tbuckley/cabot-search huggingface dataset:
Abstract 5190: CCR6-mediated molecular mechanisms involved in colon cancer
Authors: Neeraj Kapur, Hina Mir, Rajesh Singh, Shailesh Singh
Journal: Cancer Research (2015)

Abstract Colon cancer is one of the leading causes of death due to cancer worldwide. Molecular mechanism of initiation and progression of this disease is yet to be defined. Chemokines and their corresponding receptors have been shown to play important role in progression of many cancers including colon. In this study we have demonstrated that CCR6 is highly expressed in colon cancer and is associated with key steps of metastasis. Cell migration, adhesion and invasion are the key features of cancer progression. This process initiates with the change of less motile epithelial phenotype to a more motile mesenchymal type, the phenomenon known as epithelial-mesenchymal transition (EMT). Interestingly, stimulation of colon cancer cell with CCL20, which is the only natural ligand for CCR6, showed significant decrease in E-cadherin. Furthermore, increased Vimentin, beta-Catenin, N-cadherin, alpha-Smooth Muscle Actin (αSMA) and Snail following CCL20 treatment implicates potential role of CCR6-CCL20 axis in transition to mesenchymal phenotype. Hence, strategies directed to this chemokine-receptor axis may improve therapeutic outcome of colon cancer. Citation Format: Neeraj Kapur, Hina Mir, Rajesh Singh, Shailesh Singh. CCR6-mediated molecular mechanisms involved in colon cancer. [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 5190. doi:10.1158/1538-7445.AM2015-5190
342. Gene Edition for Wiskott-Aldrich Syndrome Gene Therapy
Authors: Francisco Martin, Pilar Muñoz, Marién Cobo, Almudena Sanchez-Gilabert, Pedro Real, Verónica Ramos, Philip D. Gregory, Michael C. Holmes, Miguel G. Toscano
Journal: Molecular Therapy (2015)

Site Specific nucleases (SSN) are powerful tools for genome editing that are revolutionizing basic and applied science. However, for most therapeutic applications their efficiency and/or specificity must be still improved before translation into clinic. Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency (PID) caused by mutations in the WAS gene. An interesting characteristic of this disease is that, due the growth selective advantage of the WAS-expressing cells, a small number of corrected hematopoietic stem cells (HSCs) could be enough to achieve a complete cure of the patients. In this context, our final aim is to develop gene edition tools for WAS gene therapy with the idea to achieve safe genetic correction in a small numbers of patients' HSCs. To study efficiency and safety of our tools, we first developed a WAS-specific GFP-reporter cellular model harboring GFP coding sequences disrupted by the intron 1 of the WAS gene. This reporter cell allowed us to have a direct measurement of the efficiency and specificity of WAS-specific nucleases to achieve genetic restoration. We constructed different CRISPR-based and ZFNs-based WAS-specific nucleases expressed by Lentiviral vectors (LV). With these set of plasmids we performed a side by side comparison of two different nucleases (ZFNs and CRISPR) and two different delivery systems (nucleofection versus Integrative deficient lentiviral vectors (IDLV)) to edit the WAS locus. We showed that CRISPR and ZFNs were equally efficient for WAS gene edition (over 60% gene disruption and 4% gene restoration) when delivered by plasmid nucleofection. However, IDLV-ZFNs were more efficient than IDLV-CRISPR, probably due to the low expression levels of Cas9 in the IDLV backbone. Our data indicates that CRISPR based systems can be as efficient as other SSN using standard delivery systems, however, their efficiency using IDLV is limited.
Clinical and pathological predictors of outcome for malignant pleural mesothelioma
Authors: I. Fiordoliva, R. Berardi, Z. Ballatore, M.G. De Lisa, M. Caramanti, F. Morgese, A. Savini, S. Rinaldi, M. Torniai, M. Tiberi, C. Ferrini, A. Onofri, S. Cascinu
Journal: Annals of Oncology (2015)
Impact of primary metastatic bone disease in germ cell tumors: results of an International Global Germ Cell Tumor Collaborative Group G3 Registry Study
Authors: C. Oing, K. Oechsle, A. Necchi, Y. Loriot, U. De Giorgi, A. Fléchon, G. Daugaard, M. Fedyanin, E. Faré, C. Bokemeyer
Journal: Annals of Oncology (2016)
Gefitinib (ZD1839) combined with gemcitabine or vinorelbine as single-agent in elderly patients with advanced non-small cell lung cancer (NSCLC)
Authors: G. Scagliotti, A. Rossi, S. Novello, F. De Marinis, L. Dogliotti, L. Crinò, V. Lorusso, A. Martoni, A. Paccagnella, C. Gridelli
Journal: Journal of Clinical Oncology (2004)

