tbuckley/cabot-search huggingface dataset:
Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic CRC, gastric cancer (GC), SCCHN, or other tumors.
Authors: Josep Tabernero, John D. Powderly, Omid Hamid, Michael S. Gordon, George A. Fisher, Fadi S. Braiteh, Lawrence E. Garbo, Gregg Daniel Fine, Marcin Kowanetz, Bruce McCall, Xiaodong Shen, Daniel S. Chen, Holbrook Edwin Kohrt
Journal: Journal of Clinical Oncology (2013)

3622 Background: PD-L1 has been reported to be expressed broadly in human cancer and can lead to inhibition of anti-tumor T-cell responses. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Pts with a broad range of tumors were examined in an expansion study with MPDL3280A. Methods: Pts with locally advanced or metastatic tumors received MPDL3280A administered IV q3w. Pts were treated for up to 1 y. Response was assessed by RECIST v1.1. Results: As of Jan 10, 2013, 20 pts with tumor types other than NSCLC, RCC and mM were evaluable for safety and treated at doses of 0.01-20 mg/kg (≤1 [n=3], 3 [n=1], 10 [n=3] and 20 mg/kg [n=13]). Median pt age was 67 y (range 26-80 y), 100% were PS 0-1, 90% had prior surgery and 45% had prior radiotherapy. 95% of pts received prior systemic therapy. Pts received MPDL3280A treatment for a median of 96 days (range 22-330). The incidence of all G3/4 AEs, regardless of attribution, was 50%. No G3-5 pneumonitis or diarrhea was reported. Confirmed RECIST responses were observed in several tumor types, including CRC, GC and SCCHN. Additionally, antitumor activity (tumor shrinkage that has not yet met criteria for a RECIST response) has been observed in sarcoma and lymphoma. Analysis of biomarker data from archival tumors revealed that all pts reported to have RECIST response had baseline tumors that were PD-L1 positive. Updated data will be presented. Conclusions: Treatment with MPDL3280A was well tolerated, with no pneumonitis-related deaths. Rapid responses were observed in pts with CRC, GC and SCCHN. PD-L1 tumor status appears to correlate with responses to MPDL3280A. These data suggest that PD-L1 is a conserved mechanism for mediating tumor immune escape across a range of tumor types. MPDL3280A may be broadly active as anti-cancer therapy in PD-L1–expressing tumors, supporting further investigation. Clinical trial information: NCT01375842.
Abstract 2146: YAP is an important pathway downstream of EGFR that is a potential target for EGFR-TKI-resistance lung adenocarcinomas
Authors: Ting-Fang Lee, Yu-Chi Tseng, Ying-Pu Liu, Yu-Rung Kao, Cheng-Wen Wu
Journal: Cancer Research (2016)

Abstract Epidermal growth factor receptor (EGFR) mutations are found in lung adenocarcinomas leading to tumor cells proliferation and survival. EGFR tyrosine kinase inhibitors (TKIs) that block EGFR activity are effective therapeutics for EGFR-mutant lung adenocarcinoma patients, but TKI-resistance inevitably occurs. The YES-associated protein (YAP) transcription coactivator has been implicated as an oncogene and is amplified in human cancers and provides tumor cells strong proliferation and survival cues. This study investigated the roles of YAP in lung adenocarcinoma by exploring its regulation and functions mediated by EGFR signaling. Using lung adenocarcinoma cell lines, we detected enhanced YAP expression and activity mediated by EGFR signaling due to enhanced protein stability. The Src family protein YES was involved in EGFR-regulated YAP expression. The YAP/YES pathway was crucial for proliferation in EGFR-dependent cells. Small molecules that reduced YAP levels by mechanisms bypassing EGFR were effective in killing EGFR-dependent cells including EGFR T790M, the major cause of TKI-resistance. These observations unveiled the significance of YAP in EGFR mutant lung adenocarcinomas and identified YAP as an promising therapeutic target for EGFR-dependent lung adenocarcinoma patients, including those with EGFR T790M-caused TKI resistance. Citation Format: Ting-Fang Lee, Yu-Chi Tseng, Ying-Pu Liu, Yu-Rung Kao, Cheng-Wen Wu. YAP is an important pathway downstream of EGFR that is a potential target for EGFR-TKI-resistance lung adenocarcinomas. [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 2146.
Effectiveness of cognitive behavioural therapy with people who have autistic spectrum disorders: A systematic review and meta-analysis
Authors: Lisa Weston, Joanne Hodgekins, Peter E. Langdon
Journal: Clinical Psychology Review (2016)

