tbuckley/cabot-search huggingface dataset:
Abstract 1648: ImmunoGraft®platform for the evaluation of Immuno-Oncology agents in PDX tumors models
Authors: David Cerna, Daniel Ciznadija, Bhavna Verma, David Sidransky, Evgeny Izumchenko, Angela Davies, Maria Mancini
Journal: Cancer Research (2017)

Abstract Recent breakthroughs in Immunotherapy have given new hope to treating previously untreatable tumor types and provide a better tolerated alternative to standard agents. There is an unmet need for a pre-clinical platform to test potential immune-oncology therapeutics that would also provide a tool to examine the mechanisms of response to better predict clinical outcomes. We have previously presented the Champions ImmunoGraft®, an innovative pre-clinical model enabling immunotherapeutic agents to be evaluated for efficacy in solid tumors. This platform is more reflective of the human tumor microenvironment (both immune and non-immune cell-based) and may be one of the most translationally-relevant models to date for screening therapies targeting the immune system. However, optimization of humanization and PDX implantation protocols that allow a broader reconstitution of cell linage and higher engraftment rate are necessary to further improve the pre-clinical evaluation of immune-oncology therapeutics and enhance the value of this modality for patient’s benefit. To this end, immune-compromised NOG (PrkdcscidIl2rgtm1Sug) mice were reconstituted (humanized) with human CD34+ cells using optimized procedure and blood was collected at different time points post engraftment to check for the major leukocyte linages. At ten weeks after humanization, mature human CD45+ cells comprised close to 50% of the leukocytes detected in the circulation and secondary lymphoid tissues of the humanized animals. As a result of improved methodology of the reconstitution protocol we have achieved an 85% success rate of humanization with a shortened engraftment period utilizing fewer CD34+ cells that maintain humanization reconfirmed at 22 weeks post reconstitution. Champions TumorGraft® database contains more than one-thousand clinically relevant well-annotated PDX models. We have complied data from extensive genetic and protein expression analyses to design applicable ImmunoGraft® studies for testing of Immuno-Oncology agents. We have identified tumors expressing key markers that may predict response to immunotherapy agents including PDL-1, CD40, IDO-1 and IDO-2 as well as tumors that harbor a high mutational load. Here we present the efficacy and clinically relevant endpoints of two well-studied checkpoint inhibitors Ipilimumab and Pembrolizumab in this highly translational PDX platform. Citation Format: David Cerna, Daniel Ciznadija, Bhavna Verma, David Sidransky, Evgeny Izumchenko, Angela Davies, Maria Mancini. ImmunoGraft® platform for the evaluation of Immuno-Oncology agents in PDX tumors models [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 1648. doi:10.1158/1538-7445.AM2017-1648
Abstract 5023: Disruption of Monocarboxylate transporter-4 Basigin interaction as an effective strategy to inhibit hypoxic response, tumor growth and vascularization, and stem cell phenotype in human glioblastoma <i>in vitro</i> and <i>in vivo</i>
Authors: Raffaella Spina, Dillon M. Voss, Kah Suan Lim, Constance J. Jeffery, Eli E. Bar
Journal: Cancer Research (2017)

Abstract Monocarboxylate transporters, constitute a family (SLC16) of proton-linked plasma membrane transporters that carry molecules containing a single carboxylate group across biological membranes. Basigin (CD147), is involved in many physiological functions during early stages of development and in cancer. Basigin has been shown to be required for functional plasma membrane expression of Monocarboxylate transporter-1 and Monocarboxylate transporter-4. Using a cell-based screening assay, we identified acriflavine, a small molecule that inhibits the binding between Basigin and Monocarboxylate transporters in vitro and in vivo. Surface Plasmon Resonance analysis confirmed direct binding of acriflavine to Basigin’s immunoglobulin extracellular domain with a low binding constant (kD) of 0.16µM. Acriflavine inhibits normoxic growth of glioma stem cells in vitro and this activity is augmented by hypoxia or by expression of oxygen-stable mutant forms of HIF-1α or HIF-2α. Treatment of mice bearing established glioma stem cell-derived xenografts resulted in inhibition of tumor growth. Acriflavine treatment inhibited intratumoral expression of the angiogenic cytokine vascular endothelial growth factor and tumor vascularization. Our work shows that disruption of monocarboxylate transporter binding to Basigin is an effective approach to target glioma stem cells. Citation Format: Raffaella Spina, Dillon M. Voss, Kah Suan Lim, Constance J. Jeffery, Eli E. Bar. Disruption of Monocarboxylate transporter-4 Basigin interaction as an effective strategy to inhibit hypoxic response, tumor growth and vascularization, and stem cell phenotype in human glioblastoma in vitro and in vivo [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 5023. doi:10.1158/1538-7445.AM2017-5023
Abstract 4637: Activation of toll-like receptor-2 promotes proliferation in human lung adenocarcinoma cells
Authors: Patrick Kohtz
Journal: Cancer Research (2017)

