Bonnie S Glisson

University of Texas MD Anderson Cancer Center, Houston, Texas, United States

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Publications (178)1298.08 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Treatments for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) have limited efficacy. One potential therapeutic target for HNSCC is the RAS/RAF/MEK/ERK cascade, which is one of the major signaling pathways for HNSCC cell survival. In HNSCC, RAS can be activated either by HRAS mutation or by upstream signaling. The ABL inhibitor nilotinib acts as a weak RAF inhibitor that induces RAF dimerization and subsequent activation of MEK/ERK in other cancer cell lines with activated RAS, leading to an unexpected dependence on MEK/ERK for cell survival. We hypothesized that nilotinib and the MEK inhibitor MEK162 would be synergistic in HNSCC cell lines owing to the frequent activation of RAS. We treated HNSCC cell lines with nilotinib and performed immunoblotting and cell-viability experiments. We used an orthotopic mouse model to assess synergistic effects in vivo. Nilotinib induced significant BRAF-CRAF heterodimerization and ERK activation irrespective of RAS mutation status. In cell-viability assays, nilotinib synergized with MEK162. MEK162 alone induced G1 arrest that was minimally enhanced by nilotinib. In the mouse model, treatment with MEK162 alone or combined with nilotinib led to tumor growth inhibition. In HNSCC, nilotinib-induced RAF dimerization is independent of RAS mutation status, but this dimerization does not lead to MEK dependence for cell survival in all HNSCC cell lines. MEK inhibition alone leads to decreased proliferation both in vitro and in vivo. Although nilotinib has some synergistic effects with MEK162, other agents may be more effective against HNSCC when combined with MEK162.
    Anti-cancer drugs 06/2015; DOI:10.1097/CAD.0000000000000251 · 1.89 Impact Factor
  • Brett W Carter · Bonnie S Glisson · Mylene T Truong · Jeremy J Erasmus
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    ABSTRACT: Small cell lung carcinoma (SCLC) is the most common primary pulmonary neuroendocrine malignancy and is characterized by a rapid doubling time and high growth fraction. Approximately 60%-70% of patients present with metastatic disease at the time of diagnosis, and their prognosis is poor. However, improved survival has been demonstrated when SCLC is diagnosed early and specific treatment strategies are used. A modified version of the Veterans Administration Lung Cancer Study Group (VALSG) staging system has traditionally been used to categorize SCLC as limited-stage or extensive-stage disease to guide therapy. However, the International Association for the Study of Lung Cancer has recommended that the current seventh edition of the American Joint Committee on Cancer tumor-node-metastasis staging system for lung cancer replace the VALSG system for staging of SCLC. Appropriate staging and patient management require knowledge of imaging manifestations of SCLC across multiple imaging modalities, the strengths and weaknesses of specific examinations, the correlation of these findings with the staging criteria used in clinical practice, and the impact of appropriate staging on patient treatment and survival. Computed tomography (CT) is primarily used to evaluate the primary tumor and the extent of intrathoracic disease. In recent years, however, 2-[fluorine-18]fluoro-2-deoxy-d-glucose positron emission tomography/CT has proved to be more accurate than conventional imaging in the staging of SCLC and can be used to guide therapy and assess treatment response. ©RSNA, 2014.
    Radiographics 10/2014; 34(6):1707-1721. DOI:10.1148/rg.346140178 · 2.73 Impact Factor
  • Cancer Research 09/2014; 74(19 Supplement):903-903. DOI:10.1158/1538-7445.AM2014-903 · 9.28 Impact Factor
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    ABSTRACT: The PI3K/AKT/mTOR pathway is frequently activated in head and neck squamous cell carcinoma (HNSCC), but pathway inhibition has variable efficacy. Identification of predictive biomarkers and mechanisms of resistance would allow selection of patients most likely to respond and novel therapeutic combinations. The purpose of this study was to extend recent discoveries regarding the PI3K/AKT/mTOR pathway in HNSCC by more broadly examining potential biomarkers of response, by examining pathway inhibitors with a diverse range of targets, and by defining mechanisms of resistance and potential combination therapies. We used reverse-phase protein arrays (RPPA) to simultaneously evaluate expression of 195 proteins; single-nucleotide polymorphism array to estimate gene copy number; and mass array to identify mutations. We examined altered signaling at baseline and after pathway inhibition. Likewise, we examined the activation of the PI3K/AKT/mTOR pathway in HNSCC tumors by RPPA. Cell lines with PIK3CA mutations were sensitive to pathway inhibitors, whereas amplification status did not predict sensitivity. While we identified a set of individual candidate biomarkers of response to pathway inhibitors, proteomic pathway scores did not correlate with amplification or mutation and did not predict response. Several receptor tyrosine kinases, including EGFR and ERK, were activated following PI3K inhibition in resistant cells; dual pathway inhibition of PI3K and EGFR or MEK demonstrated synergy. Combined MEK and PI3K inhibition was markedly synergistic in HRAS-mutant cell lines. Our findings indicate that clinical trials of single-agent PI3K/AKT/mTOR pathway inhibitors in selected populations and of PI3K-EGFR or PI3K-MEK inhibitor combinations are warranted; we plan to conduct such trials.
