in the DNA. Citation Format: Caleb Lareau, Martin Aryee. Genome-wide examination of topological variability reveals cell type-specific mechanisms of oncogene activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1024. doi:10.1158/1538-7445.AM2017-1024
Abstract 1913: SOX9 regulates cancer stem-like cells in non-small cell lung cancer
Authors: Maria Voronkova, Sudjit Luanpitpong, Heimo Riedel, Yon Rojanasakul
Journal: Cancer Research (2017)

Abstract Lung cancer is the leading cause of cancer death worldwide in both men and women, every year killing more people than breast, prostate and colon cancers combined. Drug/radiation resistance and tumor relapse contribute to low patient survival, which has largely been attributed to the acquisition of stem-like cells (CSCs), or tumor initiating cells. Moreover, conventional therapies are not effective against CSCs. This signifies the need to identify mechanisms of CSC regulation which could lead to the discovery of CSC-specific drug targets and the development of more effective drug therapies. An embryonic transcription factor SOX9 has been implicated in CSC regulation in a number of cancer types, but little is known about its role in non-small cell lung cancer (NSCLC). We demonstrated that high SOX9 expression correlates with poor survival in lung cancer patients by analyzing The Cancer Genome Atlas (TCGA) data. We hypothesized that SOX9 plays a key role in tumor progression and chemoresistance by upregulating CSCs in NSCLC. To test this hypothesis, SOX9 expression was stably or transiently knocked down in NSCLC cells, and their effects on CSC formation and biomarkers, and on drug resistance were investigated. Our results showed that SOX9 knockdown decreased the number of tumor spheres in NSCLC cell lines. Furthermore, SOX9 knockdown downregulated the expression and activity of stem cell marker ALDH1A1 as determined by Western blot and flow cytometric assays. Consistent with this finding, overexpression of SOX9 in non-cancer lung epithelial Beas-2B cells elevated tumor sphere formation, supporting the role of SOX9 in CSC regulation. Analysis of the soft agar colony formation assay further showed that SOX9 knockdown inhibited anchorage-independent growth in NSCLC cells. More importantly, SOX9 knockdown resulted in an increased sensitivity of the cells to a chemotherapeutic drug cisplatin, whereas SOX9 overexpression decreased it. Together, our results indicate an important role of SOX9 in the regulation of CSCs in NSCLC and suggest its potential utility as a drug target for chemoresistant lung cancer. Citation Format: Maria Voronkova, Sudjit Luanpitpong, Heimo Riedel, Yon Rojanasakul. SOX9 regulates cancer stem-like cells in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1913. doi:10.1158/1538-7445.AM2017-1913
Glutamic Pyruvate Transaminase GPT2 Promotes Tumorigenesis of Breast Cancer Cells by Activating Sonic Hedgehog Signaling
Authors: Yuan Cao, Shu-Hai Lin, Yongbin Wang, Y. Eugene Chin, Lan Kang, Jun Mi
Journal: Theranostics (2017)

Increased glutamine metabolism is a hallmark of cancer. Mitochondrial glutamic pyruvate transaminase (GPT2) catalyzes the reversible transamination between alanine and α-ketoglutarate (α-KG), also known as 2-oxoglutarate, to generate pyruvate and glutamate during cellular glutamine catabolism. However, the precise role of GPT2 in tumorigenesis remains elusive. Here, we report that in breast cancer tissue samples and breast cancer cell lines, GPT2 expression level was markedly elevated and correlated with the pathological grades of breast cancers. GPT2 overexpression increased the subpopulation of breast cancer stem cells in vitro and promoted tumorigenesis in mice. GPT2 reduced α-KG level in cells leading to the inhibition of proline hydroxylase 2 (PHD2) activity involved in the regulation of HIF1α stability. Accumulation of HIF1α, resulting from GPT2-α-KG-PHD2 axial, constitutively activates sonic hedgehog (Shh) signaling pathway. Overall, GPT2 promotes tumorigenesis and stemness of breast cancer cells by activating the Shh signaling, suggesting that GTP2 is a potential target for breast cancer therapy.
Preparation and pharmacokinetic study of fenofibrate cubic liquid crystalline
Authors: Shijie Wei, Jingbo Ren, Ning Li, Wuzhen Huo, Chongkai Gao
Journal: Asian Journal of Pharmaceutical Sciences (2017)

