Hua-Kang Wu

Publications (7)41.62 Total impact

• Article: Myeloid biomarkers associated with glioblastoma response to anti-VEGF therapy with aflibercept.

  John F de Groot, Yuji Piao, Hai Tran, Mark Gilbert, Hua-Kang Wu, Jun Liu, B Nebiyou Bekele, Tim Cloughesy, Minesh Mehta, H Ian Robins, Andrew Lassman, Lisa DeAngelis, Kevin Camphausen, Alice Chen, W K A Yung, Michael Prados, Patrick Y Wen, John V Heymach
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  ABSTRACT: VEGF and infiltrating myeloid cells are known regulators of tumor angiogenesis and vascular permeability in glioblastoma. We investigated potential blood-based markers associated with radiographic changes to aflibercept, which binds VEGF and placental growth factor (PlGF) in patients with recurrent glioblastoma. In this single-arm phase II trial, aflibercept was given intravenously every two weeks until disease progression. Plasma and peripheral blood mononuclear cells were collected at baseline and 24 hours, 14 days, and 28 days posttreatment. Plasma cytokines and angiogenic factors were quantified by using ELISA and multiplex bead assays, and myeloid cells were assessed by flow cytometry in a subset of patients. Circulating levels of VEGF significantly decreased 24 hours after treatment with aflibercept, coincident with radiographic response observed by MRI. PlGF initially decreased 24 hours posttreatment but increased significantly by days 14 and 28. Lower baseline levels of PlGF, elevated baseline levels of CTACK/CCL27, MCP3/CCL7, MIF, and IP-10/CXCL10, and a decrease in VEGFR1(+) monocytes from baseline to 24 hours were all associated with improved response. Tumor progression was associated with increases in circulating matrix metalloproteinase 9. These data suggest that decreases in VEGF posttreatment are associated with radiographic response to aflibercept. Elevated baseline chemokines of monocyte lineage in responding patients supports a role for myeloid cells and chemokines as potential biomarkers and regulators of glioma angiogenesis.
  Clinical Cancer Research 06/2011; 17(14):4872-81. · 7.74 Impact Factor
• Article: A phase 2 pilot trial of low‐dose, continuous infusion, or “metronomic” paclitaxel and oral celecoxib in patients with metastatic melanoma

  PhD Rupal S. Bhatt MD, Jaime Merchan MD, Robert Parker ScD, Hua-Kang Wu PhD, Liang Zhang MD, NP Virginia Seery MSN, PhD John V. Heymach MD, Michael B. Atkins MD, David McDermott MD, PhD Vikas P. Sukhatme MD, Rupal S. Bhatt, Jaime Merchan, Robert Parker, Hua‐Kang Wu, Liang Zhang, Virginia Seery, John V. Heymach, Michael B. Atkins, David McDermott, Vikas P. Sukhatme
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  ABSTRACT: BACKGROUND:Tumor angiogenesis has been associated with a poor prognosis in patients with metastatic melanoma (MM). Microtubule stabilizers and cyclooxygenase 2 (COX-2) inhibitors, alone and in combination, have produced inhibitory effects on endothelial cells and tumor angiogenesis. Angiogenesis, which is the growth of new blood vessels, is necessary for tumor growth and progression. Thus, the authors tested the safety and efficacy of a low dose of paclitaxel and celecoxib in patients with MM.METHODS:Patients received paclitaxel 10 mg/m2 for 96 hours weekly as a continuous intravenous infusion and oral celecoxib 400 mg twice daily. Systemic tumor response was assessed at 6-week intervals. Tumor measurements at the end of Cycle 1 were used as the baseline for assessment of tumor progression. Patients with unacceptable toxicity or disease progression after Cycle 2 relative to the end of Cycle 1 were taken off study.RESULTS:Twenty patients were enrolled. Twelve of 20 patients (60%) had received ≥2 previous systemic therapies. Three patients did not receive treatment because of rapid disease progression. Treatment-related grade 3/4 toxicities were limited to catheter-related complications. One patient achieved a partial response, and 3 of 20 patients (15%) had stable disease for >6 months. The median time to progression was 57 days (95% confidence interval, 43-151 days), and the median overall survival was 212 days (95% confidence interval, 147-811 days).CONCLUSIONS:Low-dose, continuous intravenous infusion paclitaxel and oral celecoxib produced disease stabilization in a significant proportion of heavily pretreated patients with MM. These findings support a role for metronomic therapy in patients with this disease. Cancer 2010. © 2010 American Cancer Society.
  Cancer 03/2010; 116(7):1751 - 1756. · 4.77 Impact Factor
• Article: Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance.