Abstract Objective: Toll-like receptors (TLR) have been implicated in tumor progression by affecting the immune response in the tumor microenvironment. Toll like receptors have been described to be present in human cancer cells but the presence and the role of these receptors in the growth and proliferation of human lung cancer cells is not known. We analyzed human lung cancer cells for the presence of TLR-2 receptors and evaluated the proliferation response to a specific TLR-2 agonist. Methods: Human non-small cell cancer cell (NSCLC) lines A549, (adenocarcinoma) H125 adenosquamous, and H1650 adenocarcinoma (American Type Culture Collection), were cultured using standard techniques. Cells were treated with Pam3CSK4, a specific agonist of TLR2, at doses of 0ug/ml, 5ug/ml, and 10ug/ml for 72 hours. Baseline protein levels of TLR2 were assessed using standard western blotting techniques. Proliferation assays were completed using the MTS assay in response to treatment with the agonist Results: Protein analysis demonstrated varying but consistently detectable levels of TLR2 protein in each cell line. After treatment with Pam3CSK4 we found that proliferation was significantly promoted in the human lung adenocarcinoma cell lines (p=.03), but not in the adenosquamous cell line (p=0.001). Conclusion: Toll-like receptor -2 is consistently present and detectable on human lung adenocarcinoma cells. Toll Like receptor -2 activation results in increased proliferation in human lung adenocarcinoma cells and this effect appears to be specific to adenocarcinoma cells. Further study is necessary to elucidate the downstream pathways responsible for the increased proliferation we see in these human lung adenocarcinoma cells, however these findings may suggest TLR-2 to be a possible therapeutic target in human lung cancer. Citation Format: Patrick Kohtz. Activation of toll-like receptor-2 promotes proliferation in human lung adenocarcinoma 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 4637. doi:10.1158/1538-7445.AM2017-4637
Abstract 1544: MTAP insufficiency promotes metastasis in lung cancer via diminishing protein dimethylation
Authors: Wen-Hsin Chang, Bing-Ching Ho, Kang-Yi Su, Jian-Wei Chen, Reen Wu, Pan-Chyr Yang, Sung-Liang Yu
Journal: Cancer Research (2017)

Abstract Genome instability, metabolic switch, and activating metastasis are three of the cancer hallmarks, which always collectively contribute to cancer malignancy. We identified methylthioadenosine phosphorylase (MTAP) as a metastasis suppressor in a series isogenic lung cell lines with different invasion ability by array CGH. Using siRNA silencing and ectopic expression of MTAP, we found that MTAP not only inhibited invasion and colony forming in vitro, but also reduced metastasis and tumorigenesis in vivo. Clinically, patients with low MTAP expression associated with poor overall survival and progression-free survival. Furthermore, the metabolite analysis of clinical specimens showed that low MTAP expression leads to MTA substrate accumulation and product decrease. MTA accumulation in MTAP knockout cells reduced the level of symmetric arginine dimethylation of proteins. By using LC/MS, we identified a novel methyl-protein, whose level is elevated in MTAP knockout cells with the depletion of symmetric arginine dimethylation. Functionally, the unmethylated protein would be protected from proteolysis via caspase 3 cleavage. Moreover, the unmethylated mutant protein promoted migration and invasion in vitro strongly than the wild-type one did. In conclusion, we identify a novel marker in low MTAP expression or MTAP knockout cells, providing a potential therapeutic candidate in lung adenocarcinoma. Citation Format: Wen-Hsin Chang, Bing-Ching Ho, Kang-Yi Su, Jian-Wei Chen, Reen Wu, Pan-Chyr Yang, Sung-Liang Yu. MTAP insufficiency promotes metastasis in lung cancer via diminishing protein dimethylation [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 1544. doi:10.1158/1538-7445.AM2017-1544
Circulating Tumor DNA Reveals Clinically Actionable Somatic Genome of Metastatic Bladder Cancer
Authors: Gillian Vandekerkhove, Tilman Todenhöfer, Matti Annala, Werner J. Struss, Amanda Wong, Kevin Beja, Elie Ritch, Sonal Brahmbhatt, Stanislav V. Volik, Jörg Hennenlotter, Matti Nykter, Kim N. Chi, Scott North, Arnulf Stenzl, Colin C. Collins, Bernhard J. Eigl, Peter C. Black, Alexander W. Wyatt
Journal: Clinical Cancer Research (2017)

