tbuckley/cabot-search huggingface dataset:
Abstract 795: Dovitinib exerts potent antitumor effects in gastrointestinal stromal tumors
Authors: Huynh T. Hung, Richard Ong, Pierce Chow
Journal: Cancer Research (2015)

Abstract Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumours of the gastrointestinal (GI) tract. Although Imatinib is the current first-line therapy for patients not suitable for surgical resection, 10 - 20% of GIST patients taking Imatinib do not respond to this therapy and 40-50% of the patients develop acquired resistance to Imatinib following partial response or stable disease. Thus, novel treatments are needed for GIST. In the present study, four different patient-derived xenograft (PDX) GIST models were used to demonstrate that Imatinib effectively caused tumor regression in GIST26-0208A and GIST09-0210 models with the common exon 11 KIT W557-K558 mutation (Imatinib-sensitive models), inhibited tumor growth of GIST27-0510 model with Y568-I571 and P573-L576 deletion and delayed tumor growth in GIST27-0612 with wild-type KIT. Unlike Imatinib, Dovitinib effectively caused tumor regression in all four PDX models tested regardless of their KIT mutational status. On GIST27-0510 model, tumor regression was observed as early as day 3 of Dovitinib treatment and continued to approximately 22% of the initial tumor volume. Dovitinib provided longer progression-free period than Imatinib after a 21-day treatment cycle. In the GIST26-0208A model, signs of tumor regrowth were observed on day 2 for Imatinib and day 59 for Dovitinib following a 21-day treatment. Dovitinib treatment took approximately 3.7 - 5 times longer to reach initial tumor volume than Imatinib following a 21-day treatment. Utilizing micro-Positron Emission Tomography (mPET), both Imatinib and Dovitinib treatment showed decreased SUV and TLG readings after 8-day treatment in GIST26-0208A. A trend of increasing activity was observed in Imatinib but not in Dovitinib-treated tumors at day 11 and day 21 following an 8-day treatment, suggesting mPET could potentially be used to access tumor response to Dovitinib. In Imatinib/Dovitinib-sensitive models, Imatinib and Dovitinib induced significant reduction in expression of p-ERK1/2, Bim, p-AKT (Ser473) and p-Cdc2 at 72 hours post treatment. Although inhibition of p-c-Kit (Tyr568/570) was observed, higher levels of p-Histone H2A-X (Ser139) and Cleaved PARP expression were observed in Dovitinib than Imatinib treatment, suggesting that Dovitinib was more effective than Imatinib in inducing cell death. Our data showed that Dovitinib treatment is able to provide greater advantages over Imatinib in all four PDX models regardless of their KIT mutational status, suggesting that Dovitinib may offer an alternative treatment for GIST that are insensitive to Imatinib. Citation Format: Huynh T. Hung, Richard Ong, Pierce Chow. Dovitinib exerts potent antitumor effects in gastrointestinal stromal tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 795. doi:10.1158/1538-7445.AM2015-795
Individualized Tamoxifen Dose Escalation—Response
Authors: Daniel L. Hertz, James M. Rae
Journal: Clinical Cancer Research (2016)

We thank Koolen and colleagues for their thoughtful response to our commentary about the lack of evidence supporting tamoxifen dose escalation based on predicted or measured endoxifen concentrations (1). They state that “if the concentration has been measured and it is far below the currently adopted minimum value for efficacy of approximately 6 ng/mL, we feel it is unethical not to intervene and not trying to increase the exposure.” The critical phrase in their assertion is “if the concentration has been measured,” whereas in our commentary, we take the position that endoxifen concentrations should not be measured given the current lack of evidence supporting this approach.The authors posited that breast cancer patients taking tamoxifen could benefit from systemic endoxifen concentration measurements. As clinical pharmacologists, we agree that patients with lower drug concentrations may experience inferior therapeutic effectiveness; however, there is an established translational pathway for biomarker hypotheses. The two critical steps are: (i) confirming that the biomarker is associated with a treatment outcome (“clinical validity”) and (ii) demonstrating that biomarker collection improves a treatment outcome (“clinical utility”). Currently, there are a large number of biomarkers being tested that may someday prove to benefit patients, including measurement of drug concentrations and various physiologic “pharmacodynamics” indicators, such as systemic estradiol concentrations in breast cancer patients receiving aromatase inhibitors. However, it is incumbent upon translational researchers to document the biomarker's clinical validity and utility prior to adoption into clinical practice.Koolen and colleagues refer to a “minimum value for efficacy of approximately 6 ng/mL” for circulating endoxifen concentrations and cite a single retrospective study reporting this threshold. Our commentary noted two prospective clinical trials investigating the putative association between endoxifen concentration and tamoxifen treatment efficacy, neither of which confirmed clinical validity in preliminary results reported at ASCO 2016 (2, 3).In this era of unsustainably increasing health care costs, particularly in cancer treatment, it is critical to practice evidence-based medicine. Given the lack of evidence of clinical validity or utility, measuring endoxifen concentrations is practicing one of the alternatives to evidence-based medicine (4). If endoxifen concentration has been measured and found to be low, increasing the tamoxifen dose would be reasonable based on the documented safety of this approach (5) and could potentially enhance efficacy. However, an endoxifen threshold for efficacy has not been established and, at least until one is, clinicians should not measure endoxifen concentration to inform personalized tamoxifen treatment decisions.See the original Letter to the Editor, p. 6300No potential conflicts of interest were disclosed.
