Wells A Messersmith

National Cancer Centre Singapore, Singapore

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Publications (136)909.66 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: To evaluate dabrafenib, a selective BRAF inhibitor, combined with trametinib, a selective MEK inhibitor, in patients with BRAF V600-mutant metastatic colorectal cancer (mCRC). Patients and methods: A total of 43 patients with BRAF V600-mutant mCRC were treated with dabrafenib (150 mg twice daily) plus trametinib (2 mg daily), 17 of whom were enrolled onto a pharmacodynamic cohort undergoing mandatory biopsies before and during treatment. Archival tissues were analyzed for microsatellite instability, PTEN status, and 487-gene sequencing. Patient-derived xenografts were established from core biopsy samples. Results: Of 43 patients, five (12%) achieved a partial response or better, including one (2%) complete response, with duration of response > 36 months; 24 patients (56%) achieved stable disease as best confirmed response. Ten patients (23%) remained in the study > 6 months. All nine evaluable during-treatment biopsies had reduced levels of phosphorylated ERK relative to pretreatment biopsies (average decrease ± standard deviation, 47% ± 24%). Mutational analysis revealed that the patient achieving a complete response and two of three evaluable patients achieving a partial response had PIK3CA mutations. Neither PTEN loss nor microsatellite instability correlated with efficacy. Responses to dabrafenib plus trametinib were comparable in patient-derived xenograft-bearing mice and the biopsied lesions from each corresponding patient. Conclusion: The combination of dabrafenib plus trametinib has activity in a subset of patients with BRAF V600-mutant mCRC. Mitogen-activated protein kinase signaling was inhibited in all patients evaluated, but to a lesser degree than observed in BRAF-mutant melanoma with dabrafenib alone. PIK3CA mutations were identified in responding patients and thus do not preclude response to this regimen. Additional studies targeting the mitogen-activated protein kinase pathway in this disease are warranted.
    Journal of Clinical Oncology 09/2015; DOI:10.1200/JCO.2015.63.2471 · 18.43 Impact Factor
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    ABSTRACT: The WNT signaling cascade is integral in numerous biological processes including embryonic development, cell cycle regulation, inflammation, and cancer. Hyperactivation of WNT signaling secondary to alterations to varying nodes of the pathway have been identified in multiple tumor types. These alterations converge into increased tumorigenicity, sustained proliferation, and enhanced metastatic potential. This review seeks to evaluate the evidence supporting the WNT pathway in cancer, the therapeutic strategies in modulating this pathway, and potential challenges in drug development. The WNT signaling cascade is integral in numerous biological processes, including cell cycle regulation and cancer. Alterations in WNT signaling have been identified in numerous tumor types, and in recent years, numerous WNT pathway modulators have been tested in preclinical studies. These agents are now being investigated in the clinical arena, and this review describes the WNT pathway and therapeutics currently in development. ©AlphaMed Press.
    The Oncologist 08/2015; DOI:10.1634/theoncologist.2015-0057 · 4.87 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):CT236-CT236. DOI:10.1158/1538-7445.AM2015-CT236 · 9.33 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):LB-077-LB-077. DOI:10.1158/1538-7445.AM2015-LB-077 · 9.33 Impact Factor
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    ABSTRACT: Dysregulation of the Notch1 receptor has been shown to facilitate the development and progression of CRC and has been identified as an independent predictor of disease progression and worse survival. Although mutations in the NOTCH1 receptor have not been described in CRC, we have previously discovered a NOTCH1 gene copy number gain in a proportion of CRC tumor samples. Here, we demonstrated that a NOTCH1 gene copy number gain is significantly associated with worse survival and a high percentage of gene duplication in a cohort of patients with advanced CRC. In our CRC patient-derived tumor xenograft (PDTX) model, tumors harboring a NOTCH1 gain exhibited significant elevation of the Notch1 receptor, JAG1 ligand and cleaved Notch1 activity. In addition, a significant association was identified between a gain in NOTCH1 gene copy number and sensitivity to a Notch1 targeting antibody. These findings suggest that patients with metastatic CRC that harbor a gain in NOTCH1 gene copy number have worse survival and that targeting this patient population with a Notch1 antibody may yield improved outcomes in patients with advanced CRC. This article is protected by copyright. All rights reserved. © 2015 UICC.