The aims of this study were to undertake a meta-analytic and systematic appraisal of the literature investigating the effectiveness of cognitive behavioural therapy (CBT) when used with individuals who have autistic spectrum disorders (ASDs) for either a) affective disorders, or b) the symptoms of ASDs. Following a systematic search, 48 studies were included. CBT, used for affective disorders, was associated with a non-significant small to medium effect size, g = 0.24, for self-report measures, a significant medium effect size, g = 0.66, for informant-report measures, and a significant medium effect size, g = 0.73, for clinician-report measures. CBT, used as a treatment for symptoms of ASDs, was associated with a small to medium non-significant effect size, g = 0.25, for self-report measures, a significant small to medium effect size, g = 0.48, for informant-report measures, a significant medium effect size, g = 0.65, for clinician-report measures, and a significant small to medium effect size, g = 0.35, for task-based measures. Sensitivity analyses reduced effect size magnitude, with the exception of that based on informant-report measures for the symptoms of ASDs, which increased, g = 0.52. Definitive trials are needed to demonstrate that CBT is an empirically validated treatment for use with people who have ASDs.
Abstract 3645: Low level somatic variant detection by Sanger sequencing of formalin-fixed paraffin-embedded (FFPE) samples
Authors: Arpad Gerstner, Edgar Schreiber, Stephen Jackson, Kamini Varma
Journal: Cancer Research (2016)

Abstract Deleterious sequence variants play an important role in the initiation and progression of many different cancer types. The detection of germline variants by the gold standard Sanger sequencing has been well established, however, the detection of somatic mutations, especially in heterogeneous tumor samples where variants may be present at a lower level, has been more challenging. To facilitate analysis of somatic mutations in tumor samples, we have developed Sanger sequencing panels that cover the entire coding regions of specific genes implicated in tumorigenesis (e.g. TP53, KRAS and NRAS). We have also developed companion software, Minor Variant Finder (MVF), that facilitates detection of low levels of somatic mutations in Sanger sequencing studies. To demonstrate the workflow of these panels with MVF, we analyzed DNA from lung cancer FFPE samples. We initially determined variants of TP53 and KRAS in these samples using Ion Torrent™ Personal Genome Machine (PGM™) next generation sequencing (NGS). We confirmed the identity and variant allele frequency of these variants by Sanger sequencing coupled with MVF. Furthermore, we were able to confirm these results in 1 ng, 0.5 ng or 0.1 ng of DNA from these samples. Finally, we made serial dilutions of one of these samples to establish limit of detection (LOD). We show that this workflow can detect as little as 3% of a minor variant in an FFPE sample. Sanger sequencing is the gold standard for confirmation of minor variants detected by NGS. In this study, we show that Sanger sequencing of limited number of targets, in conjunction with the MVF software, can also be an ideal first line screening choice for tumor FFPE samples where limited amount of DNA is available. For Research Use only - Not for use in diagnostic procedures. Citation Format: Arpad Gerstner, Edgar Schreiber, Stephen Jackson, Kamini Varma. Low level somatic variant detection by Sanger sequencing of formalin-fixed paraffin-embedded (FFPE) samples. [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 3645.
Abstract 4741: Targeting tumor growth in a medullary thyroid carcinoma mouse model using a combinatorial treatment with a tyrosine kinase inhibitor and histone deacetylase inhibitor
Authors: Karine Pozo, Stefan Zahler, Chunfeng Tan, Keisuke Ishimatsu, Masaya Takahashi, James Bibb
Journal: Cancer Research (2016)