Abstract 496: Checkpoint kinase 1 inhibition suppresses cell growth and enhances cisplatin sensitivity in medulloblastoma cells
Authors: Monil Shah, Eric Prince, Sujatha Venkataraman, Ilango Balakrishnan, Irina Alimova, Peter Harris, Marc Remeke, Michael D. Taylor, Michael H. Handler, Nicholas K. Foreman, Rajeev Vibhakar
Journal: Cancer Research (2015)

Abstract Background: Medulloblastoma is the most common malignant brain tumor in children and remains a therapeutic challenge due to its significant therapy-related morbidity. Checkpoint kinase 1 (CHK1) is highly expressed in many cancers and regulates critical steps in mitotic progression and DNA-damage response. Activation of CHK1 pathway promotes treatment resistance in tumor cells. Recent studies suggest that targeting CHK1 with a small molecule inhibitor, to sensitize tumors to a variety of DNA-damaging agents, is a promising approach to tumor therapy. Methods: The expression of CHK1 mRNA in medulloblastoma patient samples and cell lines were examined using microarray analysis and qRT-PCR respectively. Western blot analysis was conducted on medulloblastoma cell lines to analyze expression level of CHK1 protein. The effect of AZD7762, a small molecule inhibitor of CHK1, on colony forming ability of medulloblastoma cell lines in combination with cisplatin was examined using colony formation assay and methylcellulose assay. The impact of AZD7762 in combination with cisplatin on tumor cell proliferation was further evaluated in real-time using xCELLigence. The effect of AZD7762 on cell viability was assessed using Guava ViaCount assay. Furthermore, the effects on key signaling pathways were analyzed using immunofluorescence, senescence assay, and apoptosis assay. Results: Analysis of gene expression and western blot experiments revealed that CHK1 mRNA and protein levels are over expressed in all medulloblastoma patient samples and in cell lines when compared to normal pediatric cerebellum. High CHK1 expression correlates with adverse outcomes in a large cohort of medulloblastoma patients. Inhibition of CHK1 by a low nanomolar concentration of AZD7762 potently inhibited cell growth, suppressed the colony-forming ability, and increased cellular apoptosis of medulloblastoma cells. Furthermore, AZD7762 pretreatment sensitized medulloblastoma cells to cisplatin synergistically. Conclusions: CHK1 expression is a prognostic marker in medulloblastoma and targeting CHK1 with a small molecule inhibitor, in combination with cisplatin, is an attractive strategy in treatment of medulloblastoma that warrants further investigation. Citation Format: Monil Shah, Eric Prince, Sujatha Venkataraman, Ilango Balakrishnan, Irina Alimova, Peter Harris, Marc Remeke, Michael D. Taylor, Michael H. Handler, Nicholas K. Foreman, Rajeev Vibhakar. Checkpoint kinase 1 inhibition suppresses cell growth and enhances cisplatin sensitivity in medulloblastoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 496. doi:10.1158/1538-7445.AM2015-496
Abstract PR05: Genome-scale CRISPR-Cas9 screening to identify essential genes and pathways in pancreatic cancer
Authors: Andrew J. Aguirre, Wei Shao, Han Xu, Barbara Weir, Francisca Vazquez, Robin Meyers, Cheng-Zhong Zhang, Mihir Doshi, Glenn S. Cowley, Theodore Ewachiw, Zeshaan Rasheed, Todd R. Golub, Kimberly Stegmaier, Charles W. Roberts, Levi A. Garraway, Matthew Meyerson, Aviad Tsherniak, David E. Root, Peter J. Espenshade, William C. Hahn
Journal: Cancer Research (2016)

