tbuckley/cabot-search huggingface dataset:
Abstract 3894: A xenograft mouse model coupled with in-depth cell surface proteome analysis facilitates further elucidation of K-Ras driven tumorigenesis in lung carcinoma
Authors: Xiaoying Ye, Gordon Whiteley, Dwight Nissley, Frank McCormick, Josip Blonder
Journal: Cancer Research (2016)

Abstract The purpose of this study was to develop a proteomic approach for analysis of cell surface proteins in tissue specimens and applied it on a K-Ras driven mouse model of metastatic lung carcinoma. Metastatic disease is the leading cause of lung cancer-related mortality in the United States. In spite of continuous efforts, effective treatments targeting oncogenic K-Ras in lung and other K-Ras driven malignancies are slow to develop. To expand the treatment options for lung cancer and facilitate better understanding of metastasis new targets need to be identified and characterized at the surface of cancer cells, preferably in their native tissue microenvironment. Towards this goal we developed a mass-spectrometry (MS)-based glyco-proteomic approach targeting specifically cell surface proteins in tissue specimens and applied it on a xenograft lung cancer mouse model. We used A549 cells expressing endogenous K-RasG12S to induce lung tumor xenografts in BALB/c mice via tail vein injection. A comparative surface glyco-proteomics of cultured A549 cells, dissected tumor tissue (TT), adjacent tumor (AT) tissue and normal mouse lung tissue (NT) obtained from saline-injected age-matched littermates yielded high enrichment (i.e., ≥80%) of surface proteins. It resulted in extensive catalogue/map of more than 400 glycoproteins identified on tumor cell surface. More than 50% of proteins identified on the surface of A549 cultured cells were unambiguously identified in mouse TT, featuring proteins and pathways implicated in metastasis, invadopodia formation and cancer cell migration. These markers also provide insight regarding species determination of tissue origin (i.e., human vs. mouse) differentiation of tumor parenchyma from stroma, and regulation of tumor immune response. Citation Format: Xiaoying Ye, Gordon Whiteley, Dwight Nissley, Frank McCormick, Josip Blonder. A xenograft mouse model coupled with in-depth cell surface proteome analysis facilitates further elucidation of K-Ras driven tumorigenesis in lung carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3894.
Abstract 2093: Imaging single cell drug target engagement in vivo reveals heterogeneous fractional occupancy
Authors: Matt Dubach, Ralph Weissleder
Journal: Cancer Research (2016)

Abstract To produce effective therapeutic treatment, drugs need to reach and engage the cognate target in the cells of interest. Incomplete target occupancy may lead to cell survival and disease progression. Therefore, for maximum efficacy, it is critical to achieve high target occupancy within each cell of a tumor. However, the tumor microenvironment likely creates a dynamic, heterogenous distribution of drug that limits target occupancy in some cells. Unfortunately, we lack the tools to determine target engagement at the cellular level, which prevents studies on heterogeneous target occupancy and contributes to the poor understanding of drug failure mechanisms. Here, we developed an approach to measure target engagement of small molecule inhibitors within single cells in mouse xenograft in vivo tumor models. Our method uses fluorescently labeled, target specific companion imaging drugs, fluorescence polarization imaging, and intravital microscopy, to measure target occupancy of unlabeled, clinical drugs in single cells. We calculated the equivalent in vitro exposure of ibrutinib, a covalent BTK inhibitor, in vivo, but found increased cellular heterogeneity, highlighting differences between in vivo activity and in vitro measurements. Additionally, following systemic delivery of the reversible PARP inhibitor olaparib, we found cells with substantial uninhibited target when average measurements indicated all target was occupied, illustrating drug activity heterogeneity that may lead to tumor survival. These results demonstrate that our technique, which is the first to measure unlabeled drug engagement with target in single cells, can quantitate cellular fractional occupancy heterogeneity during drug treatment. We expect this approach to serve as a valuable tool when measuring cellular pharmacology in vivo, providing insight on dosing, drug activity in the tumor and sources of heterogeneous drug distribution. Citation Format: Matt Dubach, Ralph Weissleder. Imaging single cell drug target engagement in vivo reveals heterogeneous fractional occupancy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2093.
Abstract 1970: miRNA differential profiling between fibroblasts originated from breast cancer and normal adjacent tissue from benign disease
Authors: Patricia Bortman Rozenchan, Cristina V. de Carvalho, Tatiana Bonetti, Carina Melo, M Mitzi Brentani, Manoel JBC Girão
Journal: Cancer Research (2016)