An LCC delivery system for Fenofibrate (Fen) was developed to improve its poorly oral bioavailability. Fen-LCC preparation methods were screened, and the prepared Fen-LCC was then characterized by a polarizing microscope and transmission electron microscopy (TEM). The spray drying technique was selected to dry and solidify particles into powder. The in vitro release of Fen-LCC was measured and in vivo pharmacokinetic experiments were carried out on rats after oral administration. Particles prepared through the high-temperature input method exhibited structural characteristics of LCC, and re-dissolved particles maintained the same features. The LCC delivery system can significantly improve in vitro release outcomes. After oral administration, AUCs of the suspension and LCC systems were measured at 131.6853 µg⋅h/ml and 1435.72893 µg⋅h/ml, respectively. The spray drying process presented here better maintains cubic structures, and the LCC system significantly improves bioavailability levels.
Abstract 3053: Stability and stemness of the hybrid epithelial-mesenchymal phenotype
Authors: Mohit Kumar Jolly, Dongya Jia, Satyendra C. Tripathi, Steve Mooney, Muge Celiktas, Samir M. Hanash, Sendurai A. Mani, Kenneth J. Pienta, Eshel Ben-Jacob, Herbert Levine
Journal: Cancer Research (2017)

Abstract Transitions between epithelial and mesenchymal phenotypes – EMT and MET – are hallmarks of cellular plasticity during embryonic development and cancer metastasis. During these transitions, cells can also adopt a hybrid epithelial/mesenchymal (hybrid E/M) phenotype enabling them to migrate collectively as observed during gastrulation, wound healing, and clusters of Circulating Tumor Cells (CTCs). The hybrid E/M phenotype has largely been tacitly assumed to be 'metastable', i.e. transient state. Here, we integrate mathematical modeling with in vitro experiments to identify certain 'phenotypic stability factors' (PSFs) - GRHL2, OVOL2 and ΔNP63α that can stabilize a hybrid E/M phenotype. We show that H1975 (NSCLC cell line) cells can display a hybrid E/M phenotype stably and migrate collectively, a behavior that is impaired by knockdown of GRHL2 or OVOL2. Further, our computational model predicts that these PSFs can also associate hybrid E/M phenotype with high tumor-initiating potential, a prediction strengthened by the observation that the higher levels of one or more of these PSFs may predict poor patient outcome. Overall, our results suggest that a hybrid E/M phenotype need not be 'metastable', and bolster the notion that a hybrid E/M phenotype, but not necessarily full EMT, associates with aggressive tumor progression. Citation Format: Mohit Kumar Jolly, Dongya Jia, Satyendra C. Tripathi, Steve Mooney, Muge Celiktas, Samir M. Hanash, Sendurai A. Mani, Kenneth J. Pienta, Eshel Ben-Jacob, Herbert Levine. Stability and stemness of the hybrid epithelial-mesenchymal phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3053. doi:10.1158/1538-7445.AM2017-3053
Abstract 3418: Additional mutation in <i>PTPN11</i> gene promotes tumorigenesis of the <i>NF1</i> gene mutated cells
Authors: Yoshimi Arima, Ritsuko Harigai, Ryo Sato, Toshiki Takenouchi, Kenjiro Kosaki, Hideyuki Saya
Journal: Cancer Research (2017)