Purpose: Targeted agents and immunotherapies promise to transform the treatment of metastatic bladder cancer, but therapy selection will depend on practical tumor molecular stratification. Circulating tumor DNA (ctDNA) is established in several solid malignancies as a minimally invasive tool to profile the tumor genome in real-time, but is critically underexplored in bladder cancer.Experimental Design: We applied a combination of whole-exome sequencing and targeted sequencing across 50 bladder cancer driver genes to plasma cell-free DNA (cfDNA) from 51 patients with aggressive bladder cancer, including 37 with metastatic disease.Results: The majority of patients with metastasis, but only 14% of patients with localized disease, had ctDNA proportions above 2% of total cfDNA (median 16.5%, range 3.9%-72.6%). Twelve percent of estimable samples had evidence of genome hypermutation. We reveal an aggressive mutational landscape in metastatic bladder cancer with 95% of patients harboring deleterious alterations to TP53, RB1, or MDM2, and 70% harboring a mutation or disrupting rearrangement affecting chromatin modifiers such as ARID1A Targetable alterations in MAPK/ERK or PI3K/AKT/mTOR pathways were robustly detected, including amplification of ERBB2 (20% of patients) and activating hotspot mutations in PIK3CA (20%), with the latter mutually exclusive to truncating mutations in TSC1 A novel FGFR3 gene fusion was identified in consecutive samples from one patient.Conclusions: Our study demonstrates that ctDNA provides a practical and cost-effective snapshot of driver gene status in metastatic bladder cancer. The identification of a wide spectrum of clinically informative somatic alterations nominates ctDNA as a tool to dissect disease pathogenesis and guide therapy selection in patients with metastatic bladder cancer. Clin Cancer Res; 23(21); 6487-97. ©2017 AACR.
Abstract 9965: Echocardiography in Cardiac Arrest Prognosis in the Intensive Care Unit for Non-shockable Rhythms 1 Year of Follow-up
Authors: Uri P Flato, Ari Timerman, Edison Paiva
Journal: Circulation (2015)

Introduction: In-hospital cardiopulmonary arrest (CPA-IH) is a public health problem with high worldwide morbidity and mortality. Cases of non-shockable CPA rhythms, such as asystole and pulseless electrical activity (PEA), have remained unchanged over the last 30 years. Despite updates to resuscitation guidelines every five years, we have not been successful in increasing patient survival. Prognostic and diagnostic factors during CPA are necessary to increase survival among these patients and optimise available resources. Transthoracic echocardiography (TTE) provides valuable information about diagnosis and perhaps prognosis, through real-time images. Hypothesis: This study describes the use of TTE in patients with CPA with non-shockable rhythms in an intensive care unit (ICU), evaluating the prognostic factor of myocardial contractility in the return of spontaneous circulation (ROSC) and differential diagnoses Methods: This was a prospective cohort study conducted in an ICU of a university hospital with patients in CPA with asystole or PEA as their initial rhythm. Results: TTE performed by doctors highly trained in the method was included in the treatment protocol. In total, 49 patients were included in the study, 32 in PEA and 17 in asystole, of whom 27 patients in PEA had myocardial contractility. During the examination, the patients in PEA were subclassified into pseudo electromechanical dissociation (EMD) and true EMD. Of the 49 patients, 24 had ROSC, and two had survival &gt; 360 days. The pseudo-EMD patients (contractility present and without central pulse) had a survival rate odds ratio of 2.99 (1.22 to 7.29; p = 0.016) compared with the other groups. Conclusions: Therefore, the presence of myocardial contractility may be a short- and long-term prognostic factor during CPA.
Abstract 2355: Palbociclib enhances the antitumor activity of taxanes by abrogating cell cycle checkpoints and alleviating hypoxia in squamous cell lung cancer
Authors: Joan Cao, Zhou Zhu, Hui Wang, Tim Nichols, Edward Rosfjord, Christine Hopf, Erik Upeslacis, Paul Rejto, Scott Weinrich, Todd Vanarsdale, James Hardwick, Ping Wei
Journal: Cancer Research (2017)