Abstract The importance of tumor-stromal cells interactions in breast tumor progression and invasion has been recognized; therefore, modifications in the stromal fibroblasts can play a significant role in overall cancer development and progression. Accumulating evidence indicates that epigenetic phenomena such as microRNAs are extremely important and were already recognized as key regulators of gene expression, as well as expression of these small RNAs has been linked to human disease, including those related to estrogen-dependent disorders and in cancer homeostasis. So, deciphering molecular alterations in breast tumor microenvironment such as miRNAs differential expression could lead not solely to target for therapeutic intervention as well as to novel early diagnosis markers. Stromal fibroblasts were isolated from four invasive breast carcinoma samples (CAFs) and from five women with benign breast disorders (NAFs). RNA was extracted from low-passage cultures and transformed into cDNA and used for the Human Breast Cancer miScript® miRNA PCR Array expression analysis on StepOne Plus Real Time. This Array profiles the expression of 84 mirRNAs known or predicted to alter their expression during breast cancer initiation or progression. We could find 05 differentially expressed miRNAs in CAFs in comparison to NAFs; 04 down-regulated: mir107 (fold: -1,56, p = 0,04), miR-125b-1 (fold:-1,83, p = 0,03), miR-200b (fold: -2, p = 0,02), miR-93 (fold: -2,25, p = 0,02) and 01 up-regulated: miR-424 (fold: 5,73, p = 0,01). After bioinformatics analysis, these miRNAs were predicted to regulate genes involved in important cancer related pathways like, Cyclins and Cell Cycle Regulation; EGF Signaling Pathway; MAPKinase Signaling Pathway and Apoptotic Signaling in Response to DNA Damage. All together, our results showed that there are important differences regarding miRNAs expression profiling between CAFs and NAFs that could be determinant for breast cancer tumorigenesis. Citation Format: Patricia Bortman Rozenchan, Cristina V. de Carvalho, Tatiana Bonetti, Carina Melo, M Mitzi Brentani, Manoel JBC Girão. miRNA differential profiling between fibroblasts originated from breast cancer and normal adjacent tissue from benign disease. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1970.
P0600 : Predictive factors of cirrhosis, hepatic decompensation and hepatocellular carcinoma in patients with chronic hepatitis delta
Authors: D. Roulot, S. Brichler, R. Layese, D. Samuel, P. Marcellin, O. Chazouilleres, T. Poynard, F. Zoulim, N. Ganne, H. Fontaine, Z. Benabdesselam, E. Gordien, F. Roudot-Thoraval
Journal: Journal of Hepatology (2015)
Type 2 Interleukin-4 Receptor Signaling in Neutrophils Antagonizes Their Expansion and Migration during Infection and Inflammation
Authors: Janine Woytschak, Nadia Keller, Carsten Krieg, Daniela Impellizzieri, Robert W. Thompson, Thomas A. Wynn, Annelies S. Zinkernagel, Onur Boyman
Journal: Immunity (2016)
A pill too hard to swallow: how the NHS is limiting access to high priced drugs
Authors: Jonathan Gornall, Amanda Hoey, Piotr Ozieranski
Journal: BMJ (2016)

A joint investigation by The BMJ and Cambridge and Bath universities uncovers how NHS England tried to limit access to expensive new drugs for hepatitis C. <b>Jonathan Gornall</b>, <b>Amanda Hoey</b>, and <b>Piotr Ozieranski</b> report
Examining experiences of patients currently being treated with abiraterone acetate (AA) for metastatic castrate resistant prostate cancer (mCRPC).
Authors: Ahmad Bilal Naim, Barbara Roland, Susan Wyant
Journal: Journal of Clinical Oncology (2014)

