tbuckley/cabot-search huggingface dataset:
Novel mutational and pathway signatures in relapsed/refractory colorectal cancer patients.
Authors: Benny Johnson, Laurence Cooke, Daruka Mahadevan
Journal: Journal of Clinical Oncology (2016)

591 Background: In the management of metastatic colorectal cancer (mCRC), all RAS (KRAS, NRAS) and BRAF V600E mutation status guides therapeutic options and identify a unique cohort of patients (pts) with a more aggressive clinical course. We hypothesized that relapsed/refractory CRC pts develop unique mutational signatures that guide standard and targeted therapy but also predict for therapeutic response, identify novel driver mutations and highlight key signaling pathways for clinical decision making. Methods: Relapsed/refractory mCRC pts (N=31) were molecularly profiled by NGS Caris Molecular Intelligence (IHC, FISH/CISH, NGS) and/or Foundation One (NGS, copy number). Samples were annotated by histology, primary and/or metastatic site, biopsy location, gene mutation, domain, topology, and mutation count. Web-based bioinformatics tools (Enrichr/IntAct) were utilized to analyze mutational profiles, identifying pathway-networks. Results: Pts included progressed on fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, cetuximab or panitumumab. Most common histology was adenocarcinoma followed by squamous cell carcinoma (colon N=28; rectal N=3). TP53 was the most common mutation followed by APC, KRAS, PIK3CA, BRAF, SMAD4, SPTA1, FAT1, PDGFRA, ATM, ROS1, ALK, CDKN2A, FBXW7, TGFBR2, NOTCH1 and HER3. Pts had on average &gt;5 unique gene mutations. High mutational burden was not predictive for PD-1 (5 pts) or PD-L1 (1 pt) positivity. The most common activated signaling pathways were: ERRB2/HER2, FGFR, p38 activation through BRAF-MEK cascade via RIT and RIN, ARMS-mediated activation of MAPK cascade, and VEGFR2. Conclusions: Dominant oncogene mutations do not always equate with oncogenic dependence, therefore understanding the pathologic interactome in each patient is important to both identification of clinically relevant targets and choosing the next best therapy. Mutational signatures derived from corresponding ‘pathway-networks’ represent a meaningful tool to 1). Evaluate functional investigation in the laboratory, 2). Predict response to drug therapy, and 3). Guide rational drug combinations in relapsed/refractory mCRC pts entering targeted and immune checkpoint trials.
Abstract 4041: Glioma cells display a prognostically significant hematopoietic phenotype
Authors: Gerald Moncayo
Journal: Cancer Research (2016)

Abstract Glioblastoma multiforme (GBM) is one of the most aggressive human cancers. Glioma cells expressed immunoreceptor tyrosine-based activation motif (ITAM) bearing molecules, such as Fc receptors, T cell receptor components and C-type lectins and expression was up regulated in two distinct tumor-derived prognostic signatures identified in GBM and low-grade gliomas. Targeting SYK, downstream of ITAM molecules, attenuated GBM tumor growth and invasiveness, and reduced B and CD11b+ cell mobility and infiltration resulting in improved survival. In addition, GBM tumor cells were found to display phagocytic characteristics in vitro and in vivo by flow cytometry and two photon imaging. Our data demonstrate that gliomas are hematopoietic-like tumors that express an immune signaling network important in glioma progression, and identify targets for therapeutic intervention. Citation Format: Gerald Moncayo. Glioma cells display a prognostically significant hematopoietic phenotype. [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 4041.
Application of hot melt extrusion to enhance the dissolution and oral bioavailability of oleanolic acid
Authors: Nannan Gao, Mengran Guo, Qiang Fu, Zhonggui He
Journal: Asian Journal of Pharmaceutical Sciences (2016)