Abstract Loss-of-function genetic screens in cancer cell lines permit the systematic interrogation of genes and pathways involved in cell proliferation and viability. The CRISPR-Cas9 system enables effective genome editing for perturbation of gene function. To identify genes that are essential for cancer cell proliferation and survival, we have optimized an approach for efficient genome-scale CRISPR-Cas9 pooled screening and performed negative-selection knock-out screens in 43 human cancer cell lines with diverse genetic and phenotypic features, including 8 pancreatic cancer cell lines. We report that CRISPR-Cas9 efficacy varies depending on the cell context and propose methods to effectively identify differential cancer dependencies across cell lines. Additionally, we identify a strong correlation between genomic copy number and perceived gene dependency, and further elucidate a gene-independent effect of CRISPR-Cas9 cutting. Using these screening data, we performed a detailed interrogation of gene and pathway dependencies in pancreatic cancer. Through integrative analysis of CRISPR-Cas9 screening results with RNA-interference and small molecule screening data, as well as DNA and RNA sequencing, we identified a high-confidence set of recurrently essential genes in pancreatic cancer, including several with associated biomarkers. Moreover, through pathway analyses of CRISPR-Cas9 screening data, we have identified a number of essential biologic processes including key metabolic and cell signaling pathways that may represent potential therapeutic avenues. In particular, we characterize the sterol regulatory element binding protein (SREBP) signaling pathway as a recurrent vulnerability in pancreatic cancer and credential this pathway as a potential therapeutic target. This abstract is also being presented as Poster A13 Citation Format: Andrew J. Aguirre, Wei Shao, Han Xu, Barbara Weir, Francisca Vazquez, Robin Meyers, Cheng-Zhong Zhang, Mihir Doshi, Glenn S. Cowley, Theodore Ewachiw, Zeshaan Rasheed, Todd R. Golub, Kimberly Stegmaier, Charles W. Roberts, Levi A. Garraway, Matthew Meyerson, Aviad Tsherniak, David E. Root, Peter J. Espenshade, William C. Hahn.{Authors}. Genome-scale CRISPR-Cas9 screening to identify essential genes and pathways in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr PR05.
Concurrent aerobic plus resistance exercise versus aerobic exercise alone to improve health outcomes in paediatric obesity: a systematic review and meta-analysis
Authors: Antonio García-Hermoso, Robinson Ramírez-Vélez, Rodrigo Ramírez-Campillo, Mark D Peterson, Vicente Martínez-Vizcaíno
Journal: British Journal of Sports Medicine (2016)

Objective To determine if the combination of aerobic and resistance exercise is superior to aerobic exercise alone for the health of obese children and adolescents. Design Systematic review with meta-analysis. Data sources Computerised search of 3 databases (MEDLINE, EMBASE, and Cochrane Controlled Trials Registry). Eligibility criteria for selecting studies Studies that compared the effect of supervised concurrent exercise versus aerobic exercise interventions, with anthropometric and metabolic outcomes in paediatric obesity (6–18 years old). The mean differences (MD) of the parameters from preintervention to postintervention between groups were pooled using a random-effects model. Results 12 trials with 555 youths were included in the meta-analysis. Compared with aerobic exercise alone, concurrent exercise resulted in greater reductions in body mass (MD=−2.28 kg), fat mass (MD=−3.49%; and MD=−4.34 kg) and low-density lipoprotein cholesterol (MD=−10.20 mg/dL); as well as greater increases in lean body mass (MD=2.20 kg) and adiponectin level (MD=2.59 μg/mL). Differences were larger for longer term programmes (&gt;24 weeks). Summary Concurrent aerobic plus resistance exercise improves body composition, metabolic profiles, and inflammatory state in the obese paediatric population. Trial registration number CRD42016039807.
