Wells A Messersmith

University of Colorado, Denver, Colorado, United States

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Publications (124)807.23 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Rigosertib (ON 01910.Na), a first-in-class Ras mimetic and small molecule inhibitor of multiple signaling pathways including polo-like kinase 1 (PLK1) and phosphoinositide 3-kinase (PI3K), has shown efficacy in preclinical pancreatic cancer models. In this study, rigosertib was assessed in combination with gemcitabine in patients with treatment-naïve metastatic pancreatic adenocarcinoma. Patients with metastatic pancreatic adenocarcinoma were randomized in a 2:1 fashion to gemcitabine 1000 mg/m(2) weekly for 3 weeks of a 4-week cycle plus rigosertib 1800mg/m(2) via 2-hr continuous IV infusions given twice weekly for 3 weeks of a 4-week cycle (RIG+GEM) versus gemcitabine 1000 mg/m(2) weekly for 3 weeks in a 4-week cycle (GEM). A total of 160 patients were enrolled globally and randomly assigned to RIG+GEM (106 patients) or GEM (54). The most common grade 3 or higher adverse events were neutropenia (8% in the RIG+GEM group vs. 6% in the GEM group), hyponatremia (17% vs. 4%), and anemia (8% vs. 4%). The median overall survival (OS) was 6.1 months for RIG+GEM versus 6.4 months for GEM (hazard ratio (HR), 1.24; 95% confidence interval [CI], 0.85-1.81). The median progression-free survival was 3.4 months for both groups (HR= 0.96; 95% CI, 0.68-1.36). The partial response rate was 19% versus 13% for RIG+GEM versus GEM, respectively. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations (40 cases). Other mutations detected included TP53 (13 cases) and PIK3CA (1 case). No correlation between mutational status and efficacy was detected. The combination of RIG+GEM failed to demonstrate an improvement in survival or response compared to GEM in patients with metastatic pancreatic adenocarcinoma. Rigosertib showed a similar safety profile to that seen in previous trials using the IV formulation. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
    Annals of Oncology 06/2015; DOI:10.1093/annonc/mdv264 · 6.58 Impact Factor
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    ABSTRACT: In the normal human colon, aldehyde dehydrogenase 1B1 (ALDH1B1) is expressed only at the crypt base, along with stem cells. It is also highly expressed in the human colonic adenocarcinomas. This pattern of expression corresponds closely to that observed for Wnt/β-catenin signaling activity. The present study examines the role of ALDH1B1 in colon tumorigenesis and signalling pathways mediating its effects. In a 3-dimensional spheroid growth model and a nude mouse xenograft tumor model, shRNA-induced suppression of ALDH1B1 expression decreased the number and size of spheroids formed in vitro and the size of xenograft tumors formed in vivo by SW 480 cells. Six binding elements for Wnt/β-catenin signalling transcription factor binding elements (T-cell factor/ lymphoid enhancing factor) were identified in the human ALDH1B1 gene promoter (3 kb) but shown by dual luciferase reporter assay to not be necessary for ALDH1B1 mRNA expression in colon adenocarcinoma cell lines. We examined Wnt-reporter activity and protein/mRNA expression for Wnt, Notch and PI3K/Akt signaling pathways. Wnt/β-catenin, Notch and PI3K/Akt-signaling pathways were down-regulated in SW 480 cells in which ALDH1B1 expression had been suppressed. In summary, our data demonstrate that ALDH1B1 may promote colon cancer tumorigenesis by modulating the Wnt/β-catenin, Notch and PI3K/Akt signaling pathways. Selective targeting of ALDH1B1 may represent a novel means to prevent or treat colon cancer.