Abstract Neuroendocrine tumors are rare forms of cancers arising from hormone-producing cells that are scattered throughout the body. Medullary thyroid carcinoma (MTC) originates from the thyroid gland parafollicular cells. Treatment options for progressive, metastatic MTC patients are limited to the recently FDA-approved tyrosine kinase inhibitors (TKIs), Vandetanib and Cabozantinib, which target multiple receptor tyrosine kinases, including VEGFR2. However, the efficacy of TKIs is limited and development of TKI resistance is common. Here we examined, the effect of a combinatorial drug therapy using the TKI, Nintedanib, and the histone deacetylase (HDAC) inhibitor, Romidepsin, on MTC growth in the NSE/p25-gfp bi-transgenic mouse line, an inducible MTC mouse model (see Pozo et al. 2013). The TKI- and HDAC inhibitors were administered intraperitoneally for 3 weeks and tumor growth progression was monitored using a T2 weighted magnetic resonance imaging on a 7 Tesla system. Tumor tissues were analyzed for oncogenic signaling pathways by immunoblotting and immunohistochemistry. We find that co-administration of Nintedanib and Romidepsin stops tumor growth and increases the number of necrotic foci within the tumor tissue. Interestingly, Nintedanib treatment alone reduced tumor vascularization as shown by decreased density of the vascular marker, CD31, but did not stop parafollicular cell proliferation. Taken together, these results suggest that a combinatorial drug therapy with a TKI- and an HDAC inhibitor may be a more efficient strategy to target MTC progression and overcome recurrence. Citation Format: Karine Pozo, Stefan Zahler, Chunfeng Tan, Keisuke Ishimatsu, Masaya Takahashi, James Bibb. Targeting tumor growth in a medullary thyroid carcinoma mouse model using a combinatorial treatment with a tyrosine kinase inhibitor and histone deacetylase inhibitor. [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 4741.
Elucidating the biophysic mechanims of axitinib-induced dysphonia.
Authors: Luis Antón-Aparicio, Javier Cassinello, Maria Carmen Lata Caneda
Journal: Journal of Clinical Oncology (2015)

e15607 Background: Dysphonia is the medical term for disorders of the voice: an impairment in the ability to produce voice sounds using the vocal organs. Thus, dysphonia is a phonation disorder. The dysphonia voice can be hoarse or excessively breathy, harsh, or rough, but some kind of phonation is still possible. Pathophysiology of dysphonia has either organic or functional causes due to impairment of any one of the vocal organs. Dysphonia, as secondary effect of TKis , mainly with Axitinib, has been overlooked by the other side effects of these drugs. Methods: A search was performed in two electronic databases: ClinicalTrials.gov and pubmed. Search words that were used included TKIs drugs, voice alteration and dysphonia and focused on the last 20 years (1993-2014). Citations from the studies from ClinicalTrials.gov were used to identify relevant trials. We also show our clinical daily practice with speech spectrograms performed in all the patients. Results: In almost all studies of TKIs drugs, voice changes were reported including all grades of severity, dysphonia ranging from 7% to 33% (Pazopanib, Sunitinib, Sorafenib, Axitinib). The reported incidence of dysphonia in patients treated with Axitinib was 31% versus 14% of patients treated with Sunitinib ( Ho et al 2011). We have shown a relationship with the perceptual correlates of dysphonia that are assessment in agreement with the grade roughness-breathiness-asthenia-strain (GRBAS) Scale, based on acoustic voice analysis on perturbation measured as Jitter, Shimmer and Noise to Harmonics ratio. Conclusions: Today, the possible mechanisms underlying dysphonia may be related to on-target vascular effect but also to off-target effect, such as myocyte dysfunction. From our point of view intrinsic muscle chord voice was elicited as target of potentially important source of dysphonia TKIs induced, and we undertook to determine if features of myocyte of the intrinsic muscle voice status may be predictive of target-limiting toxicity in patients treated with Axitinib. We suggest that vocal cord myocites, that elicited selective sarcoasthenia, are the target of the biophysics mechanism leading dysphonia, although does not seem to be a commonly reported target of Axitinib.
Surgical Treatment of Temporal Lobe Epilepsy—Reply
Authors: Gregory D. Cascino, Amy L. Jones
Journal: JAMA Neurology (2016)

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GCS-100, a galectin-3 antagonist, in refractory solid tumors: A phase I study
Authors: J. J. Grous, C. H. Redfern, D. Mahadevan, J. Schindler
Journal: Journal of Clinical Oncology (2006)