The aim of this study was to improve the in vitro dissolution rate and oral bioavailability of oleanolic acid (OA), a water insoluble drug belonging to BCS class IV. Hot melt extrusion (HME) was applied to develop OA amorphous solid dispersions. The characterizations of the optimal formulation were performed by differential scanning calorimetry, X-ray powder diffraction, Fourier transform infrared spectroscopy and in vitro dissolution test. The in vivo pharmacokinetic study was conducted in rats. As a result, OA solid dispersion based on PVP VA 64 (OA-PVP) was successfully prepared. In the dissolution medium containing 0.3% SDS, OA-PVP dramatically increased the releasing rate of OA compared with the physical mixture (PM-PVP) and commercial tablet. Furthermore, OA-PVP exhibited higher AUC (P < 0.05) and Cmax (P < 0.05) than PM-PVP and commercial tablet. The superior dissolution property and bioavailability of OA-PVP mainly attributed to the amorphous state of OA in PVP VA64 and the well dispersion caused by thermal melting and shearing. Overall, hot melt extrusion was an efficient strategy to enhance the dissolution rate and oral bioavailability of OA.
Abstract 766: Control of lung cancer with aspirin-triggered stimulation of resolution
Authors: Molly M. Gilligan, Megan L. Sulciner, Yael Gus-Brautbar, Sesquile Ramon, Romain A. Colas, Sui Huang, Charles N. Serhan, Dipak Panigrahy
Journal: Cancer Research (2016)

Abstract Objective: To establish aspirin-triggered resolvins as a novel treatment to enhance current cancer therapies through the resolution of inflammation and clearance of cancer therapy-induced tumor cell debris. Background: Inflammation in the tumor microenvironment is now recognized as a strong promoter of tumor growth. Substantial epidemiological evidence suggests that aspirin, which suppresses inflammation, also reduces the risk of cancer. However, the mechanism by which aspirin reduces cancer risk and improves survival remains unclear, and toxicity has limited its clinical use. Low-dose aspirin stimulates the endogenous production of aspirin-triggered (AT) resolvins, novel omega-3 fatty acid-derived pro-resolving lipid autacoid mediators. We recently discovered that resolvins have potent anti-tumor activity, making resolvins potential candidates to mediate the anti-cancer activity of aspirin. Thus, we hypothesize that aspirin's anti-cancer activity is mediated in part by AT-resolvins via novel anti-inflammatory and pro-resolution mechanisms. Methods: Flow cytometry confirmed apoptotic and necrotic lung tumor cell debris following chemotherapy (etoposide) or targeted therapy (erlotinib) treatment in vitro. Macrophage phagocytosis was quantified via Relative Fluorescent Units (RFU). Cytokine levels were quantified via ELISA. Results: AT-resolvins counter therapy-induced debris-stimulated tumor growth and spontaneous lung metastases via enhancing endogenous clearance of tumor debris via macrophages and counter-regulating macrophage cytokine production. Pharmacological and genetic antagonism of the AT-resolvin D1 receptor (ALX/FPR2) neutralized aspirin's anti-cancer activity. Conclusions: AT-resolvins may provide a novel pathway and molecular mechanism to explain how aspirin reduces cancer risk so broadly. These anti-inflammatory and pro-resolving lipid autacoid mediators may complement current therapies for lung cancer with minimal toxicity. Citation Format: Molly M. Gilligan, Megan L. Sulciner, Yael Gus-Brautbar, Sesquile Ramon, Romain A. Colas, Sui Huang, Charles N. Serhan, Dipak Panigrahy. Control of lung cancer with aspirin-triggered stimulation of resolution. [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 766.
An adjuvant clinical trial of SCIB1, a DNA vaccine that targets dendritic cells <i>in vivo</i>, in fully resected melanoma patients.
Authors: Poulam M. Patel, Christian Ottensmeier, Clive Mulatero, Paul Lorigan, Ruth Plummer, Drew Hannaman, Michelle Cunnell, Rachael Metheringham, Victoria Brentville, Ian Daniels, Lee Machado, Linda G Durrant
Journal: Journal of Clinical Oncology (2015)