    PLoS ONE 05/2015; 10(5):e0121648. DOI:10.1371/journal.pone.0121648 · 3.53 Impact Factor
  • A.J. Scott, W.A. Messersmith, A. Jimeno
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    ABSTRACT: Aberrant proangiogenic pathways have long been implicated in tumorigenesis and metastasis. Antiangiogenic therapies have shown efficacy in the treatment of a variety of solid tumors including lung, breast, colon, glioblastomas, and other solid tumor types. Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2), is an orally bioavailable agent currently being studied in multiple tumor types. Apatinib has shown a survival benefit in gastric cancer in a phase III trial and non-small cell lung cancer in a phase II trial. With a favorable side effect profile and improved outcomes, apatinib has demonstrated a substantial potential to augment therapeutic options in a variety of tumor types. Copyright 2015 Prous Science, S.A.U. or its licensors. All rights reserved.
    Drugs of today (Barcelona, Spain: 1998) 04/2015; 51(4):223. DOI:10.1358/dot.2015.51.4.2320599 · 1.00 Impact Factor
  • Christopher H Lieu, Alison Sorkin, Wells A Messersmith
    Journal of Clinical Oncology 03/2015; 33(13). DOI:10.1200/JCO.2014.60.6004 · 17.88 Impact Factor
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    ABSTRACT: Purpose:Enoticumab (REGN421) is a fully human IgG1 monoclonal antibody that binds human Dll4 and disrupts Notch-mediated signaling. The main objectives of this trial were to determine the safety, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and recommended phase II dose (RP2D) of enoticumab. Experimental Design:Enoticumab was administered intravenously with dose escalations from 0.25 to 4mg/kg every 3 weeks (Q3W) and 0.75 to 3mg/kg every 2 weeks (Q2W). Results:Of 53 enrolled patients, 31 patients were treated Q3W and 22 patients were treated Q2W. Two DLTs occurred: grade 3 nausea (0.5mg/kg Q3W) and grade 3 abdominal pain (1 mg/kg Q2W). A maximum tolerated dose (MTD) was not reached on either schedule. The most frequent adverse events (AEs) were fatigue, nausea, vomiting, hypertension, headache, and anorexia. Six treatment-related serious AEs were reported in 4 patients: Brain natriuretic peptide (BNP) increase (0.25mg/kg Q3W, Gr1), troponin I increase (4mg/kg Q3W, Gr3), right ventricular dysfunction and pulmonary hypertension (1.5mg/kg Q2W, both Gr3), left ventricular dysfunction and pulmonary hypertension (3mg/kg Q2W, both Gr3). Enoticumab was characterized by non-linear, target-mediated PK, and had a terminal half-life of 8 to 9 days. With multiple Q2W or Q3W dosing, accumulation was not observed. Antitumor activity included 2 partial responses (NSCLC bronchoalveolar-type with a β-catenin mutation, and ovarian cancer), and 16 patients with stable disease (three > 6 months). Conclusions: Enoticumab was tolerated, with RP2D of 4mg/kg Q3W and 3mg/kg Q2W based on PK profile and clinical activity. Responses and SD were noted in ovarian cancer and other solid tumors. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 02/2015; DOI:10.1158/1078-0432.CCR-14-2797 · 8.19 Impact Factor
  • J. L. Greene, S. Bagby, W. Messersmith, J. Aracaroli
    Journal of Investigative Medicine 01/2015; 63(1):210-210. · 1.50 Impact Factor
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    ABSTRACT: Background: The activation of the MAPK and PI3K/AKT/mTOR pathways is implicated in the majority of cancers. Activating mutations in both of these pathways has been described in colorectal cancer (CRC), thus indicating their potential as therapeutic targets. This study evaluated the combination of a PI3K/mTOR inhibitor (PF-04691502/PF-502) in combination with a MEK inhibitor (PD-0325901/PD-901) in CRC cell lines and patient-derived CRC tumor xenograft models (PDTX). Materials and Methods: The anti-proliferative effects of PF-502 and PD-901 were assessed as single agents and in combination against a panel of CRC cell lines with various molecular backgrounds. Synergy was evaluated using the Bliss Additivity method. In selected cell lines, we investigated the combination effects on downstream effectors by immunoblotting. The combination was then evaluated in several fully genetically annotated CRC PDTX models. Results: The in vitro experiments demonstrated a wide range of IC50 values for both agents against a cell line panel. The combination of PF-502 and PD-901 demonstrated synergistic anti-proliferative activity with Bliss values in the additive range. As expected, p-AKT and p-ERK were downregulated by PF-502 and PD-901, respectively. In PDTX models, following a 30-day exposure to PF-502, PD-901 or the combination, the combination demonstrated enhanced reduction in tumor growth as compared to either single agent regardless of KRAS or PI3K mutational status. Conclusions: The combination of a PI3K/mTOR and a MEK inhibitor demonstrated enhanced anti-proliferative effects against CRC cell lines and PDTX models.