13023 Background: Galectin-3 is a galactoside-binding protein implicated in inhibition of apoptosis, and promotion of angiogenesis, metastasis, cellular proliferation by a direct association with oncogenic K-ras. Modified citrus pectin (MCP) is a complex carbohydrate derived from citrus fruit and is rich in galactoside residues. GCS-100 is an MCP capable of binding to and antagonizing galectin-3, resulting in anti-tumor activity in vitro and in vivo. Methods: GCS-100 was administered to patients with refractory solid tumors in a Phase I dose-escalating study using standard eligibility criteria. Objectives were to determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK) and efficacy. Study drug was delivered by IV infusion over 1–2 hours for 5 consecutive days of a 21 day cycle. Results: 24 patients (17 F, 7 M, age 45–80 yo) were enrolled at 6 dose levels between 30–200 mg/m 2 . DLT and MTD for this dosing regimen were established at 200 mg/m 2 and 160 mg/m 2 , respectively. DLT was a Grade 3 erythematous, maculopapular rash, resolving with systemic steroid treatment. There were no associated systemic findings, and the rash did not preclude further GCS-100 therapy. Skin biopsy revealed a vasculitis similar to findings seen in dog models. 9 other patients experienced Grade 1–2 rashes that did not require systemic treatment. The majority of adverse events (AEs) were Grade 1 or 2; the most common being nausea, vomiting, diarrhea, fatigue, fever and hyperglycemia. AEs thought to be related to treatment were rash, nausea and fatigue. Linear PKs were observed with a terminal half-life (t 1/2 ) between 30–40 h and an effective t 1/2 of 36 h. Peak GCS-100 concentrations reached 424 μg/mL at MTD. The median number of cycles was 4 (range 1–17). Best overall response per RECIST was stable disease observed in 16 patients with 6 of these patients on study for ≥ 6 months. Conclusion: Overall tolerability of GCS-100 was excellent with serum concentrations at MTD reaching levels associated with preclinical activity. Sustained periods of stable disease were achieved in patients with previously treated advanced solid tumors warranting Phase II studies. [Table: see text]
Notch1 signalling regulates endothelial proliferation and apoptosis in pulmonary arterial hypertension
Authors: Swati Dabral, Xia Tian, Baktybek Kojonazarov, Rajkumar Savai, Hossein Ardeschir Ghofrani, Norbert Weissmann, Monica Florio, Jan Sun, Danny Jonigk, Lavinia Maegel, Friedrich Grimminger, Werner Seeger, Soni Savai Pullamsetti, Ralph Theo Schermuly
Journal: European Respiratory Journal (2016)

Pulmonary arterial hypertension (PAH) is characterised by excessive pulmonary vascular remodelling involving deregulated proliferation of cells in intima, media as well as adventitia. Pulmonary arterial endothelial cell (PAEC) hyperproliferation and survival underlies the endothelial pathobiology of the disease. The indispensable involvement of Notch1 in the arterial endothelial phenotype and angiogenesis provides intriguing prospects for its involvement in the pathogenesis of PAH. We observed an increased expression of Notch1 in lungs of idiopathic PAH (IPAH) patients and hypoxia/SU5416 (SUHx) rats compared with healthy subjects. In vitro loss- and gain-of-function studies demonstrated that Notch1 increased proliferation of human PAECs (hPAECs) via downregulation of p21 and inhibited apoptosis via Bcl-2 and Survivin. Inhibition of Notch signalling using the γ-secretase inhibitor dibenzazepine dose-dependently decreased proliferation and migration of hPAECs. Notably, Notch1 expression and transcriptional activity were increased under hypoxia in hPAECs and knockdown of Notch1 inhibited hypoxia-induced proliferation of the cells. Furthermore, in vivo treatment with a γ-secretase inhibitor (AMG2008827) significantly reduced the right ventricular systolic pressure and right heart hypertrophy in SUHx rats. Here, we conclude that Notch1 plays a critical role in PAH and Notch inhibitors may be a promising therapeutic option for PAH.
Evaluation of UNC569, a Novel Small Molecule Mer Inhibitor for the Treatment of ALL in Vitro and in Vivo.
Authors: Sandra Christoph, Deborah DeRyckere, Jennifer Schlegel, Susan Sather, Amy McGranahan, J. Kimble Franzer, Alesia Trakhimets, Xiaodong Wang, Dmitri Kireev, William Janzen, Jing Liu, Chao Yang, Catherine Simpson, Jacqueline Norris-Drouin, Stephen Frye, H. Shelton Earp, Gary L. Johnson, Douglas K. Graham
Journal: Blood (2012)
Results of the interim analysis of the EORTC randomized phase III CATNON trial on concurrent and adjuvant temozolomide in anaplastic glioma without 1p/19q co-deletion: An Intergroup trial.
Authors: Martin J. Van Den Bent, Sara Erridge, Michael A. Vogelbaum, Anna K. Nowak, Marc Sanson, Alba Ariela Brandes, Wolfgang Wick, Paul M. Clement, Jean-Francois Baurain, Warren P. Mason, Helen Wheeler, Olivier L. Chinot, Michael Weller, Vassilis Golfinopoulos, Ken Aldape, Winand N.M. Dinjens, Pieter Wesseling, Thierry Gorlia, Johan M Kros, Brigitta G. Baumert
Journal: Journal of Clinical Oncology (2016)