The Aberrantly Expressed Long Noncoding RNA, TRERNA1, Predicts for Aggressive Disease in Chronic Lymphocytic Leukemia
Authors: Cecelia R Miller, Amy S. Ruppert, Kevin Coombes, Amy M. Lehman, James S. Blachly, David M. Lucas, Michael R. Grever, Martin S Tallman, Ian W. Flinn, Laura Z. Rassenti, Thomas J. Kipps, Deepa Sampath, John C Byrd, Erin K. Hertlein
Journal: Blood (2015)
A phase II clinical trial with proteomic profiling of imatinib mesylate in patients with refractory or relapsed epithelial ovarian cancer (EOC)
Authors: E. M. Posadas, M. M. Hussain, V. Espina, H. Kotz, L. Minasian, S. M. Shreeve, A. Premkumar, L. A. Liotta, S. M. Steinberg, E. C. Kohn
Journal: Journal of Clinical Oncology (2004)

9651 Background: PDGFR-β and c-kit expression have been described in EOC and imatinib is an inhibitor of both. A phase II clinical trial with proteomic signal pathway profiling is underway to elucidate both the clinical and biological activity of this new agent in EOC. Methods: Patients with relapsed or refractory EOC and no more than 4 prior regimens received imatinib at 400 mg bid; the starting dose was lowered to 600 mg daily due to toxicity. Patients were treated continuously in 28 day cycles and examined every 4 weeks, with imaging every 8 weeks. Tumors were biopsied prior to and after 4 weeks of treatment. Cytokine and growth factor concentrations were measured by ELISA in plasma and fluid samples. Results: Sixteen patients with a median of 4 prior regimens have been enrolled with 15 evaluable. Seven patients (47%) started treatment at 400 mg bid; 4 withdrew within 1 month. The remainder (9) started at 600 mg qd. Five patients (33%) without evidence of disease progression experienced unacceptable toxicities. Eleven patients (73%) experienced grade 3/4 toxicities. Fluid related toxicities included the following events: ascites 40% (6/15), pleural effusion 27% (4/15), and/or peripheral edema 13% (2/15). Non-fluid related grade 3 toxicities included nausea 27% (4/15), vomiting 20% (3/15), constipation, anorexia, hypoalbuminemia, anemia, and leucopenia (1 each); Median time on study was 63 days. Disease stabilization was observed for 4 and 5 months in 2 patients, respectively. Plasma VEGF and PDGF-AB increases were greater in patients who developed symptomatic ascites (p= 0.0012 and 0.04, respectively). Ascites reversed with cessation of imatinib. Profiling by tumor lysate arrays of proliferation, survival, and angiogenesis signaling pathways in tumor and stroma, and a potential mechanism for imatinib-related ascites accumulation will be presented. Conclusions: Imatinib has significant fluid related toxicity in patients with EOC precluding assessment of clear benefit. Based on this data there may be potential benefits from combination therapy with angiogenesis inhibitors. No significant financial relationships to disclose.
A Phase 1 Trial of Daily Oral Green Tea Extract in Asymptomatic, Rai Stage 0–II Patients with Chronic Lymphocytic Leukemia.
Authors: T.D. Shanafelt, S.H. Kaufmann, T.G. Call, Clive S. Zent, W. Wu, D.A. Bowen, C. Secreto, A.K. Ghosh, B. Kabat, C.S. Yang, D.F. Jelinek, C. Erlichman, Neil E. Kay
Journal: Blood (2007)
Peripheral Blood Stem Cell Mobilization After Bendamustine Containing Chemotherapy in Indolent Lymphomas Is Possible. Results From the Phase III Study of B-R Vs. CHOP-R (NHL 1-2003 trial) of the StiL (Study group indolent Lymphomas, Germany).
Authors: Christoph Alexander Burchardt, Wolfram Brugger, Georg Maschmeyer, Dorothea Kofahl-Krause, Lars Fischer, Fritz Roller, Juergen Barth, Mathias J Rummel
Journal: Blood (2009)
178. Early Treatment for Growth Hormone Deficiency Based on Naked DNA Administration in Dwarf Mice Allows Efficient Catch-Up Growth
Authors: Eliza Higuti, Claudia R. Cecchi, Eliana R. Lima, Lars Aagaard, Thomas G. Jensen, Paolo Bartolini, Cibele N. Peroni
Journal: Molecular Therapy (2015)

Growth hormone deficiency (GHD) is the major disease of the pituitary gland and is characterized by significant changes in body composition, bone density, lipid metabolism amongst others. Current treatment consists of daily administration of recombinant human growth hormone. As an alternative, our group investigates a gene therapy strategy for GHD based on the administration of a plasmid encoding the human growth hormone gene (hGH) under the control of ubiquitin C promoter, followed by electrotransfer. In order to get the maximize phenotype correction and to compare treatment of pubertal relative to adult mice, a bioassay was performed using 40 or 80 days old lit/scid mice, respectively. The mice were injected with 50mg of