e16102 Background: New targeted treatments for advanced prostate cancer have been available for 2-3 years. Abiraterone acetate (AA) is a prodrug of abiraterone, which is a novel oral androgen biosynthesis inhibitor, and is approved for metastatic castration resistant prostate cancer (mCRPC). Very limited information is available about patient experiences with the use of these novel agents. This study examines overall experiences of patients currently being treated with AA therapy for mCRPC. Methods: 100 mCRPC patients currently being treated with AA completed a 30 minute survey in 4Q13. 48 were on AA for >6 months. Majority (n=62) were ≤62 years, 55 were employed full-time. 57 patients had chemotherapy prior to starting AA, while 43 had no past chemotherapy. Results: When asked about their experiences with AA therapy, three-quarters (76%) of the patients reported that they feel more positive about their disease condition, and 91% reported that friends and family have a more positive view of their disease. Furthermore, 86% said they are less reliant/dependent on others, 78% said they have greater control over their life and treatment, 78% reported they are better able to continue working and/or doing my daily activities, 76% said they are less restricted in being able to plan and participate in social activities, and 72% said they are better able to do the things they want to do. Vast majority of patients (86%) reported that their fatigue has not worsened since they started on AA. Over a third (35%) reported that their fatigue has improved. Nearly half (49%) reported that their pain has not worsened since they started on AA. Conclusions: Results from this self-reported patient survey show that majority of patients view their treatment experiences with AA therapy to be mostly positive. Patients feel that their fatigue is stable or has not worsened. Furthermore, they have favorable perceptions of well-being, and feel that they have more control over their disease and life. More research is needed to further understand the patient-centered benefits of AA treatment.
Final Survival Analysis of ROSE/TRIO-012
Authors: John R. Mackey, Nicole McCarthy, Karen A. Gelmon, Sunil Verma, Rodrigo Fresco, Francois Thireau, Helena Fung, Miguel Martín
Journal: Journal of Clinical Oncology (2016)

TO THE EDITOR: No antiangiogenic strategy in breast cancer has yet demonstrated a clinically meaningful improvement in the ultimate end point of all-cause mortality despite improvements in progression-free survival and response rates in metastatic disease and improvements in pathologic complete response rates in the neoadjuvant setting. Why antiangiogenic studies have not produced long-term survival effects is unclear, triggering speculation that interrupting antiangiogenic treatment increases the aggressiveness of the disease, or that resistance mechanisms circumventing the vascular endothelial growth factor pathway evolve rapidly. The ROSE/TRIO-012 (Phase III Study of Docetaxel 1 Ramucirumab or Placebo in Breast Cancer) trial was a study in women with metastatic breast cancer receiving first-line docetaxel; the primary analysis showed no significant improvement in progressionfree survival with the addition of ramucirumab over placebo, and the interim survival analysis was immature. We now report the completed protocol-specified final analysis for overall survival. In the intention-to-treat population, there were 492 survival events in the ramucirumab group (492 of 759 [65%]) and 264 in the placebo group (264 of 385 [69%]). Median survival was 30.3 months (95% CI, 27.5 to 33.5 months) for the ramucirumab group and 28.7 months (95% CI, 25.6 to 32.3 months) for the placebo group, with the stratified hazard ratio of 0.95 (95% CI, 0.81 to 1.10) for overall survival showing no difference (stratified log-rank P 5 .49; Fig 1). We conclude that ramucirumab, like other antiangiogenic strategies used in the therapy of metastatic breast cancer does not influence all-cause mortality. Given that the goals of treatment of metastatic breast cancer are to improve duration and quality of life, there remains no indication for the addition of ramucirumab to docetaxel in the first-line therapy of metastatic breast cancer.
Two or More Chemotherapy Consolidation Courses, Followed By Autologous Bone Marrow Transplantation, and MRD Negativity, Give Long Term Overall Survival in Acute Myeloid Leukemia Patients
Authors: Giovanni Marconi, Cristina Papayannidis, Federico Mosna, Michele Gottardi, Giorgia Simonetti, Simona Soverini, Antonio Curti, Elisa Zuffa, Maria Chiara Abbenante, Sarah Parisi, Stefania Paolini, Chiara Sartor, Eugenia Franchini, Emanuela Ottaviani, Claudia Venturi, Maria Chiara Fontana, Antonella Padella, Viviana Guadagnuolo, Maria Teresa Bochicchio, Anna Ferrari, Nicoletta Testoni, Carmen Baldazzi, Marco Manfrini, Debora Capelli, Piero Galieni, Andrea Piccin, Giuseppe Visani, Francesco Rodeghiero, Cristina Tecchio, Filippo Gherlinzoni, Michele Cavo, Giovanni Martinelli
Journal: Blood (2015)
Development of an Attenuated Tat Protein as a Highly-effective Agent to Specifically Activate HIV-1 Latency
Authors: Guannan Geng, Bingfeng Liu, Cancan Chen, Kang Wu, Jun Liu, Yijun Zhang, Ting Pan, Jun Li, Yue Yin, Junsong Zhang, Feng Huang, Fei Yu, Jingliang Chen, Xiancai Ma, Jie Zhou, Ersheng Kuang, Chao Liu, Weiping Cai, Hui Zhang
Journal: Molecular Therapy (2016)