7081 Background: The activity and tolerability of either gemcitabine or vinorelbine given with gefitinib ('Iressa', ZD1839), an Epidermal Growth Factor Receptor-Tyrosine Kinase inhibitor was evaluated in an Italian multicentre randomised non-comparative phase II study in elderly patients with chemo-naive stage IIIB/IV NSCLC using a Fleming's single stage method. Methods: Fiftynine patients aged >=70 with measurable disease were randomised to receive gefitinib (250 mg/die orally until progression) plus either vinorelbine (30 mg/m2 iv) (armA) or gemcitabine (1200 mg/m2 iv) (arm B) both given on days 1 and 8 every 21 days for 6 cycles. Primary end-point was the assessment of tumour response rate measured by RECIST criteria. Results: Main patients' characteristics are (Arm A/B): median age 72/74 yrs.; males 58%/80%; WHO PS 0–1: 96%/91%; squamous histology 17%/31%. Arm A was prematurely closed after 87,5% of 24 randomised patients with grade 3–4 adverse events (AEs), 72% grade 3–4 neutropenia and 3 deaths treatment-related (one sudden cardiac arrest, one grade IV neutropenia with septic shock and cerebral infarction, one grade IV diarrhea followed by cardiac arrest). Arm B completed the planned accrual. Preliminary efficacy data are as follows : Arm A : 1 CR, 3 PR, 7 SD, 6 PD, 7 NE; median duration of response 36 days, median TTPD 91 days, MST 371 days; % of patients alive at 6 months 63%; Arm B : 3 PR, 13 SD, 9 PD, 10 NE, median duration of response 139 days, median TTPD 94 days, MST 275 days, % of patients alive at 6 months 61%. In both arms the most commonest gefitinib-related AE was skin toxicity (mainly grade 1–2) . In the arm B grade 3–4 neutropenia was 11.4% and thrombocitopenia 8.6% (0% in the arm A).Asthenia grade 3–4 was 5.7 in the arm B and 12% in the arm A. Diarrhea grade 3–4 occurred in 12% in arm A and 5.7 in arm B. Conclusions: In elderly patients with advanced NSCLC vinorelbine plus gefitinib was active but toxicity was unacceptable while gemcitabine plus gefitinib was safe, and a remarkable percentage of patients achieved disease control. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly AstraZeneca; Eli Lilly Italian Research Council
Trends in overall survival and costs of multiple myeloma, 2000–2014
Authors: R Fonseca, S Abouzaid, M Bonafede, Q Cai, K Parikh, L Cosler, P Richardson
Journal: Leukemia (2016)

Little real-world evidence is available to describe the recent trends in treatment costs and outcomes for patients with multiple myeloma (MM). Using the Truven Health MarketScan Research Databases linked with social security administration death records, this study found that the percentage of MM patients using novel therapy continuously increased from 8.7% in 2000 to 61.3% in 2014. Compared with MM patients diagnosed in earlier years, those diagnosed after 2010 had higher rates of novel therapy use and better survival outcomes; patients diagnosed in 2012 were 1.25 times more likely to survive 2 years than those diagnosed in 2006. MM patients showed improved survival over the study period, with the 2-year survival gap between MM patients and matched controls decreasing at a rate of 3% per year. Total costs among MM patients have increased in all healthcare services over the years; however, the relative contribution of drug costs has remained fairly stable since 2009 despite new novel therapies coming to market. Findings from this study corroborate clinical data, suggesting a paradigm shift in MM treatment over the past decade that is associated with substantial survival gains. Future studies should focus on the impact on specific novel agents on patients' outcomes.
Abstract 3663: Discovery of sulfonamide-piperidinones as potent inhibitors of the MDM2-p53 protein-protein interaction
Authors: Zhihong Li, Jiasheng Fu, Yosup Rew, Michael W. Gribble, Jude Canon, Ada Chen, John Eksterowicz, Xin Huang, Lixia Jin, Mei-Chu Lo, Lawrence R. McGee, Tao Osgood, Anne Y. Saiki, Paul Shaffer, Daqing Sun, Sarah Wortman, Qiuping Ye, Dongyin Yu, Xiaoning Zhao, Jing Zhou, Jonathan D. Oliner, Steve H. Olson, Julio C. Medina
Journal: Cancer Research (2015)