  George N Naumov, Monique B Nilsson, Tina Cascone, Alexandra Briggs, Oddbjorn Straume, Lars A Akslen, Eugene Lifshits, Lauren Averett Byers, Li Xu, Hua-Kang Wu, Pasi Jänne, Susumu Kobayashi, Balazs Halmos, Daniel Tenen, Xi M Tang, Jeffrey Engelman, Beow Yeap, Judah Folkman, Bruce E Johnson, John V Heymach
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  ABSTRACT: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) gefitinib and erlotinib benefit some non-small cell lung cancer (NSCLC) patients, but most do not respond (primary resistance) and those who initially respond eventually progress (acquired resistance). EGFR TKI resistance is not completely understood and has been associated with certain EGFR and K-RAS mutations and MET amplification. We hypothesized that dual inhibition of the vascular endothelial growth factor (VEGF) and EGFR pathways may overcome primary and acquired resistance. We investigated the VEGF receptor/EGFR TKI vandetanib, and the combination of bevacizumab and erlotinib in vivo using xenograft models of EGFR TKI sensitivity, primary resistance, and three models of acquired resistance, including models with mutated K-RAS and secondary EGFR T790M mutation. Vandetanib, gefitinib, and erlotinib had similar profiles of in vitro activity and caused sustained tumor regressions in vivo in the sensitive HCC827 model. In all four resistant models, vandetanib and bevacizumab/erlotinib were significantly more effective than erlotinib or gefitinib alone. Erlotinib resistance was associated with a rise in both host and tumor-derived VEGF but not EGFR secondary mutations in the KRAS mutant-bearing A549 xenografts. Dual inhibition reduced tumor endothelial proliferation compared with VEGF or EGFR blockade alone, suggesting that the enhanced activity of dual inhibition is due at least in part to antiendothelial effects. These studies suggest that erlotinib resistance may be associated with a rise in both tumor cell and host stromal VEGF and that combined blockade of the VEGFR and EGFR pathways can abrogate primary or acquired resistance to EGFR TKIs. This approach merits further evaluation in NSCLC patients.
  Clinical Cancer Research 06/2009; 15(10):3484-94. · 7.74 Impact Factor
• Article: Circulating biomarkers for vascular endothelial growth factor inhibitors in renal cell carcinoma.

  Amado J Zurita, Eric Jonasch, Hua-Kang Wu, Hai T Tran, John V Heymach
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  ABSTRACT: In recent years, there has been significant progress in the clinical development and application of antiangiogenic therapies in renal cell carcinomas, particularly inhibitors of the vascular endothelial growth factor (VEGF) pathway. Despite this progress, no validated methods are currently available for identifying which patients are most likely to respond to treatment or experience toxic effects, selecting the optimal dose, or determining whether the intended molecular target has been effectively inhibited. However, recent studies have suggested that some of the biomarkers currently under investigation in clear cell renal cell carcinoma for VEGF pathway inhibitors are promising. These biomarkers include circulating proangiogenic factors and receptors; markers of hypoxia and endothelial damage; and cellular populations in peripheral blood, such as circulating endothelial cells. Further preclinical and translational validation studies are still needed to determine their practical utility in the clinical setting.
  Cancer 05/2009; 115(10 Suppl):2346-54. · 4.77 Impact Factor
• Article: Validation of a standardized method for enumerating circulating endothelial cells and progenitors: flow cytometry and molecular and ultrastructural analyses.