    Molecular Cancer Therapeutics 09/2014; 13(11). DOI:10.1158/1535-7163.MCT-13-1090 · 6.11 Impact Factor
  • International journal of radiation oncology, biology, physics 09/2014; 90(1):S534-S535. DOI:10.1016/j.ijrobp.2014.05.1627 · 4.18 Impact Factor
  • International journal of radiation oncology, biology, physics 09/2014; 90(1):S528. DOI:10.1016/j.ijrobp.2014.05.1613 · 4.18 Impact Factor
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    ABSTRACT: Targeting oncogenic drivers (genomic alterations critical to cancer development and maintenance) has transformed the care of patients with lung adenocarcinomas. The Lung Cancer Mutation Consortium was formed to perform multiplexed assays testing adenocarcinomas of the lung for drivers in 10 genes to enable clinicians to select targeted treatments and enroll patients into clinical trials.
    JAMA The Journal of the American Medical Association 05/2014; 311(19):1998-2006. DOI:10.1001/jama.2014.3741 · 30.39 Impact Factor
  • Milena P Mak · Bonnie S Glisson
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    ABSTRACT: Despite decades of research, the role of induction chemotherapy (ICT) in the treatment of locally advanced head and neck squamous cell carcinoma remains controversial. When nonsurgical approaches are preferred, chemoradiation (CRT) is the standard of care. However, ICT continues to be investigated, as it can cytoreduce tumors, improve radiotherapy feasibility and tolerability, select patients for organ preservation with radiation, and decrease the risk of distant metastasis. Herein, we review the recent randomized trials that investigated the role of taxanes in ICT, compared with surgery or CRT alone. A metaanalysis of older trials comparing taxane-containing ICT to cisplatin and 5-fluorouracil is discussed. In addition, long-term results from Radiation Therapy Oncology Group 91-11, a three-arm trial of larynx preservation approaches, are discussed, as well as a recent trial of sequential CRT for larynx preservation. As in previous randomized trials, no survival benefit for ICT was demonstrated. However, two studies showed a reduced risk of distant metastasis in advanced nodal stage patients. As regards larynx preservation, ICT followed by radiation alone in responders to chemotherapy remains an effective option. ICT is still controversial and in general, should remain investigational. An exception may be its use in a larynx preservation approach, albeit with a lower crude larynx preservation rate compared with CRT. The results of recent trials provide rationale and support hypothesis generation for future research, which should focus on subsets of patients most likely to benefit, for example, high nodal stage. It will be critical to study human papillomavirus (HPV)-associated oropharynx cancer separately or, at least, stratify by HPV status given its influence on prognosis and attendant implications for statistical design.
    Current opinion in oncology 03/2014; DOI:10.1097/CCO.0000000000000073 · 3.76 Impact Factor
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    ABSTRACT: Background The purpose of this study was to determine the antitumor activity of the epidermal growth factor receptor (EGFR) inhibitor gefitinib in patients with recurrent/metastatic salivary gland cancer.Methods We conducted a phase II study in adenoid cystic carcinoma (ACC) and non-ACC. Gefitinib was administered 250 mg orally daily. The primary endpoint was tumor response. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and disease control rates. EGFR and human epidermal growth factor receptor 2 (HER2) expression were evaluated and correlated with outcomes.ResultsThirty-seven patients were enrolled in this study, and 36 were evaluable (18 with ACC and 18 with non-ACC). No responses were observed. Median PFS was 4.3 months and 2.1 months, and median OS was 25.9 months and 16 months for patients with ACC and non-ACC, respectively. The disease control rate at 8 weeks was higher in patients with ACC. No unexpected toxicities occurred. EGFR and HER2 overexpression did not correlate with outcomes.Conclusion We did not observe significant clinical activity of gefitinib in advanced salivary gland cancer. NCT00509002. © 2014 Wiley Periodicals, Inc. Head Neck, 2014
    Head & Neck 03/2014; 37(5). DOI:10.1002/hed.23647 · 3.01 Impact Factor