Abstract The p53 tumor suppressor is controlled by MDM2, which binds p53 and negatively regulates its transcriptional activity and stability. Many tumors overproduce MDM2 to impair p53 function. Therefore, restoration of p53 activity by inhibiting p53-MDM2 binding represents an attractive, novel approach to cancer therapy. We previously reported the discovery of AM-8553, a potent and selective piperidinone inhibitor of the MDM2-p53 interaction (Rew et al. J. Med. Chem. 2012, 55, 4936). We report here continued optimization of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface that led to the discovery of a variety of extremely potent sulfonamides such as 14 with an IC50 of 5.3 nM in the cell proliferation assay. The compound 14 interacts specifically with the p53-binding pocket of MDM2 and releases the p53 protein from negative control. Treatment of cancer cells expressing wild-type p53 with sulfonamide 14 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest and apoptosis. The compound 14 showed excellent efficacy and caused tumor regression in the SJSA-1 tumor xenograft model. Citation Format: Zhihong Li, Jiasheng Fu, Yosup Rew, Michael W. Gribble, Jude Canon, Ada Chen, John Eksterowicz, Xin Huang, Lixia Jin, Mei-Chu Lo, Lawrence R. McGee, Tao Osgood, Anne Y. Saiki, Paul Shaffer, Daqing Sun, Sarah Wortman, Qiuping Ye, Dongyin Yu, Xiaoning Zhao, Jing Zhou, Jonathan D. Oliner, Steve H. Olson, Julio C. Medina. Discovery of sulfonamide-piperidinones as potent inhibitors of the MDM2-p53 protein-protein interaction. [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 3663. doi:10.1158/1538-7445.AM2015-3663
Abstract #4828: Effects of exercise on prostate cancer growth in a mouse model
Authors: Jodi Antonelli, Lee Jones, Susan Poulton, Tameika Phillips, Mark Dewhirst, Stephen Freedland
Journal: Cancer Research (2009)

Purpose: There is a suggestion in the epidemiologic literature that exercise may confer a prostate cancer (PC) risk reduction, however, little is known about the therapeutic potential of exercise for PC. We sought to characterize the effect of exercise on PC growth using a hormone-sensitive human PC xenograft in a post-diagnosis model. Materials and Methods: Seventy athymic Nude-nu male mice (~9 weeks old) were orthotopically implanted with 5x105 LAPC-4 cells. All mice were fed ad libitum Western diet (40% calories from fat; 45% from simple carbohydrates) throughout the study. At 14 days post-implantation, the remaining 62 mice (8 died after orthotopic implant) were randomized to exercise (n=29) or sedentary control (n=33). The exercise mice were housed individually in a cage with 24 hour access to a running wheel and the control mice were housed in identical cages without a running wheel. At 21, 28, and 42 days post-implantation, 4 mice from each group were sacrificed and the tumor (i.e. prostate gland and surrounding tumor) was weighed. The remaining 38 mice were sacrificed at 57 days post-implantation and the tumor was weighed. Comparisons between groups were performed using the rank sum test and the association between running distance and tumor weight was assessed using the Spearman correlation test. Results: There were no significant differences in body weight between the groups at any time during the study. For mice sacrificed on day 57 the median total running distance (IQR) was 104.5km (42.9-189.0). Among the mice sacrificed at 21, 28, and 42 days, there were no significant differences in tumor weight between the groups (p= 0.60). Similarly, there were no significant differences in tumor weight between the groups for the mice sacrificed on day 57 (p= 0.56). Among the exercising mice sacrificed on day 57, running distance was positively correlated with tumor weight (r= 0.44, p= 0.07). Moreover, mice exercising more than 104.5km (the median total running distance) over the course of the study had larger tumors than the sedentary control mice (p= 0.06). Conclusions: Overall, in mice orthotopically implanted with LAPC-4 cells exercise had no effect on tumor growth, however, greater running distance was associated with larger tumors. These findings suggest that initiating moderate to high level exercise after prostate cancer diagnosis may increase prostate tumor growth. Further investigation is required to confirm these findings as well as to determine the molecular mechanisms responsible for the effect of exercise in a post-diagnosis model of prostate cancer.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4828.
Abstract 1675: MEF2 plays a significant role in the tumor inhibitory effects of agarose encapsulated RENCA cells through the EGF receptor
Authors: Prithy C. Martis, Melissa A. Laramore, Atira Dudley, Barry H. Smith, Lawrence S. Gazda
Journal: Cancer Research (2015)