    PLoS ONE 11/2014; 9(11):e113037. DOI:10.1371/journal.pone.0113037 · 3.53 Impact Factor
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    ABSTRACT: Purpose: To estimate the maximum tolerated dose (MTD) of single-agent PF-04449913, and to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity in patients with advanced tumors. Experimental Design: A 3+3 design was used in this open-label, multicenter, phase I study and dose escalation/de-escalation applied until identification of the MTD. PF-04449913 was orally administered once daily (QD) in continuous 28-day treatment cycles. The starting dose was 80 mg. Results: A total of 23 patients were enrolled; 19 were evaluable for first-cycle dose-limiting toxicity (DLT). The first-cycle DLT rate at the 640-mg dose level was 33.3% and the MTD was estimated to be 320 mg QD. The recommended phase 2 dose was not determined. PF-04449913 was generally well tolerated at doses of 80-320 mg QD. The most common treatment-related adverse events (AEs) were grade 1-2 dysgeusia, fatigue, decreased appetite, nausea, dizziness, dehydration, and diarrhea. Treatment-related grade 3 AEs only occurred in patients receiving PF-04449913 640 mg QD. No treatment-related grade 4-5 AEs were reported. Pharmacokinetic analysis indicated a generally dose-proportional kinetics with biphasic elimination, supporting QD dosing. PF-04449913 modulated hedgehog signaling at the dose levels tested, as demonstrated by >80% down-regulation of GLI1 expression in the skin of treated patients. Eight (34.8%) patients achieved stable disease; none had complete or partial response. Three patients with disease progression at enrollment had prolonged disease stabilization (≥6 months). Conclusions: The results obtained in this study support further evaluation of PF-04449913 in patients with advanced solid tumors.
    Clinical Cancer Research 11/2014; 21(5). DOI:10.1158/1078-0432.CCR-14-1116 · 8.19 Impact Factor
  • A Scott, W A Messersmith, A Jimeno, S L Davies
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    ABSTRACT: Panitumumab is a fully human monoclonal antibody targeting epidermal growth factor receptor (EGFR) approved for use in colorectal cancer (CRC). Critical information regarding biomarkers in CRC has been discovered through the investigation of panitumumab treatment. The discovery of anti-EGFR resistance in the setting of Kirsten rat sarcoma viral oncogene (KRAS) and more recently, neuroblastoma RAS viral oncogene (NRAS) mutations in CRC has changed the focus of therapy for metastatic disease to one based on the molecular characteristics of the tumor. This review will give a brief background on panitumumab and its current uses in CRC.
    Drugs of today (Barcelona, Spain: 1998) 10/2014; 50(10):679-90. DOI:10.1358/dot.2014.50.10.2221787 · 1.00 Impact Factor
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    ABSTRACT: Purpose: To estimate the maximum tolerated dose (MTD) for continuous oral administration of the gamma-secretase inhibitor PF-03084014, determine the recommended phase 2 dose (RP2D), and evaluate safety and preliminary activity in patients with advanced solid tumors. Experimental Design: This open-label, phase I study consisted of a dose-finding portion based on a 3+3 design, followed by an expansion cohort. PF-03084014 was administered orally, twice daily (BID) for 21 continuous days. Tested doses ranged from 20 to 330 mg BID. In the expansion cohort, patients were to receive the estimated MTD or a lower dose of PF-03084014. Results: A total of 64 patients received treatment. The MTD was estimated to be 220 mg BID. The RP2D was determined to be 150 mg BID, based on the better safety profile versus the 220-mg BID dose, given comparable NOTCH-related target inhibition. The most common treatment-related AEs were diarrhea, nausea, fatigue, hypophosphatemia, vomiting, rash, and decreased appetite, which were generally mild to moderate in severity. One patient with advanced thyroid cancer had a complete response and five of seven response-evaluable patients with desmoid tumor achieved a partial response (71.4% objective response rate). Tumor responses were mostly durable, ranging from 1.74+ to 24+ months. PF-03084014 demonstrated a generally dose-dependent pharmacokinetic profile at doses ranging from 20 to 330 mg BID. Consistent down-modulation of NOTCH-related HES4 gene expression was observed in peripheral blood from all evaluable patients. Conclusions: Further development of PF-03084014 for the treatment of patients with advanced solid tumors is warranted and currently under evaluation.