Although combined antiretroviral therapy (cART) successfully decreases plasma viremia to undetectable levels, the complete eradication of human immunodeficiency virus type 1 (HIV-1) remains impractical because of the existence of a viral reservoir, mainly in resting memory CD4+ T cells. Various cytokines, protein kinase C activators, and histone deacetylase inhibitors (HDACi) have been used as latency-reversing agents (LRAs), but their unacceptable side effects or low efficiencies limit their clinical use. Here, by a mutation accumulation strategy, we generated an attenuated HIV-1 Tat protein named Tat-R5M4, which has significantly reduced cytotoxicity and immunogenicity, yet retaining potent transactivation and membrane-penetration activity. Combined with HDACi, Tat-R5M4 activates highly genetically diverse and replication-competent viruses from resting CD4+ T lymphocytes isolated from HIV-1-infected individuals receiving suppressive cART. Thus, Tat-R5M4 has promising potential as a safe, efficient, and specific LRA in HIV-1 treatment. Although combined antiretroviral therapy (cART) successfully decreases plasma viremia to undetectable levels, the complete eradication of human immunodeficiency virus type 1 (HIV-1) remains impractical because of the existence of a viral reservoir, mainly in resting memory CD4+ T cells. Various cytokines, protein kinase C activators, and histone deacetylase inhibitors (HDACi) have been used as latency-reversing agents (LRAs), but their unacceptable side effects or low efficiencies limit their clinical use. Here, by a mutation accumulation strategy, we generated an attenuated HIV-1 Tat protein named Tat-R5M4, which has significantly reduced cytotoxicity and immunogenicity, yet retaining potent transactivation and membrane-penetration activity. Combined with HDACi, Tat-R5M4 activates highly genetically diverse and replication-competent viruses from resting CD4+ T lymphocytes isolated from HIV-1-infected individuals receiving suppressive cART. Thus, Tat-R5M4 has promising potential as a safe, efficient, and specific LRA in HIV-1 treatment.
Abstract 2921: The retinoblastoma protein regulates hypoxia-inducible factor-1α-mediated transcriptional programs, tumor cell invasiveness, tumor growth and metastasis in human breast cancer cells
Authors: Mandeep K. Takhar, Mark P. Labrecque, Kevin J. Tam, Anne Haegert, Robert H. Bell, Manuel Altamirano-Dimas, Colin C. Collins, Gratien G. Prefontaine, Michael E. Cox, Kevin L. Bennewith, Timothy V. Beischlag
Journal: Cancer Research (2016)