Abstract Identification of the molecular targets involved in the tumor growth inhibition induced by agarose encapsulated mouse renal adenocarcinoma (RENCA) cells will aid in an understanding of the mechanism of action and may allow for the discovery of key targets for therapeutic intervention. The epidermal growth factor receptor (EGFR/ERBB1/HER1) and related family members have been shown to transduce extracellular signals through the mitogen-activated protein kinase (MAPK) pathway to regulate post-translational regulation of myocyte enhancer factor 2 (MEF2) proteins. We have previously reported that suppression of MEF2 isoforms in target tumor cells reduced the growth inhibitory effect of RENCA macrobeads. In this study, we evaluated signaling through EGFR in response to RENCA macrobead conditioned media and examined post-translational activation of MEF2D, using the human prostate cancer, DU145 and the human breast adenocarcinoma, MCF7 cell lines. DU145 and MCF7 cells exposed to naïve or conditioned media were evaluated using In-Cell Western™ analysis for the expression of phospho-EGFR Y1068 in parallel with total EGFR. Phospho-MEF2D and total MEF2D were assessed in nuclear extracts using western blotting. In the DU145 cells, exposure to RENCA macrobead conditioned media activates EGFR as evidenced by phosphorylation of the receptor at tyrosine 1068 in parallel with the increasing age and inhibitory capacity of macrobeads. Further, the growth inhibition of DU145 cells exposed to RENCA macrobead conditioned media is accompanied by dephosphorylation of MEF2D at Serine 444 supporting a role for increased MEF2D transcriptional activity in the inhibitory effect. MCF7 cells are less sensitive to RENCA macrobead-induced growth inhibition, EGFR is not phosphorylated by 2 hours following exposure to macrobead conditioned media and MEF2D remains phosphorylated at Serine 444. These findings support the hypothesis that RENCA macrobeads signal, at least in part, through the EGF receptor to differentially regulate MEF2D, which is significant for macrobead-induced tumor growth inhibition. Citation Format: Prithy C. Martis, Melissa A. Laramore, Atira Dudley, Barry H. Smith, Lawrence S. Gazda. MEF2 plays a significant role in the tumor inhibitory effects of agarose encapsulated RENCA cells through the EGF receptor. [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 1675. doi:10.1158/1538-7445.AM2015-1675
Systemic therapy of brain metastases: non–small cell lung cancer, breast cancer, and melanoma
Authors: Marc C. Chamberlain, Christina S. Baik, Vijayakrishna K. Gadi, Shailender Bhatia, Laura Q.M. Chow
Journal: Neuro-Oncology (2016)

Brain metastases (BM) occur frequently in many cancers, particularly non-small cell lung cancer (NSCLC), breast cancer, and melanoma. The development of BM is associated with poor prognosis and has an adverse impact on survival and quality of life. Commonly used therapies for BM such as surgery or radiotherapy are associated with only modest benefits. However, recent advances in systemic therapy of many cancers have generated considerable interest in exploration of those therapies for treatment of intracranial metastases.This review discusses the epidemiology of BM from the aforementioned primary tumors and the challenges of using systemic therapies for metastatic disease located within the central nervous system. Cumulative data from several retrospective and small prospective studies suggest that molecularly targeted systemic therapies may be an effective option for the treatment of BM from NSCLC, breast cancer, and melanoma, either as monotherapy or in conjunction with other therapies. Larger prospective studies are warranted to further characterize the efficacy and safety profiles of these targeted agents for the treatment of BM.
Phase II trial of high-dose interleukin-2 (IL-2) and stereotactic radiation therapy (SABR) for metastatic clear cell renal cell carcinoma (ccRCC): Interim analysis.
Authors: Raquibul Hannan, Dan Ishihara, Kristi Louder, Chul Ahn, Vitaly Margulis, Yull Edwin Arriaga, Kevin Dale Courtney, Robert D. Timmerman, James Brugarolas
Journal: Journal of Clinical Oncology (2016)