    International Journal of Cancer 07/2015; DOI:10.1002/ijc.29676 · 5.09 Impact Factor
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    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; 26(9). DOI:10.1093/annonc/mdv264 · 7.04 Impact Factor
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    ABSTRACT: Aurora A kinase and MEK inhibitors induce different, and potentially complementary, effects on the cell cycle of malignant cells, suggesting a rational basis for utilizing these agents in combination. In this work, the combination of an Aurora A kinase and MEK inhibitor was evaluated in pre-clinical colorectal cancer models, with a focus on identifying a subpopulation in which it might be most effective. Increased synergistic activity of the drug combination was identified in colorectal cancer cell lines with concomitant KRAS and PIK3CA mutations. Anti-proliferative effects were observed upon treatment of these double-mutant cell lines with the drug combination, and tumor growth inhibition was observed in double-mutant human tumor xenografts, though effects were variable within this subset. Additional evaluation suggests that degree of G2/M delay and p53 mutation status affect apoptotic activity induced by combination therapy with an Aurora A kinase and MEK inhibitor in KRAS and PIK3CA mutant colorectal cancer. Overall, in vitro and in vivo testing was unable to identify a subset of colorectal cancer that was consistently responsive to the combination of a MEK and Aurora A kinase inhibitor.
    Frontiers in Pharmacology 06/2015; 6:120. DOI:10.3389/fphar.2015.00120 · 3.80 Impact Factor
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    ABSTRACT: The NCCN Guidelines for Rectal Cancer begin with the clinical presentation of the patient to the primary care physician or gastroenterologist and address diagnosis, pathologic staging, surgical management, perioperative treatment, posttreatment surveillance, management of recurrent and metastatic disease, and survivorship. The NCCN Rectal Cancer Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize major discussion points from the 2015 NCCN Rectal Cancer Panel meeting. Major discussion topics this year were perioperative therapy options and surveillance for patients with stage I through III disease. © National Comprehensive Cancer Network, Inc. 2015, All rights reserved.
    Journal of the National Comprehensive Cancer Network: JNCCN 06/2015; 13(6):719-728. · 4.18 Impact Factor
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    ABSTRACT: The novel dual-action humanized IgG1 antibody MEHD7945A targeting HER3 and EGFR inhibits ligand-dependent HER dimer signaling. This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of MEHD7945A. Patients with locally advanced or metastatic epithelial tumors received escalating doses of MEHD7945A (1-30 mg/kg) every 2 weeks (q2w) until disease progression or intolerable toxicity. An expansion cohort was enrolled at the recommended phase II dose (14 mg/kg, q2w). Plasma samples, tumor biopsies, FDG-PET were obtained for assessment of pharmacokinetics, and pharmacodynamic modulation downstream of EGFR and HER3. No dose-limiting toxicities or MEHD7945A-related grade ≥ 4 adverse events (AE) were reported in dose-escalation (n = 30) or expansion (n = 36) cohorts. Related grade 3 AEs were limited to diarrhea and nausea in the same patient (30 mg/kg). Related AEs in ≥20% of patients ≤24 hours after the first infusion included grade 1/2 headache, fever, and chills, which were managed with premedication and/or symptomatic treatment. Pharmacodynamic data indicated target inhibition in 25% of evaluable patients. Best response by RECIST included 2 confirmed partial responses in squamous cell carcinomas of head and neck (SCCHN) patients with high tumor tissue levels of the HER3 ligand heregulin; 14 patients had stable disease ≥8 weeks, including SCCHN (n = 3), colorectal cancer (n = 6), and non-small cell lung cancer (n = 3). MEHD7945A was well-tolerated as single agent with evidence of tumor pharmacodynamic modulation and antitumor activity in SCCHN. Phase II studies were initiated with flat (nonweight-based) dosing at 1,100 mg q2w in SCCHN and colorectal cancer. Clin Cancer Res; 21(11); 2462-70. ©2015 AACR. ©2015 American Association for Cancer Research.
    Clinical Cancer Research 06/2015; 21(11):2462-70. DOI:10.1158/1078-0432.CCR-14-2412 · 8.72 Impact Factor