    Clinical Cancer Research 09/2014; 21(1). DOI:10.1158/1078-0432.CCR-14-0607 · 8.19 Impact Factor
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    ABSTRACT: Recently, we characterized neoamphimedine (neo) as an ATP-competitive inhibitor of the ATPase domain of human Topoisomerase IIα. Thus far, neo is the only pyridoacridine with this mechanism of action. One limiting factor in the development of neo as a therapeutic agent has been access to sufficient amounts of material for biological testing. Although there are two reported syntheses of neo, both require 12 steps with low overall yields (≤6%). In this article, we report an improved total synthesis of neo achieved in 10 steps with a 25% overall yield. In addition, we report an expanded cytotoxicity study using a panel of human cancer cell lines, including: breast, colorectal, lung, and leukemia. Neo displays potent cytotoxicity (nM IC50 values) in all, with significant potency against colorectal cancer (lowest IC50 = 6 nM). We show that neo is cytotoxic not cytostatic, and that neo exerts cytotoxicity by inducing G2-M cell cycle arrest and apoptosis.
    Marine Drugs 09/2014; 12(9):4833-4850. DOI:10.3390/md12094833 · 3.51 Impact Factor
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    ABSTRACT: Anti-angiogenic therapy is commonly used for the treatment of CRC. Although patients derive some clinical benefit, treatment resistance inevitably occurs. The MET signaling pathway has been proposed to be a major contributor of resistance to anti-angiogenic therapy. MET is upregulated in response to VEGF pathway inhibition and plays an essential role in tumorigenesis and progression of tumors. In this study we set out to determine the efficacy of cabozantinib in a preclinical CRC PDTX model. We demonstrate potent inhibitory effects on tumor growth in 80% of tumors treated. The greatest antitumor effects were observed in tumors that possess a mutation in the PIK3CA gene. The underlying antitumor mechanisms of cabozantinib consisted of inhibition of angiogenesis and Akt activation and significantly decreased expression of genes involved in the PI3K pathway. These findings support further evaluation of cabozantinib in patients with CRC. PIK3CA mutation as a predictive biomarker of sensitivity is intriguing and warrants further elucidation. A clinical trial of cabozantinib in refractory metastatic CRC is being activated. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 09/2014; 136(8). DOI:10.1002/ijc.29225 · 5.01 Impact Factor
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    ABSTRACT: The NCCN Guidelines for Colon Cancer address diagnosis, pathologic staging, surgical management, perioperative treatment, posttreatment surveillance, management of recurrent and metastatic disease,and survivorship. This portion of the guidelines focuses on the use of systemic therapy in metastatic disease. The management of metastatic colorectal cancer involves a continuum of care in which patients are exposed sequentially to a variety of active agents, either in combinations or as single agents. Choice of therapy is based on the goals of treatment, the type and timing of prior therapy, the different efficacy and toxicity profiles of the drugs, the mutational status of the tumor, and patient preference.