532 Background: We report a planned interim analysis of a single-arm, open-label, phase II trial of HD IL-2 and SABR in multiple ccRCC metastatic sites. Methods: Metastatic ccRCC patients eligible for IL-2 were enrolled and received SABR of 1 or 3 fractions (fx) to up to 6 sites. IL-2 (Proleukin) was administered within 84 hours from the last SABR fx at 600,000 IU/kg every 8h for up to 14 doses in a monitored setting followed by another week after a week break. Eligible (responding) patients received a second course in &gt; 12 weeks. The primary endpoint is the response rate (RR) as evaluated by iRECIST. The study is powered to detect a 60% improvement compared to the historically reported 23% RR for IL-2. Results: 16 patients were enrolled between August 2013 and July 2015; two were withdrawn from the study due to cardiac events prior to receiving IL-2 infusions. The median follow up was 9 months. A median of 2 (1-3) sites were treated with SABR with a median dose of 24.5 Gy (21-27 Gy) for single fx and 30Gy for 3 fx (25-33 Gy). All patients received the first week of IL-2 with a median of 10.5/14 doses; 64% received the second week (9/14) with a median of 7/14 doses. Two patients refused a second week of IL-2 and one was unable to receive it due to thyrotoxicosis. PICC line DVT delayed the second week of IL-2 in two patients. 29% of patients (4/14) received a second course of IL-2. The rate of grade 3 toxicity was 64% with no &gt; grade 3 toxicity. The overall toxicities were expected of IL-2 treatment, transient and resolved after treatment discontinuation. In two cases, grade 1 toxicity was attributed to SABR. At this interim, ten patients underwent at least two follow up scans and were evaluable for outcome analysis. The RR was 40%, with one patient presenting complete response and 3 patients showing partial response. The median duration of overall response was 5 months, with a median stable disease duration of 6 months. Local control rate for SABR-treated lesions was 95%. Conclusions: The addition of SABR to IL-2 increased the RR in mRCC patients of about 2-folds compared to IL-2 alone, despite the reduced number of patients receiving the second week of IL-2. No significant increase in toxicity was observed. Clinical trial information: NCT01896271.
Frequency and predictors of patient deviation from prescribed opioids and barriers to opioid pain-management in patients (pts) with advanced cancer.
Authors: L. M. T. Nguyen, M. De la Cruz, D. Hui, J. L. Palmer, H. A. Parsons, E. Bruera
Journal: Journal of Clinical Oncology (2011)

9081 Background: 75-80% of pts with advanced cancer report pain and almost all receive opioids. There is limited knowledge on deviations from prescribed opioids (MD-Rx) and barriers to pain control. Poor adherence to opioids has been reported in 49-70% of pts. Methods: In this prospective study, we examined the frequency and predictors of pt-reported opioid deviation, and barriers to opioid use in 198 outpatients followed at the Supportive Care Clinic (SCC). We collected pain score (0-10), MD-Rx, confidential patient-reported prescription (Pt-Rx) and opioid intake (Pt-In), barriers to pain management (Barriers Questionnaire II, BQ-II), and adherence to medications (modified Morisky scale, MMS). We defined opioid deviation as <70% or >130% from prescribed dose. Results: Median age was 55, 91 (46%) females, 187 (94%) had solid tumors. The median pain was 4 (IQR 3-7). The median morphine equivalent daily dose was 120mg [Q1-Q3 45-270] for MD-Rx, 100mg [40-270] for Pt-Rx, and 100mg [30-250] for Pt-In. There was a high correlation between MD-Rx and Pt-Rx for regular [r = 0.9, p<0.001], and regular + breakthrough opioids intake [r = 0.94, p<0.001]. 19/198 pts (9.6%) deviated: 11 (6%) used lower doses than prescribed, and 8 (4%) used higher doses. Deviation was more frequent in males [p=0.04] and non-whites [p=0.027]. Non-white race was also associated with higher barriers to opioid use (mean BQ-II 2.16 for other races and 1.76 for African-Americans vs. 1.6 for whites, p=0.01). Higher barrier by BQ-II was in turn associated with lower adherence according to MMS (mean BQ-II 2.0 vs. 1.6, p=0.007 in the motivation domain; mean BQ-II 2.13 vs. 1.57, p=0.0001 in the knowledge domain). Higher BQ-II scores were also associated with taking less/no opioids due to cost (p=0.0017). Conclusions: A small percentage of interdisciplinary supportive care pts reported confidential opioid deviation and most commonly towards less dose intake. These findings suggest SCCs are more successful than other settings in opioid management. Non-white race and male gender were associated with higher risk of opioid deviation. Non-white race was also associated with higher barrier to opioid use.
Rig-I Activates Expression of Interferon-Stimulated Genes (ISGs) and Inhibits the Proliferation of Acute Myeloid Leukemia Cells
Authors: Nan-Nan Zhang, Lei Chen, Wu Zhang, Xian-Yang Li, Lin-Jia Jiang, Fei Ding, Hong-Xin Zhang, Sai-Juan Chen, Zhu-Gang Wang, Zhu Chen, Jiang Zhu
Journal: Blood (2008)