9035 Background: SCIB1 is a DNA vaccine encoding a human IgG1 antibody, with T cell epitopes from gp100 and TRP-2 antigens engineered into its CDRs. It targets dendritic cells in vivo via the high affinity Fc receptor. A clinical trial in stage III/IV melanoma patients showed that doses of 2-8 mg could induce T cell responses in 7/9 patients with no associated toxicity. Overall median survival was 24 months. In this study SCIB1 is used as an adjuvant therapy. Methods: 16 patients with fully resected stage III (9) or stage IV (7) melanoma, were immunised with SCIB1 by Intramuscular electroporation at 0, 3, 6, 12 and 24 weeks. Patients tolerating treatment were allowed to continue treatment for up to 5 years. Results: Thirteen patients received 4mg doses of SCIB1 on 5 occasions and one received 4 doses of 4mg followed by one dose of 2mg. One patient only tolerated administration of three 2mg doses of SCIB1. One patient received three 2mg doses and then two 4mg doses. Seven patients received additional doses of SCIB1. One patient received 3 doses prior to withdrawal due to disease progression and one patient received 5 doses. The other six patients remain on continuation: three have received 5 doses and two have received 6 doses of SCIB1. Apart from soreness at the injection site, there have been no significant toxicities. All sixteen patients showed an epitope specific proliferation response ex vivo and an γIFN Elispot response in-vitroafter T cell expansion. Eleven patients responded to all 4 epitopes, three patients to 3 epitopes, one patients to 2 epitopes and one patients to 1 epitope. All patients with continued treatment showed strong T cell memory responses. Currently patients have a median survival time from trial entry of 29.5 months and from diagnosis of metastases of 34 months. Progression free survival is 78% and 72% for stage III and IV respectively and overall survival is 100% for both groups. Only 4 patients have relapsed at 4, 14, 18 and 18 months, since the last relapse there have been no further recurrences for 23 months. Conclusions: These results suggest that SCIB1 may confer protection from recurrence of melanoma with little associated toxicity. This vaccine deserves further evaluation as an adjuvant therapy. Clinical trial information: 2009-017355-10.
Abstract 2053: Effects of thymoquinone encapsulation on its uptake, delivery and anticancer activity in breast cancer cells
Authors: Isabelle Fakhoury, Walid Saad, Kamal Bou Hadir, Regine Schneider-Stock, Hala Gali-Muhtasib
Journal: Cancer Research (2016)

Abstract Introduction: Thymoquinone (TQ) is a promising anticancer molecule which suffers from limited bioavailability. Drug encapsulation is commonly used to overcome low drug solubility, bioavailability as well as nonspecific targeting. For this project, we synthesized different TQ nanoparticles (TQ-NPs), characterized their properties, uptake and delivery mechanisms, and assessed their anticancer potential in a panel of breast cancer cells. Methods: The different TQ-NPs were prepared using Flash nanoprecipitation. Dynamic light scattering and scanning electron microscope were used for the characterization of the size, morphology and stability of the NPs. The anticancer effect was assessed by MTT. We subsequently formulated fluorescent TQ-NPs and evaluated their uptake and subcellular intake mechanism by both fluorometry and confocal microscopy. Results: We were successful at formulating four different stable TQ-NPs that had an average diameter size between 45-130 nm. All TQ-NPs had also high entrapment efficiency and loading content. In vitro, TQ-NPs enhanced the antitumor activity of the drug in both MCF-7 and MDA-MB-231 cells, when compared to free TQ with no significant cytotoxicity of the blank NPs. Fluorescent TQ-NPs uptake was further found to be both time and concentration dependent. Finally, using inhibitors of endocytosis we determined that the endocytosis of TQ-NPs is caveolin mediated. This was also confirmed by examining the subcellular localization of TQ-NPs. The nanoparticle formulations colocalized with both caveolin and transferrin but not with lamp-1 and EEA-1 proteins. Conclusion: Altogether, our results describe a new approach for the enhancement of TQ anticancer activity and provide insights on the uptake dynamics specific to our formulation. Citation Format: Isabelle Fakhoury, Walid Saad, Kamal Bou Hadir, Regine Schneider-Stock, Hala Gali-Muhtasib. Effects of thymoquinone encapsulation on its uptake, delivery and anticancer activity in 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 2053.
Making physical activity evidence accessible: are these infographics the answer?
Authors: Hamish Reid, Karen Milton, George Bownes, Charlie Foster
Journal: British Journal of Sports Medicine (2016)

Non-communicable diseases (NCDs) account for 68% of all deaths worldwide. In the UK, NCDs are responsible for 80% of all deaths.1 Physical inactivity is one of the four key behavioural risk factors for NCDs. Across the four countries of the UK, at least one-third of adults are insufficiently active, which is higher than the global average, the majority of our European neighbours and the USA.2