plasmid DNA in each side of non-exposed tibialis cranialis muscle, followed by electrotransfer at high and low voltage pulses. At day 30, the treated groups showed a significant body weight variation of 3.64g/mice/day for pubertal mice, 2.07g/mice/day for the adult mice, and -0.01g/mice/day for the control group. After 40 days, a second round of DNA administration was carried out, and as no significant body weight gain in the following days was observed, the assay was terminated at day 60. Remarkably, the parameters directly related to linear growth (table 1), like increases in nose-to-tail, tail and femur lengths, were 1.2 – 2.0 fold higher for pubertal mice as compared to the adult group, and treatment of pubertal mice resulted in a striking catch-up growth of 36 to 77%.Table 1Parameters directly related to longitudinal growth after 60 days of hGH-DNA administration in 40 days or 80 days old mice lit/scid micenIncrease %Catch-up (%)Nose-to-tail length (cm)saline – 40 days411.6hGH-DNA – 40 days322.235.6untreated scid – 40 days49.0saline – 80 days42.9hGH-DNA – 80 days311.725.7untreated scid – 80 days511.2Tail lenght (cm)saline – 40 days413.1hGH-DNA – 40 days324.239.0untreated scid – 40 days45.8saline – 80 days41.0hGH-DNA – 80 days312.023.6untreated scid – 80 days511.3Femur lenght (mm)hGH-DNA – 40 days318.71Calculated with basis on saline-treated co-aged mice77.5hGH-DNA – 80 days416.11Calculated with basis on saline-treated co-aged mice39.91 Calculated with basis on saline-treated co-aged mice Open table in a new tab Moreover mIGF-I, the main GH-dependent mediator of growth, was measured in plasma samples and the levels of mIGF-I in treated pubertal lit/scid mice were completely normalized 15 days post treatment and not significantly different to values for co-aged untreated non-dwarf mice, however the same did not occur to the adult lit/scid treated mice and their co-aged scid mice. These results are very promising and demonstrates the significance of early onset of gene therapy treatment in the lit/scid mouse model for phenotypic correction of GHD.
<i>P16<sup>INK4a</sup></i>expression after chemotherapy in older women with early-stage breast cancer.
Authors: H. B. Muss, J. Krishnamurthy, S. M. Alston, A. C. Lacy, T. A. Jolly, G. Williams, L. A. Carey, E. C. Dees, C. K. Anders, W. J. Irvin, N. E. Sharpless
Journal: Journal of Clinical Oncology (2011)

9002 Background: Breast cancer (BC) is a disease of aging. In healthy humans, p16INK4a expression increases markedly in peripheral blood T-lymphocytes with chronologic age and exposure to mutagens such as tobacco. The expression of p16INK4a increases exponentially with age, with an average 10-fold increase between ages 20 and 80 years old (Liu et al, Aging Cell, 2010). To determine the effects of BC therapy on a molecular marker of aging, we measured T-cell expression of p16INK4a in older women undergoing therapy for early stage BC. Methods: Pts ≥65 yrs with Stage I-III BC had p16INK4a expression measured in peripheral blood T-cells isolated by magnetic bead sorting on the same day as phlebotomy. Expression of p16INK4a was determined at least 3 months after the completion of BC therapy by TaqMan qRT-PCR. Expression of p16INK4a was measured in replicate and normalized to a housekeeping control gene (18S ribosomal RNA). Expression analysis was determined by investigators blinded to clinical data. Results: 73 of 200 planned patients have had T-cell expression of p16INK4a assessed. Mean/median age range (years) for all pts was 73/71 and (65-93). All pts had surgery, 42 (58%, mean age 74), had no chemotherapy (CRx) and 31 (42%, mean age 71) had CRx. Of the 31 with CRx 19 (61%) had anthracyclines, 24 (77%) cyclophosphamide, and 20 (65%) breast irradiation. Expression of p16INK4a was not correlated with endocrine therapy use or radiotherapy. Expression was increased in patients treated with CRx (Table). Conclusions: In the oldest patients, CRx use was associated with increased expression of p16INK4a, a molecular marker of aging. In patients over the age of 65, CRx use is associated with a more than one decade increase in a marker of molecular age. Accrual continues and expanded data will include toxicity assessment based on pre-treatment p16INK4a. Supported by the Breast Cancer Research Foundation, New York, NY; the Burroughs Wellcome Fund; and the National Institute of Aging (AG024379). Age group No. of pts. No CRx vs. CRx Log2 [p16INK4a] (SEM) No CRx vs. CRx P value All (age adjusted) 42 / 31 7.52 (0.15) / 8.12 (0.14) 0.009 Age 65-74 25 / 23 7.89 (0.18) / 8.23 (0.17) 0.23 Age ≥ 75 17 / 8 8.23 (0.23) / 9.22 (0.30) 0.03