Abstract Lung cancer remains one of the leading causes of cancer-related mortality. Squamous cell lung cancer (SqCLC) is the second most common subtype of non-small cell lung cancer (NSCLC) and is responsible for ~100,000 deaths in the US and EU. Most SqCLC patients receive chemotherapy as 1st line treatments and have a high un-met medical need for new therapies. Therapeutic approaches that enhance the efficacy of chemotherapy would therefore improve clinical outcomes for this patient population. CDK inhibitors comprise a class of drugs that target the dysregulated cell cycle in malignant cells. Treatment of tumor cells with the CDK4/6 inhibitor palbociclib inhibits tumor growth by decreasing retinoblastoma (RB) protein phosphorylation and inducing cell cycle arrest at the G1/S phase transition. Based on promising clinical trial results, palbociclib in combination with letrozole was granted accelerated approval by the US FDA for the treatment of postmenopausal women with ER-positive, HER2-negative advanced breast cancer. Like hormone receptor positive breast cancer patients, the vast majority of SqCLC patients harbor wild type RB and thus may also benefit from palbociclib treatment. Previously, we reported robust cytotoxicity and antitumor effects of palbociclib plus taxanes, including nanoparticle albumin-bound paclitaxel (Nab-PTX) or docetaxel (DTX), in several preclinical models of SqCLC. In the present study, we extended our efficacy studies of this combination to additional RB+ SqCLC models with diverse molecular genetic backgrounds. In search of mechanisms of action underlying the observed combinatorial effects, we identified several novel mechanisms, including cell cycle checkpoint abrogation as well as reduction of hypoxia-inducible factor 1 alpha (HIF-1α). Decrease in HIF-1α protein led to strong modulation of downstream genes involved in angiogenesis, resulting in reduced blood vessel size in tumor vasculature. Our results suggest that palbociclib enhances the antitumor activity of taxanes by abrogating cell cycle checkpoints and alleviating hypoxia in SqCLC. Citation Format: Joan Cao, Zhou Zhu, Hui Wang, Tim Nichols, Edward Rosfjord, Christine Hopf, Erik Upeslacis, Paul Rejto, Scott Weinrich, Todd Vanarsdale, James Hardwick, Ping Wei. Palbociclib enhances the antitumor activity of taxanes by abrogating cell cycle checkpoints and alleviating hypoxia in squamous 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 2355. doi:10.1158/1538-7445.AM2017-2355
Response to comment on “Using geospatial mapping to design HIV elimination strategies for sub-Saharan Africa”
Authors: Justin T. Okano, Brian J. Coburn, Sally Blower
Journal: Science Translational Medicine (2017)

Detailed geospatial mapping of a generalized HIV epidemic in sub-Saharan Africa shows that implementing the UNAIDS 90-90-90 strategy could potentially exacerbate urban-rural health care disparities.
Abstract 2841: Investigating drivers of disease progression in invasive lobular carcinoma
Authors: Nilgun Tasdemir, Matthew Sikora, Zhu Li, Kevin Levine, Ahmed Basudan, Soumya Luthra, Esther Elishaev, Uma Chandran, George C. Tseng, Rachel Jankowitz, David J. Dabbs, Priscilla McAuliffe, Nancy E. Davidson, Steffi Oesterreich
Journal: Cancer Research (2017)