The 2011 physical activity recommendations, published by the four UK Chief Medical Officers (CMOs), emphasised the goal of achieving an active lifestyle across the life course. The challenge of increasing and sustaining the physical activity levels of the UK's child and adult populations has been central to national policies and plans since the mid-1990s. A consistent feature of these plans has been the role of the healthcare setting in the promotion of physical activity for the prevention and treatment of disease. Reports by the Royal Colleges,3 ,4 House of Commons Health Committee,5 Public Health England (PHE)6 and the National …
Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIa Investigators.
Journal: Circulation (1994)

Although intravenous heparin is routinely used in the treatment of patients with acute coronary syndromes, this anticoagulant requires antithrombin III as a cofactor, has no affinity to clot-bound thrombin, and is bound or inactivated by several plasma proteins and platelet factor 4. Recombinant hirudin, the prototypic direct thrombin inhibitor, has been demonstrated in pilot studies to yield improved angiographic and clinical outcomes compared with heparin. We compared these two antithrombins in a large-scale randomized trial.At 275 participating hospitals in 12 countries, patients within 12 hours from the onset of ischemic chest discomfort with an abnormal ECG were randomly assigned to receive a 72- to 120-hour infusion of heparin (5000-U bolus and 1000- to 1300-U/h infusion, adjusted to activated partial thromboplastin time (APTT) of 60 to 90 seconds or hirudin (0.6-mg/kg bolus and 0.2-mg/kg per hour infusion without aPTT adjustment) on a double-blind basis. Although recruitment of 12,000 patients was planned, the trial was stopped earlier because of an excess of intracerebral hemorrhagic events after 2564 patients were enrolled. The overall incidence of hemorrhagic stroke tended to be higher for patients receiving hirudin (1.3%) compared with heparin (0.7%), P = .11, but the incidence was significantly higher in patients receiving thrombolytic therapy (1264 patients, 1.8%) compared with those who did not (1168 patients, 0.3%), P < .001. The hemorrhagic stroke rate varied by the thrombolytic and antithrombin combination: tissue-type plasminogen activator and heparin, 0.9%; with hirudin, 1.7%; streptokinase with heparin, 2.7%; with hirudin, 3.2%. All these rates are higher than the overall incidence of hemorrhagic stroke in the patients receiving thrombolytic therapy and intravenous heparin in the GUSTO I trial (30,892 patients with rate of 0.7%, 95% CI of 0.6 to 0.8%). Among the 26 patients who had intracerebral hemorrhages, the aPTT was significantly elevated compared with the event-free patients (110 +/- 46 versus 87 +/- 36 seconds at 12 hours of therapy, respectively), P = .03.At the dose of hirudin tested, there was a trend of an excess of hemorrhagic stroke compared with heparin. Heparin, at a slightly higher dose than previously used in a large-scale trial (approximately 20% increase) was accompanied by a twofold risk of hemorrhagic stroke in patients receiving thrombolytic therapy. With both thrombin inhibitors, the aPTT appears to be a useful index for predicting risk of hemorrhagic stroke in patients receiving thrombolytic therapy.
A phase 2 study of JNJ-42756493, a pan-FGFR tyrosine kinase inhibitor, in patients (pts) with metastatic or unresectable urothelial cancer (UC) harboring FGFR gene alterations.
Authors: Arlene O. Siefker-Radtke, Begona Mellado, Karel Decaestecker, John M. Burke, Anne O'Hagan, Anjali Narayan Avadhani, Bob Zhong, Ademi E. Santiago-Walker, Peter De Porre, Sabine Brookman-May, Jesús García-Donas
Journal: Journal of Clinical Oncology (2016)