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    ABSTRACT: Several phase II/III trials of anti-insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibodies (mAbs) have shown limited efficacy. The mechanisms of resistance to IGF-1R mAb-based therapies and clinically applicable strategies for overcoming drug resistance are still undefined. IGF-1R mAb cixutumumab efficacy, alone or in combination with Src inhibitors, was evaluated in 10 human head and neck squamous cell carcinoma (HNSCC) and six non-small cell lung cancer (NSCLC) cell lines in vitro in two- or three-dimensional culture systems and in vivo in cell line- or patient-derived xenograft tumors in athymic nude mice (n = 6-9 per group). Cixutumumab-induced changes in cell signaling and IGF-1 binding to integrin β3 were determined by Western or ligand blotting, immunoprecipitation, immunofluorescence, and cell adhesion analyses and enzyme-linked immunosorbent assay. Data were analyzed by the two-sided Student t test or one-way analysis of variance. Integrin β3-Src signaling cascade was activated by IGF-1 in HNSCC and NSCLC cells, when IGF-1 binding to IGF-1R was hampered by cixutumumab, resulting in Akt activation and cixutumumab resistance. Targeting integrin β3 or Src enhanced antitumor activity of cixutumumab in multiple cixutumumab-resistant cell lines and patient-derived tumors in vitro and in vivo. Mean tumor volume of mice cotreated with cixutumumab and integrin β3 siRNA was 133.7mm(3) (95% confidence interval [CI] = 57.6 to 209.8mm(3)) compared with those treated with cixutumumab (1472.5mm(3); 95% CI = 1150.7 to 1794.3mm(3); P < .001) or integrin β3 siRNA (903.2mm(3); 95% CI = 636.1 to 1170.3mm(3); P < .001) alone. Increased Src activation through integrin ανβ3 confers considerable resistance against anti-IGF-1R mAb-based therapies in HNSCC and NSCLC cells. Dual targeting of the IGF-1R pathway and collateral integrin β3-Src signaling module may override this resistance.
    CancerSpectrum Knowledge Environment 10/2013; 105(20). DOI:10.1093/jnci/djt263 · 15.16 Impact Factor
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    ABSTRACT: BACKGROUND: We performed this study to define the incidence of radiographic retropharyngeal lymph node (RPLN) involvement in oropharyngeal cancer (OPC) and its impact on clinical outcomes, neither of which has been well established to date. METHODS: Our departmental database was queried for patients irradiated for OPC between 2001 and 2007. Analyzable patients were those with imaging data available for review to determine radiographic RPLN status. Demographic, clinical, and outcome data were retrieved and analyzed. RESULTS: The cohort consisted of 981 patients. The median follow-up was 69 months. The base of the tongue (47%) and the tonsil (46%) were the most common primary sites. The majority of patients had stage T1 to T2 primary tumors (64%), and 94% had stage 3 to 4B disease. Intensity-modulated radiation therapy was used in 77% of patients, and systemic therapy was administered in 58% of patients. The incidence of radiographic RPLN involvement was 10% and was highest for the pharyngeal wall (23%) and lowest for the base of the tongue (6%). RPLN adenopathy correlated with several patient and tumor factors. RPLN involvement was associated with poorer 5-year outcomes on univariate analysis (P<.001 for all) for local control (79% vs 92%), nodal control (80% vs 93%), recurrence-free survival (51% vs 81%), distant metastases-free survival (66% vs 89%), and overall survival (52% vs 82%) and maintained significance on multivariate analysis for local control (P = .023), recurrence-free survival (P = .001), distant metastases-free survival (P = .003), and overall survival (P = .001). CONCLUSIONS: In this cohort of nearly 1000 patients with radiographic RPLN adenopathy in OPC, RPLN involvement was observed in 10% of patients and indicates a negative influence on disease recurrence, distant relapse, and survival. Cancer 2013. © 2013 American Cancer Society.
    Cancer 09/2013; 119(17). DOI:10.1002/cncr.28195 · 4.90 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):5645-5645. DOI:10.1158/1538-7445.AM2013-5645 · 9.28 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):2388-2388. DOI:10.1158/1538-7445.AM2013-2388 · 9.28 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):4095-4095. DOI:10.1158/1538-7445.AM2013-4095 · 9.28 Impact Factor
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    ABSTRACT: Background We performed this study to assess outcomes of patients with oropharyngeal cancer treated with modern therapy approaches. Methods Demographics, treatments and outcomes of patients diagnosed with Stage 3- 4B squamous carcinoma of the oropharynx, between 2000 – 2007 were tabulated and analyzed. Results The cohort consisted of 1046 patients. The 5- year actuarial overall survival, recurrence-free survival and local-regional control rates for the entire cohort were 78%, 77% and 87% respectively. More advanced disease, increasing T-stage and smoking were associated with higher rates of local-regional recurrence and poorer survival. Conclusions Patients with locally advanced oropharyngeal cancer have a relatively high survival rate. Patients’ demographics and primary tumor volume were very influential on these favorable outcomes. In particular, patients with small primary tumors did very well even when treatment was not intensified with the addition of chemotherapy.