    Journal of the National Comprehensive Cancer Network: JNCCN 07/2014; 12(7):1028-59. · 4.24 Impact Factor
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    ABSTRACT: Purpose The notch pathway is overexpressed in pancreatic adenocarcinoma. RO4929097, an oral inhibitor of the γ-secretase enzyme has been safely given as a single agent in patients with advanced solid tumors. We aimed to evaluate the efficacy of RO4929097 in patients with pancreatic adenocarcinoma (PDA). Methods A two-stage, single-arm Phase II trial was conducted in patients with previously treated metastatic PDA. RO4929097 was administered at a dose of 20 mg daily on days 1-3, 8-10 and 15-17 of 21-day cycles. The primary endpoint was survival at 6 months. Secondary endpoints included overall survival (OS), response rate, toxicities, pharmacokinetic and pharmacodynamic analyses. Results Eighteen patients were recruited, 17 in the first stage and one in the 2nd stage. It was decided to stop further enrollment after RO4929097 was discontinued by the sponsor and was no longer a development candidate. Three (25 %) of 12 evaluable patients achieved stable disease. The 6-month survival rate was 27.8 % (95 % CI 9.7-53.5). The median OS was 4.1 months (95 % CI 2.7-5.8 months) and median progression-free survival was 1.5 months (95 % CI 1.3-1.6 months). Pharmacokinetic properties of RO4929097 in patients (n = 5) with PDA was similar to that previously reported in other patient populations. There was a trend towards a decrease in HeyL (p = 0.08) gene expression in three patients following study drug administration. Conclusions RO4929097 was well-tolerated in patients with previously treated PDA. Development of RO4929097 has been discontinued, but development of other notch-targeting agents in pancreatic cancer is continuing.
    Investigational New Drugs 03/2014; DOI:10.1007/s10637-014-0083-8 · 2.93 Impact Factor
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    ABSTRACT: MNRP1685A is a human monoclonal antibody that blocks binding of vascular endothelial growth factor (VEGF), VEGF-B, and placental growth factor 2 to neuropilin-1 resulting in vessel immaturity and VEGF dependency. The safety of combining MNRP1685A with bevacizumab, with or without paclitaxel, was examined. Patients with advanced solid tumors received escalating doses of MNRP1685A (7.5, 15, 24, and 36 mg/kg) with bevacizumab 15 mg/kg every 3 weeks in Arm A (n = 14). Arm B (n = 10) dosing consisted of MNRP1685A (12 and 16 mg/kg) with bevacizumab 10 mg/kg (every 2 weeks) and paclitaxel 90 mg/m(2) (weekly, 3 of 4 weeks). Objectives were to determine safety, pharmacokinetics, pharmacodynamics, and the maximum tolerated dose of MNRP1685A. Infusion reactions (88 %) and transient thrombocytopenia (67 %) represent the most frequent study drug-related adverse events (AEs). Drug-related Grade 2 or 3 proteinuria occurred in 13 patients (54 %). Additional study drug-related AEs occurring in >20 % of patients included neutropenia, alopecia, dysphonia, fatigue, and nausea. Neutropenia occurred only in Arm B. Grade ≥3 study drug-related AEs in ≥3 patients included neutropenia (Arm B), proteinuria, and thrombocytopenia. Two confirmed and three unconfirmed partial responses were observed. The safety profiles were consistent with the single-agent profiles of all study drugs. However, a higher than expected rate of clinically significant proteinuria was observed that does not support further testing of MNRP1685A in combination with bevacizumab.
    Cancer Chemotherapy and Pharmacology 03/2014; 73(5). DOI:10.1007/s00280-014-2426-8 · 2.57 Impact Factor
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    ABSTRACT: To determine the pharmacokinetics (PK), maximum-tolerated dose (MTD), safety, and antitumor activity of an oral formulation of rigosertib, a dual phosphatidyl-inositol 3-kinase (PI3K) and polo-like kinase 1 (Plk1) pathway inhibitor, in patients with advanced solid malignancies. Patients with advanced solid malignancies received rigosertib twice daily (BID) continuously in 21-day cycles. Doses were escalated until intolerable grade ≥2 toxicities, at which point the previous dose level was expanded to define the MTD. All patients were assessed for safety, PK, and response. Urinary PK were performed at the MTD. Archival tumors were assessed for potential molecular biomarkers with multiplex mutation testing. A subset of squamous cell carcinomas (SCCs) underwent exome sequencing. Forty-eight patients received a median of 2 cycles of therapy at 5 dose levels. Rigosertib exposure increased with escalating doses. Dose-limiting toxicities were hematuria and dysuria. The most common grade ≥2 drug-related toxicities involved urothelial irritation. The MTD is 560 mg BID. Activity was seen in head and neck SCCs (1 complete response, 1 partial response) and stable disease for ≥12 weeks was observed in 8 additional patients. Tumors experiencing ≥partial response had PI3K pathway activation, inactivated p53, and unique variants in ROBO3 and FAT1, two genes interacting with the Wnt/β-catenin pathway. The recommended phase 2 dose of oral rigosertib is 560 mg BID given continuously. Urinary toxicity is the dose limiting and most common toxicity. Alterations in PI3K, p53, and Wnt/β-catenin pathway signaling should be investigated as potential biomarkers of response in future trials.