TPS4575 Background: Current treatment options for metastatic UC remain limited, and tolerability is a concern in many pts. Alterations in the fibroblast growth factor receptor (FGFR) pathway are implicated in development of non-muscle–invasive bladder cancer; FGFR3 mutations or FGFR translocations are present in ~10-20% of pts with metastatic UC. Treatment with pan-FGFR (FGFR1-4) inhibitor JNJ-42756493 resulted in promising antitumor activity in a phase 1 trial in pts with advanced solid tumors, including 3 partial responses among 8 pts with UC (Tabernero J, et al. J Clin Oncol. 2015). Safety was manageable and as anticipated with a potent FGFR inhibitor. This phase 2 open-label study of JNJ-42756493 (NCT02365597) is being conducted to determine efficacy and safety of 2 different dose regimens in pts with metastatic or unresectable UC with specific FGFR translocations or mutations. Methods: Eligible pts must have disease progression following chemotherapy for metastatic or surgically unresectable UC or relapse within 12 mos of the last dose of neoadjuvant/adjuvant chemotherapy. There is no limit on number of prior lines of treatment. Prior immunotherapy (eg, programmed-death 1/death-ligand 1 inhibitor) is allowed. Enrollment of cisplatin-ineligible (chemotherapy naïve) pts is allowed. Pts must have measurable disease (RECIST v1.1); Eastern Cooperative Oncology Group performance status ≤ 2; and adequate bone marrow, liver, and kidney function (creatinine clearance ≥ 40 mL/min). Pts with uncontrolled cardiovascular disease or baseline phosphate persistently above the upper limit of normal are not eligible. Eligible pts are randomized to 1 of 2 oral dose regimens of JNJ-42756493 in a 28-d cycle: an intermittent (10 mg/d for 7 d followed by 7 d off drug) or a continuous (6 mg/d) regimen until a dose regimen is selected. Approximately 110 pts will be treated at the selected dose regimen. Primary end point is objective response rate; secondary end points include progression-free survival, duration of response, overall survival, safety, biomarker, and pharmacokinetic assessments. This trial is currently enrolling at 93 sites in 14 countries. Clinical trial information: NCT02365597.
Abstract 2206: Development and characterization of an injectable copper clioquinol formulation: repurposing of a topical antifungal for treatment of cancer
Authors: Moe Wehbe, Malathi Anantha, Ian Backstrom, Armaan Malhotra, Katarina Edwards, Marcel Bally
Journal: Cancer Research (2016)

Abstract Clioquinol is an FDA approved antifungal and antiprotozoal drug that has recently garnered attention for its anti-cancer activities. In vitro studies with CQ activity suggest that its mechanism of activity may be dependent its ability to bind and transport copper. CQ binds copper to form a stable dimeric complex (2 mol CQ:1 mol Cu ((CuCQ2)). Although therapeutically interesting, CuCQ2 is virtually insoluble in aqueous solutions and therefore it has been difficult to develop formulations suitable for administration. To address this, a liposomal CuCQ2 formulation was developed and characterized for maximum tolerated dose, pharmacokinetics and efficacy in xenograft models. Liposomes (∼100nm) composed of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol (CHOL) (55:45 molar ratio) were prepared to contain 300 mM CuSO4. CQ is added to the outside of these pre-formed liposomes; at the appropriate incubation temperature CQ crosses the liposomal membrane where it can interact with the encapsulated Cu to form the insoluble CuCQ2 complex which becomes trapped. The maximum tolerated dose of the resultant formulation was determined in CD-1 mice. The pharmacokinetics of the formulation (liposomal lipid, CQ and Cu) were measured following intravenous administration at a well tolerated dose. Efficacy was measured in two cancer models (sc U251 glioblastoma and i.p A2780 ovarian). The maximum tolerated dose of liposomal CuCQ2 was 30 mg/kg when administered i.v (q2d for two weeks) and 15 mg/kg when administered i.p (QD for two weeks). Pharmacokinetics studies with liposomalCuCQ2 administered iv at 30 mg/kg indicated an terminal elimination half-life (t1/2) of 5.4 hr and an AUC of 994 ug•hr/mL. Results demonstrate that the CuCQ2 complex remains intact upon injection. When used to treat animals bearing established sc U251 glioblastoma tumors showed 30% smaller tumours than those treated with vehicle alone. The activity of liposomal CuCQ2 in the A2780 intraperitoneal cancer model will be presented. This work describes, for the first time, a novel injectable formulation of CuCQ2; this formulation is active against established xenograft models. The activity of this formulation will now be assessed in the context of copper-dependent inhibition of NFκB signalling. Citation Format: Moe Wehbe, Malathi Anantha, Ian Backstrom, Armaan Malhotra, Katarina Edwards, Marcel Bally. Development and characterization of an injectable copper clioquinol formulation: repurposing of a topical antifungal for treatment of cancer. [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 2206.