    Radiation Oncology 01/2013; 8(1):21. DOI:10.1186/1748-717X-8-21 · 2.36 Impact Factor
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    ABSTRACT: BACKGROUND: In this retrospective review, the authors examined demographic/clinical characteristics and overall survival in patients with squamous cell carcinoma of the oropharynx at a tertiary cancer center, and they report the characteristics that influenced any observed survival trends over time. METHODS: The study included 3891 newly diagnosed, previously untreated patients who presented at the authors' institution between 1955 and 2004. RESULTS: Over time, patients presented at younger ages and were more likely to have base of tongue or tonsil tumors and to be never-smokers or former smokers. Patients who were diagnosed between 1995 and 2004 were almost half as likely to die as those who were diagnosed before 1995 (hazard ratio, 0.6; 95% confidence interval, 0.6-0.8). In both multivariable and recursive partitioning survival analyses, the TNM staging system predicted the survival of patients who received treatment before 1995 but did not predict the survival patients treated during the period from 1995 to 2004. CONCLUSIONS: Survival among patients with squamous cell carcinoma of the oropharynx improved substantially over the past 50 years. The main contributing factors were changes in clinical characteristics, in particular surrogates for positive human papillomavirus status. The current TNM staging system for squamous cell carcinoma of the oropharynx is inadequate. The incorporation of human papillomavirus status and perhaps smoking status into the TNM system is encouraged. Cancer 2012. © 2012 American Cancer Society.
    Cancer 01/2013; 119(1). DOI:10.1002/cncr.27727 · 4.90 Impact Factor
  • Archives of ophthalmology 12/2012; 130(12):1608-11. DOI:10.1001/archophthalmol.2012.2515 · 4.49 Impact Factor
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    ABSTRACT: PURPOSETo report the long-term results of the Intergroup Radiation Therapy Oncology Group 91-11 study evaluating the contribution of chemotherapy added to radiation therapy (RT) for larynx preservation. PATIENTS AND METHODS Patients with stage III or IV glottic or supraglottic squamous cell cancer were randomly assigned to induction cisplatin/fluorouracil (PF) followed by RT (control arm), concomitant cisplatin/RT, or RT alone. The composite end point of laryngectomy-free survival (LFS) was the primary end point. RESULTS: hazard ratio [HR], 0.75; 95% CI, 0.59 to 0.95; P = .02; concomitant chemotherapy v RT alone: HR, 0.78; 95% CI, 0.78 to 0.98; P = .03). Overall survival did not differ significantly, although there was a possibility of worse outcome with concomitant relative to induction chemotherapy (HR, 1.25; 95% CI, 0.98 to 1.61; P = .08). Concomitant cisplatin/RT significantly improved the larynx preservation rate over induction PF followed by RT (HR, 0.58; 95% CI, 0.37 to 0.89; P = .0050) and over RT alone (P < .001), whereas induction PF followed by RT was not better than treatment with RT alone (HR, 1.26; 95% CI, 0.88 to 1.82; P = .35). No difference in late effects was detected, but deaths not attributed to larynx cancer or treatment were higher with concomitant chemotherapy (30.8% v 20.8% with induction chemotherapy and 16.9% with RT alone). CONCLUSION These 10-year results show that induction PF followed by RT and concomitant cisplatin/RT show similar efficacy for the composite end point of LFS. Locoregional control and larynx preservation were significantly improved with concomitant cisplatin/RT compared with the induction arm or RT alone. New strategies that improve organ preservation and function with less morbidity are needed.