    Clinical Cancer Research 02/2014; 20(6). DOI:10.1158/1078-0432.CCR-13-2506 · 8.19 Impact Factor
  • Molecular Cancer Therapeutics 01/2014; 12(11_Supplement):B30-B30. DOI:10.1158/1535-7163.TARG-13-B30 · 6.11 Impact Factor
  • Molecular Cancer Therapeutics 01/2014; 12(11_Supplement):B79-B79. DOI:10.1158/1535-7163.TARG-13-B79 · 6.11 Impact Factor
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    ABSTRACT: The study objectives were to evaluate the safety, tolerability, and preliminary efficacy of multiple doses of dulanermin in combination with modified FOLFOX6 and bevacizumab in previously untreated patients with locally advanced, recurrent, or metastatic colorectal cancer. A total of 23 patients received dulanermin at dosages of 4.5 or 9 mg/kg/d given on days 1 to 3 of each 14-day cycle along with standard dosing of modified FOLFOX6 plus bevacizumab. Dose-limiting toxicities, adverse events (AEs), maximum tolerated dose, and response according to Response Evaluation Criteria in Solid Tumors were assessed. In the first cohort (3 patients given dulanermin at 4.5 mg/kg/d) and second cohort (6 patients given dulanermin at 9 mg/kg/day), no dose-limiting toxicities were observed. The subsequent 14 patients were treated with a dulanermin dosage of 9 mg/kg/d. Patients (N = 23) received 2 to 42 cycles of dulanermin (median 15). The most common grade 3 or 4 AEs were neutropenia (39%), hypertension (17%), peripheral neuropathy (17%), hand-foot syndrome (13%), and pulmonary embolism (13%). Three patients (13%) discontinued the study because of serious AEs. Overall, a best response of partial response was observed in 13 patients (57%) (9 confirmed, 4 unconfirmed), stable disease was observed in 7 patients (30%), and disease progression was observed in 3 patients (13%). The median progression-free survival was 9.9 months (95% confidence interval, 7.0-12.7). Overall, the addition of dulanermin to first-line FOLFOX plus bevacizumab was well tolerated in patients with advanced colorectal cancer, with similar AEs that would be expected from FOLFOX plus bevacizumab. A randomized study is required to assess the clinical efficacy of dulanermin in this patient population.
    Clinical Colorectal Cancer 09/2013; DOI:10.1016/j.clcc.2013.06.002 · 2.91 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):3263-3263. DOI:10.1158/1538-7445.AM2013-3263 · 9.28 Impact Factor

Publication Stats

2k Citations
807.23 Total Impact Points

Institutions

  • 2008–2015
    • University of Colorado
      • • Division of Medical Oncology
      • • Department of Medicine
      Denver, Colorado, United States
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 2005–2012
    • Johns Hopkins University
      • Department of Surgery
      Baltimore, Maryland, United States
  • 2010
    • South Texas Accelerated Research Therapeutics
      San Antonio, Texas, United States
  • 2009
    • Roswell Park Cancer Institute
      Buffalo, New York, United States
  • 2006
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States
  • 2004
    • Mary Crowley Medical Research Center
      Dallas, Texas, United States