Abstract Invasive lobular carcinoma (ILC) is the second most common type of breast cancer following invasive ductal carcinoma (IDC) and accounts for 10-15% of all cases. Unlike the masses or lumps formed by IDCs, ILCs grow as small, dis-cohesive cells in a single-file pattern within dense layers of extracellular matrix. Paradoxically, while patients with ILC display favorable prognostic and predictive factors (ER+, PR+, HER2-, low Ki67), their long-term response to endocrine therapy is worse than patients with IDC. Despite such histological and clinical differences, ILC has remained a gravely understudied subtype of breast cancer. Thus, there is urgent need to investigate molecular drivers of ILC progression in order to develop more effective therapeutic strategies and improve patient outcome. To this end, we used the Nanostring platform to measure the expression of 577 copy number variation-associated genes in 131 primary ILC tumors and identified two candidate drivers that exhibit higher expression in tumors from patients with recurrent versus non-current disease: CTTN (cortical actin binding protein) and QSOX1 (quiescin sulfhydryl oxidase). In follow-up studies, we observed high CTTN and QSOX1 expression in human ILC cell lines, tumors and patient-derived xenografts. In addition, QSOX1 expression was further increased in ILC ovarian metastases compared to their matched primary tumors. In functional in vitro studies, RNAi-mediated inhibition of CTTN led to decreased adhesion and haptotaxis to Collagen I, while QSOX1 knockdown diminished the growth of human ILC cell lines. We are currently assessing the in vivo therapeutic utility of CTTN and QSOX1 inhibition in tumor growth and metastasis using human ILC cell line and patient-derived xenograft mouse models. This study greatly advances our understanding of ILC disease mechanisms and identifies novel therapeutic targets towards improving the clinical outcome of patients with this understudied subtype of breast cancer. Citation Format: Nilgun Tasdemir, Matthew Sikora, Zhu Li, Kevin Levine, Ahmed Basudan, Soumya Luthra, Esther Elishaev, Uma Chandran, George C. Tseng, Rachel Jankowitz, David J. Dabbs, Priscilla McAuliffe, Nancy E. Davidson, Steffi Oesterreich. Investigating drivers of disease progression in invasive lobular carcinoma [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 2841. doi:10.1158/1538-7445.AM2017-2841
Abstract 4127: Targeting MDM4 in hepatocellular carcinoma to reactivate p53 signaling
Authors: Sarah E. Woodfield, Yan Shi, Roma H. Patel, Zhenghu Chen, Aryana M. Ibarra, Sanjeev A. Vasudevan
Journal: Cancer Research (2017)

Abstract Objective: New therapeutic strategies are desperately needed for hepatocellular carcinoma (HCC), the fourth most common cause of cancer-related deaths worldwide. Most patients with HCC lack mutations in the p53 tumor suppressor gene. Therefore, we hypothesized that targeting MDM4 or MDM2 to reactivate p53 signaling could be effective in this disease. Methods: HCC cell lines (SK-Hep1, Huh-7, Hep3B) were profiled for gene and protein expression of MDM4 with qPCR and immunoblotting assays, respectively. The effects of MDM4 inhibitor NSC207895 on the same cell lines were analyzed with MTT assays for cytotoxicity and qPCR experiments to look at changes in expression of p53 downstream targets, in comparison to the effects of MDM2 inhibitor Nutlin-3a. Effects of MDM4 on targets other than p53, including family members p63 and p73, were examined in cells with mutant or null p53 for changes in expression with qPCR experiments. Results: Three HCC cell lines showed expression of MDM4. Inhibition of MDM4 showed cytotoxic (high dose, 0.16-15.0 μM) and anti-proliferative (low dose, 0.05-0.3 μM) effects in all three cell lines, including p53 mutant Huh-7 and p53 null Hep3B cells. The same cell lines were strongly resistant to Nutlin-3a. Gene expression analyses were conducted with cells exposed to NSC207895 to examine effects of MDM4 inhibition on p53 targets Bax, Puma, and p21. In SK-Hep1 cells, NSC207895 treatment led to 2.5-fold overexpression of Bax, 27.4-fold of Puma, and 23.1-fold of p21. Huh-7 showed 11.8-fold upregulation of Puma and 12.4-fold of p21, and Hep3B exhibited a very strong 58.4-fold increase in p21 gene expression with the same treatment. Interestingly, Hep3B showed 5.9-fold overexpression of p63 and 1.99-fold of p73 gene expression with NSC207895 exposure, suggesting novel interactions between MDM4 and p63/p73 in the absence of p53. Conclusions: Inhibition of MDM4 shows efficacy in in vitro models of HCC through upregulation of p53, p63, and p73 to activate p53 tumor suppressive signaling. Thus, targeting MDM4 may be a viable option for all HCC patients, no matter the p53 mutation status. Citation Format: Sarah E. Woodfield, Yan Shi, Roma H. Patel, Zhenghu Chen, Aryana M. Ibarra, Sanjeev A. Vasudevan. Targeting MDM4 in hepatocellular carcinoma to reactivate p53 signaling [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 4127. doi:10.1158/1538-7445.AM2017-4127