Abstract The retinoblastoma protein (Rb) is capable of attenuating the hypoxic response in tumor cells. This process is mediated by the hypoxia inducible factor 1α/2α (HIF1α/2α) and its dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT/ HIF1β). Rb modulates HIF activity by virtue of its association with the thyroid hormone receptor/retinoblastoma interacting protein 230 (TRIP230), an essential cofactor of the HIF1α/ARNT transcriptional complex. We used short hairpin RNA (shRNA) technology and microarray analysis to interrogate the Rb-negative and wild-type MCF7 cell transcriptomes and generated lists of genes that were either up- or downregulated in response to both loss of Rb and hypoxia. We found that loss of Rb enhances the expression of hypoxia-regulated genes involved in invasion and epithelial-to-mesenchymal transition and significantly decreases the expression of genes involved in cell anchoring and differentiation in MCF7 and MDA-MB-231 breast cancer cells. Genes were validated using both qRT-PCR and immuno-blot analysis. Additionally, gene ontology analysis revealed that AKT and ERK1/2 are downstream effectors of hypoxic gene programs that are sensitive to loss of Rb. Furthermore, these factors regulate the acquisition of a more invasive phenotype in breast cancer cells. Finally, we found that Rb knockdown in combination with pre-treatment of cells with hypoxia increased growth of tumor foci in the lungs after i.v. injection and increased the development of spontaneous metastases from orthotopically implanted breast tumor cells in female NOD-SCID mice. Primary tumors lacking Rb demonstrated enriched protein levels of genes identified in our arrays when compared to negative control tumors. These results show that Rb is a negative modulator of hypoxia-regulated genetic programs by virtue of its direct effects on the HIF-complex. Understanding the HIF complex and the molecular mechanisms controlling the progression from benign tumors to metastasized and lethal forms will allow us to develop more specific breast cancer therapies. Citation Format: Mandeep K. Takhar, Mark P. Labrecque, Kevin J. Tam, Anne Haegert, Robert H. Bell, Manuel Altamirano-Dimas, Colin C. Collins, Gratien G. Prefontaine, Michael E. Cox, Kevin L. Bennewith, Timothy V. Beischlag. The retinoblastoma protein regulates hypoxia-inducible factor-1α-mediated transcriptional programs, tumor cell invasiveness, tumor growth and metastasis in human breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2921.
Therapeutic dual inhibition of HER2 pathway for metastatic colorectal cancer (mCRC): The HERACLES trial.
Authors: Salvatore Siena, Andrea Sartore-Bianchi, Livio Trusolino, Cosimo Martino, Katia Bencardino, Sara Lonardi, Francesco Leone, Vittorina Zagonel, Andrea Bertotti, Emanuele Valtorta, Giulia Siravegna, Alessio Amatu, Angelo Vanzulli, Daniele Regge, Silvia Ghezzi, Fortunato Ciardiello, Silvio Veronese, Paolo Maria Comoglio, Alberto Bardelli, Silvia Marsoni
Journal: Journal of Clinical Oncology (2015)

565 Background: HER2 amplification in mCRC associates with resistance to anti-EGFR moAbs and, based on studies in patient-derived xenografts (Bertotti et al, Cancer Discov 2011), predicts response to combined therapy with anti-HER2 moAbs and lapatinib (L). Accordingly, we conducted an independent proof-of-concept phase II study of trastuzumab (T) and L in HER2+ mCRC after failure of standard therapies (HERACLES Trial - EudraCT 2012-002128-33). Methods: mCRC patients (pts) progressing after fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, and cetuximab or panitumumab were eligible if tumors were HER2+ [IHC 3+ or 2+ and FISH positive (HER2:CEP17 &gt;2) in &gt;50% cells]. L was given po daily and T iv weekly at standard doses. Tumor response was assessed every 8 weeks. The primary end-point was objective response (OR, RECIST v1.1). To consider the study positive 6/27 ORs had to be observed (α=0.05; β=85%; H 1 =30%). Serial liquid biopsies for ctDNA (ddPCR), and HER2 ectodomain (ECD) plasma levels (ELISA) were collected until progression. Results: We screened 646 pts with KRAS exon 2 WT mCRC and found 28 (4.3%) HER2+; 18 (2.8%) were fully eligible and evaluable for response as of September 10, 2014. Pts had a median of 5 (r=3-8) prior therapies, median age 61 (r=41-86), ECOG PS ≤1, 2F/16M. Primary endpoint was met with 6/18 ORs (1 CR, 4 PR, 1 PRunc; ORR=33.3%, 95% CI 0.16-0.56). Stable disease (SD) lasting &gt; 4 mos. was obtained in four further pts. Five of six ORs and the longest SD (10 mos.) were observed in pts with HER2 gene copy number variations (CNVs) ≥20 copies. Treatment was well tolerated with toxicities limited to grade 2 diarrhea, fatigue, and skin toxicities (one grade 3). HER2 CNV in ctDNA decreased in 2/3 ORs and 0/2 non responders. HER2 ECD plasma levels also decreased in 2/2 ORs but not in 6/6 pts with SD or progression. Exome analysis of index cases will be presented. Conclusions: As predicted by HER2+ mCRC xenografts, the combination of T and L was remarkably active in standard therapy refractory mCRCs with HER2 amplification. HERACLES represents the first precision medicine trial with positive results in mCRC. HERACLES is funded by Associazione Italiana Ricerca Cancro. Clinical trial information: 2012-002128-33.