    Journal of Clinical Oncology 11/2012; 31(7). DOI:10.1200/JCO.2012.43.6097 · 18.43 Impact Factor
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    ABSTRACT: Overexpression of insulin-like growth factor binding protein (IGFBP)-3 induces apoptosis of cancer cells. However, preexisting resistance to IGFBP-3 could limit its antitumor activities. This study characterizes the efficacy and mechanism of the combination of recombinant IGFBP-3 (rIGFBP-3) and HDAC inhibitors to overcome IGFBP-3 resistance in a subset of non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) cells. The effects of the combination of rIGFBP-3 and a number of HDAC inhibitors on cell proliferation and apoptosis were assessed in vitro and in vivo by using the MTT assay, a flow cytometry-based TUNEL assay, Western blot analyses and the NSCLC xenograft tumor model. Combined treatment with HDAC inhibitors and rIGFBP-3 had synergistic antiproliferative effects accompanied by increased apoptosis rates in a subset of NSCLC and HNSCC cell lines in vitro. Moreover, combined treatment with depsipeptide and rIGFBP-3 completely suppressed tumor growth and increased the apoptosis rate in vivo in H1299 NSCLC xenografts. Evidence suggests that HDAC inhibitors increased the half-life of rIGFBP-3 protein by blocking protein kinase C (PKC)-mediated phosphorylation and degradation of rIGFBP-3. In addition, combined treatment of IGFBP-3 with an HDAC inhibitor facilitates apoptosis through upregulation of rIGFBP-3 stability and Akt signaling inhibition. The ability of HDAC inhibitors to decrease PKC activation may enhance apoptotic activities of rIGFBP-3 in NSCLC cells in vitro and in vivo. These results indicated that combined treatment with HDAC inhibitor and rIGFBP-3 could be an effective treatment strategy for NSCLC and HNSCC with highly activated PKC.
    International Journal of Cancer 11/2012; 131(10):2253-63. DOI:10.1002/ijc.27509 · 5.01 Impact Factor
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    ABSTRACT: BACKGROUND AND PURPOSE: Although inhibition of epidermal growth factor receptor (EGFR) signaling during radiation led to improvement of tumor control and survival, novel strategies are needed to further improve the outcome of patients with locally advanced head and neck carcinoma. Because EGFR is known to interact with c-Src kinases, the present study investigated dasatinib (BMS-354825), an inhibitor of c-Src kinases, for its efficacy in enhancing radiosensitivity of human head and neck squamous cell carcinomas (HNSCC) in vitro and examined the underlying mechanisms for this effect. MATERIALS AND METHODS: Six HNSCC lines were exposed to dasatinib, radiation, or both, and assessed for c-Src and EGFR expression, cell survival and colony forming ability. Among these cell lines, HN-5 and FaDu lines were analyzed for induction of apoptosis, cell cycle re-distribution and for nuclear localization of EGFR, γ-H2AX and 53BP1 proteins. Immuno-precipitation and Western blots were performed to analyze the levels and binding of proteins involved in cell survival, apoptosis and DNA repair pathways. Suppression of c-Src by siRNA and subsequent clonogenic assay was performed in HN-5 cells. RESULTS: All six HNSCC lines that were examined expressed high levels of c-Src. Two (HN-5 and MDA-183) expressed higher levels of EGFR than other lines. Dasatinib suppressed cell survival of all cell lines tested independent of c-Src or EGFR levels but enhanced the radiosensitivity of HN-5 and MDA-183. HN-5 and FaDu were analyzed further. Dasatinib suppressed phosphorylation of c-Src in both cell lines, but decreased repair of radiation-induced DNA damage in HN-5 cells only as evidenced by suppression of c-Abl and Nbs-1 activity, inhibition of the association between c-Src and EGFR or Her-2, prolongation of nuclear γ-H2AX and 53BP1 foci and inhibition of EGFR nuclear localization and its association with DNA-PKcs. Finally, partial suppression of c-Src resulted in a small increase in HN-5 cell radiosensitivity. CONCLUSIONS: Our data demonstrate that dasatinib induces apoptosis and blocks DNA repair in EGFR-expressing HNSCC cells and improves radiotherapy outcome. These findings warrant further investigation using in vivo tumor models for potential translation into clinical testing.
    Radiotherapy and Oncology 09/2012; 105(2). DOI:10.1016/j.radonc.2012.08.010 · 4.86 Impact Factor

Publication Stats

7k Citations
1,298.08 Total Impact Points


  • 1988–2014
    • University of Texas MD Anderson Cancer Center
      • • Department of Thoracic Head Neck Medical Oncology
      • • Division of Radiation Oncology
      • • Department of Gynecologic Oncology
      • • Department of Medical Oncology
      Houston, Texas, United States
  • 2013
    • Seoul National University
      • Research Institute of Pharmaceutical Sciences
      Sŏul, Seoul, South Korea
  • 2009
    • Memorial Sloan-Kettering Cancer Center
      • Department of Radiation Oncology
      New York City, New York, United States
  • 2004
    • Emory University
      • Winship Cancer Institute
      Atlanta, GA, United States
  • 1998–2004
    • University of Houston
      Houston, Texas, United States
  • 2002
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2001
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 1984–1987
    • University of Florida
      • Department of Medicine
      Gainesville, Florida, United States