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    ABSTRACT: The NCCN Guidelines for Rectal Cancer begin with the clinical presentation of the patient to the primary care physician or gastroenterologist and address diagnosis, pathologic staging, surgical management, perioperative treatment, posttreatment surveillance, management of recurrent and metastatic disease, and survivorship. The NCCN Rectal Cancer Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize major discussion points from the 2015 NCCN Rectal Cancer Panel meeting. Major discussion topics this year were perioperative therapy options and surveillance for patients with stage I through III disease. Copyright © 2015 by the National Comprehensive Cancer Network.
    Journal of the National Comprehensive Cancer Network: JNCCN 06/2015; 13(6):719-28. · 4.18 Impact Factor
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    Annals of Oncology 06/2015; 26(suppl 4). DOI:10.1093/annonc/mdv233.162 · 7.04 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 · 3.23 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 · 1.20 Impact Factor
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    Christopher H Lieu · Alison Sorkin · Wells A Messersmith
    Journal of Clinical Oncology 03/2015; 33(13). DOI:10.1200/JCO.2014.60.6004 · 18.43 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; 21(12). DOI:10.1158/1078-0432.CCR-14-2797 · 8.72 Impact Factor
  • J. L. Greene · S. Bagby · W. Messersmith · J. Aracaroli
    Journal of Investigative Medicine 01/2015; 63(1):210-210. · 1.69 Impact Factor
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    ABSTRACT: Erratum to: Cancer Chemother Pharmacol DOI 10.1007/s00280-014-2609-3Unfortunately, a co-author’s name was not listed in the original publication. The missing author’s name is given below: H.-J. Lenz,University of Southern California, Los Angeles, CA, USA
    Cancer Chemotherapy and Pharmacology 12/2014; 75(1). DOI:10.1007/s00280-014-2625-3 · 2.77 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 · 3.23 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 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 once daily. The recommended phase II dose was not determined. PF-04449913 was generally well tolerated at doses of 80 to 320 mg once daily. The most common treatment-related adverse events (AE) 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 once daily. No treatment-related grade 4-5 AEs were reported. Pharmacokinetic analysis indicated a generally dose-proportional kinetics with biphasic elimination, supporting once-daily dosing. PF-04449913 modulated hedgehog signaling at the dose levels tested, as demonstrated by >80% downregulation of GLI1 expression in the skin of treated patients. Eight patients (34.8%) 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 · 8.72 Impact Factor
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    ABSTRACT: Background: More than half of colorectal tumors harbor activating mutations in RAS/RAF proteins. Selumetinib (AZD6244, ARRY-142886) is a small molecule kinase inhibitor targeting MEK kinase, downstream of RAS. We examined the efficacy and safety of selumetinib with irinotecan in second-line therapy. Methods: Patients with K-RAS mutated colorectal cancer, progressing on first-line oxaliplatin-based chemotherapy with bevacizumab, were eligible for this multicenter open-label phase I/II trial. In part A, a dose was determined using a standard "3 + 3" design; in part B, efficacy was determined. The primary endpoint was RECIST response rate. Historical data for irinotecan were used as reference. Secondary endpoints included progression-free survival and overall survival. Results: Thirty-two patients entered the study, and 31 were treated. All had K-RAS exon 2 mutated tumors. In phase I, the recommended oral dose of selumetinib was 75 mg twice per day with intravenous (IV) irinotecan, 180 mg/m² every 2 weeks. Three patients (9.7 %) had partial response . Sixteen patients (51.6 %) had stable disease for ≥4 weeks, including three >1 year. The most common grade 3 adverse events included diarrhea, neutropenia, fatigue, anemia, nausea, and dehydration. The study was terminated before a pre-planned accrual of 45 subjects. Conclusions: Despite termination before full accrual, the point estimates of RR and median PFS show promising results, suggesting that further investigations of MEK inhibition in the treatment of metastatic colorectal cancer are warranted. Studies combining MEK inhibitors with cytotoxics or other targeted agents may lead to improved clinical activity based on the emerging preclinical data.
    Cancer Chemotherapy and Pharmacology 10/2014; 75(1). DOI:10.1007/s00280-014-2609-3 · 2.77 Impact Factor

Publication Stats

2k Citations
909.66 Total Impact Points


  • 2015
    • National Cancer Centre Singapore
  • 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
      • • Department of Pathology
      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