LBA2000 Background: The benefit of adding chemotherapy to radiotherapy (RT) in newly diagnosed anaplastic glioma without 1p/19q co-deletion is unknown. The CATNON trial investigated the impact of adjuvant and/or concurrent chemotherapy with temozolomide (TMZ) in these tumors. Methods: Eligible were patients with newly diagnosed WHO grade III glioma without 1p/19q co-deletion, ≥ 18 years, and WHO performance status (PS) 0-2. All patients received RT 59.4 Gy in 33 fractions, and in a 2 x 2 factorial design were randomized to: RT alone; RT with concurrent daily 75 mg/m 2 TMZ; RT followed with 12 cycles of 150-200 mg/m 2 adjuvant TMZ day 1-5/4 weeks; or RT with both concurrent and 12 cycles of adjuvant TMZ. Stratification factors included O6-methyl-guanine DNA methyltransferase ( MGMT) promoter methylation and PS. Primary endpoint was overall survival (OS). 748 patients and 534 events were needed to detect a HR reduction of 0.775 for both concurrent and adjuvant TMZ. An interim analysis was foreseen after 219 events (41%), and required a p value of 0.0084 for rejecting the Null hypothesis of no OS difference. Results: Between Dec 2007 and Aug 2015 748 patients were randomized. On Oct 6, 2015 the interim analysis was conducted based on 221 events (median follow-up: 27 months). The analysis showed a HR reduction for OS of 0.645 (95% CI 0.450, 0.926; p= 0.0014) after adjuvant TMZ (arms iii and iv). MGMT status could be determined in 74% of patients, and was found methylated in 42% of them. MGMT methylation was prognostic for OS (HR 0.54, 95% CI 0.38, 0.77; p= 0.001), but at this stage did not predict improved outcome to adjuvant TMZ. For progression free survival (PFS), the risk adjusted HR of adjuvant TMZ was 0.586 (95% CI 0.472, 0.727; p &lt; 0.0001). Conclusions: 12 cycles adjuvant TMZ improve OS in anaplastic glioma without 1p/19q co-deletion. Further follow-up will elucidate the role of concurrent TMZ . Molecular studies to address the impact of isocitrate dehydrogenase (IDH) mutational status and methylation profiling are ongoing. Clinical trial information: NCT00626990. [Table: see text]
Abstract 685: Selective inhibitor of nuclear export (SINE) compounds prevent migration and proliferation of triple negative breast cancer (TNBC) cells by restoring expression of ARRDC3
Authors: Young Hwa Soung, Trinayan Kashyap, Thalia Nguyen, Yosef Landesman, Jun Chung
Journal: Cancer Research (2016)

Abstract Arrestin-related domain-containing protein-3 (ARRDC3) is one of 6 mammalian arrestins, which has been shown to possess tumor suppressor activity by inducing degradation of phosphorylated â2-adrenergic receptor (â2 AR) and integrin â4 (ITG â4). Our previous studies demonstrated that Sirt2 epigenetically silenced expression of ARRDC3 in TNBC cells and overexpression of ARRDC3 significantly reduced their invasive potential. Therefore, we hypothesized that compounds, which restore ARRDC3 expression levels could serve as novel therapeutic options for TNBC. To test this, we examined the ability of SINE compounds: KPT-185 and KPT-330 (selinexor), to effectively restore ARRDC3 expression. We observed that KPT-185 and selinexor significantly induced ARRDC3 expression and inhibited the proliferation and the invasiveness of the TNBC cell lines MDA-MB-231 and MDA-MB-468 in vitro. In vivo, selinexor inhibited the tumor growth of MDA-MB-231 and MDA-MB-468 xenografts by nearly 100% compared with vehicle treated animals. Furthermore, immunohistochemical analysis of TNBC tumors from selinexor treated mice revealed increased ARRDC3 expression versus vehicle treated animals. Our results suggest that restoration of ARRDC3 expression is an important antineoplastic mechanism of SINE compounds in TNBC and suggest that selinexor could be an effective treatment against tumors with downregulated ARRDC3. Citation Format: Young Hwa Soung, Trinayan Kashyap, Thalia Nguyen, Yosef Landesman, Jun Chung. Selective inhibitor of nuclear export (SINE) compounds prevent migration and proliferation of triple negative breast cancer (TNBC) cells by restoring expression of ARRDC3. [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 685.