Abstract The NF1 tumor suppressor gene encodes neurofibromin and is a functional Ras GTPase-activating protein (RasGAP) involved in negatively regulating the Ras signal by accelerating the conversion of activated Ras-GTP to inactive Ras-GDP. NF1 gene germline mutations cause Neurofibromatosis type 1 (NF1, von Recklinghausen disease). We hypothesized that additional genetic alterations promote the malignancy of NF1-associated tumors. To test our hypothesis, we inoculated a GFP-labeled human NF1-deficient cell line, sNF96.2-GFP, which has a frame-shift mutation (c.3683delC, p.Asn1229MetfsTer11) in the NF1 gene, into the renal sub-capsules of immunodeficient mice. A subclonal cell line, the A-1 cell, was established from the developed tumor. We found that A-1 cells show much higher tumorigenic activity and phosphorylation status of MEK and Akt than the parental sNF96.2-GFP cells. We analyzed the genomic DNA of both the sNF96.2 and the A-1 cells by using the next-generation sequencing and our medical exome panel of 4813 genes, which are known to be responsible for most human genetic disorders. We identified 18 heterozygous variants within coding regions of 17 genes that were present in the A-1 cells, but not in the original sNF96.2 cells. We found a single base substitution (c.1508G&amp;gt;T, p.Gly503Val) in the PTPN11 gene, which encodes the tyrosine phosphatese SHP-2, and is associated with the regulation of the Ras signaling pathway. It is critical to note that constitutional gain-of-function mutations in the PTPN11 gene cause Noonan Syndrome in humans due to activation of the Ras pathway. To determine the role of PTPN11 mutation in NF1-associated tumors, we established a cell line overexpressing PTPN11mut in sNF96.2-GFP cells. We inoculated parental cells and PTPN11mut cells into the subcutaneous of nude mice, and we found that PTPN11mut cells show much higher tumorigenic activity than the parental sNF96.2-GFP cells. Our data suggests that this additional gene mutation in PTPN11 promotes the malignant characteristics of NF1-associated tumors. Citation Format: Yoshimi Arima, Ritsuko Harigai, Ryo Sato, Toshiki Takenouchi, Kenjiro Kosaki, Hideyuki Saya. Additional mutation in PTPN11 gene promotes tumorigenesis of the NF1 gene mutated cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3418. doi:10.1158/1538-7445.AM2017-3418
Abstract 3387: Mutational analysis in metastatic melanoma to the breast and ovary: correlation with clinic-pathological and immunohistochemical findings
Authors: Alessio Giubellino, Vanessa Moreno, Xu Naizhen, Liqiang Xi, Mark Raffeld, Maria Merino
Journal: Cancer Research (2017)

Abstract Metastatic malignant melanoma or stage IV melanoma is the most deadly skin cancer, claiming an estimated 10,000 deaths every year. The occurrence of metastatic malignant melanoma to the breast and ovary is uncommon, and can represent a challenge for the diagnosis and clinical management. We investigated and correlated the morphologic, immunohistochemical and molecular aspects of these tumors. Morphologic analysis of the cases revealed a predominance of epithelioid pattern, and few of these were associated with more spindle cell areas. Most of the tumor cells aberrantly expressed high levels of PD-L1, especially in the metastatic melanoma to the breast. Other relevant melanoma targets for immunotherapy were also explored by immunohistochemistry. Of note, most of the metastatic tumors were negative for NY-ESO. The mutational analysis of these metastatic lesions, using next generation sequencing for the detection of cancer gene mutations including rare mutations at low frequency, found an heterogeneous mutational landscape, reinforcing the importance of personalized treatments. Mutations in RAS gene family members in these metastatic tumors were the most frequent in our samples, followed by CDKN2A and CTNNB1 mutations. Other less frequent mutations were also detected, including ATM and KIT. Interestingly, one rapidly progressive melanoma metastatic to the breast in a young patient had areas of spindle cell morphology and no common melanoma gene mutations. Overall, our cases illustrate the pathologic and molecular variability of metastatic malignant melanoma to uncommon organs of involvement, such as breast and ovary, and provide novel insights into their diagnostic and clinical management algorithm. Note: This abstract was not presented at the meeting. Citation Format: Alessio Giubellino, Vanessa Moreno, Xu Naizhen, Liqiang Xi, Mark Raffeld, Maria Merino. Mutational analysis in metastatic melanoma to the breast and ovary: correlation with clinic-pathological and immunohistochemical findings [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3387. doi:10.1158/1538-7445.AM2017-3387