  Patrizia Mancuso, Pierluigi Antoniotti, Jessica Quarna, Angelica Calleri, Cristina Rabascio, Carlo Tacchetti, Paola Braidotti, Hua-Kang Wu, Amado J Zurita, Luca Saronni, John B Cheng, David R Shalinsky, John V Heymach, Francesco Bertolini
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  ABSTRACT: Antigenic overlap among circulating endothelial cells (CEC) and progenitors (CEP), platelets, and other blood cells led to the need to develop a reliable standardized method for CEC and CEP quantification. These cells are emerging as promising preclinical/clinical tools to define optimal biological doses of antiangiogenic therapies and to help stratify patients in clinical trials. We report the experimental validation of a novel flow cytometry method that precisely dissects CEC/CEP from platelets and other cell populations and provides information about CEC/CEP viability. Sorted DNA/Syto16(+)CD45(-)CD31(+)CD146(+) CECs, investigated by electron microscopy, were found to be bona fide endothelial cells by the presence of Weibel-Palade bodies. More than 75% of the circulating mRNAs of the endothelial-specific gene, VE-cadherin, found in the blood were present in the sorted population. CECs were 140 +/- 171/mL in healthy subjects (n = 37) and 951 +/- 1,876/mL in cancer patients (n = 78; P < 0.0001). The fraction of apoptotic/necrotic CECs was 77 +/- 14% in healthy subjects and 43 +/- 23% in cancer patients (P < 0.0001). CEPs were 181 +/- 167/mL in healthy donors and 429 +/- 507/mL in patients (P = 0.00019). Coefficients of variation were 4 +/- 4% (intrareader), 17 +/- 4% (interreader), and 17 +/- 7% (variability over 0-72 h), respectively. Parallel samples were frozen by a standardized protocol. After thawing, coefficients of variation were 12 +/- 8% (intrareader), 16 +/- 10% (interreader), and 26 +/- 16% (variability over 0-14 days of frozen storage), respectively. This procedure enumerates a truly endothelial cell population with limited intrareader and interreader variability. It appears possible to freeze samples for large-scale CEC enumeration during clinical trials. This approach could be enlarged to investigate other angiogenic cell populations as well.
  Clinical Cancer Research 02/2009; 15(1):267-73. · 7.74 Impact Factor
• Source

  Available from: Arumugam Jayakumar

  Article: Proteolytic processing of human growth hormone by multiple tissue kallikreins and regulation by the serine protease inhibitor Kazal-Type5 (SPINK5) protein.

  Nahoko Komatsu, Kiyofumi Saijoh, Norio Otsuki, Tadaaki Kishi, Iacovos P Micheal, Christina V Obiezu, Carla A Borgono, Kazuhiko Takehara, Arumugam Jayakumar, Hua Kang Wu, Gary L Clayman, Eleftherios P Diamandis
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  ABSTRACT: Human growth hormone (hGH) is naturally present in numerous isoforms, some of which arise from proteolytic processing in both the pituitary and periphery. The nature of the enzymes that proteolytically cleave hGH and the regulation of this process are not fully understood. Our objective is to examine if members of a newly discovered human tissue kallikrein family (KLKs) are expressed in the pituitary and if these enzymes can cleave hGH in-vitro. Expression of 12 of the KLKs (KLKs 4-15) and serine protease inhibitor Kazal-type 5 (SPINK5) genes and their proteins in the pituitary was examined by RT-PCR and immunohistochemistry. Recombinant hGH was digested by various recombinant KLKs and fragments were characterized by N-terminal sequencing. SPINK5 recombinant fragments were used for inhibition of KLK activities. We here describe for the first time expression of numerous KLKs (KLKs 5-8, 10-14) and SPINK5 in the pituitary. KLK6 and SPINK5 appeared to be localized to hGH-producing cells. KLKs 4-6, 8, 13 and 14 were able to cleave hGH, yielding various isoforms, in vitro. Inhibitor SPINK5 fragments were able to suppress activity of KLKs 4, 5 and 14 in vitro. Based on these data, we propose a model for the proteolytic processing of hGH in the pituitary and the regulation of this system by SPINK5 inhibitory domains. We speculate that loss of SPINK5 inhibitory domains, as in the case of Netherton syndrome, may lead to proteolytic over-processing of hGH and to growth retardation. We conclude that many KLKs and SPINK5 are expressed in the pituitary. This serine protease-inhibitor system is likely to participate in the regulated proteolytic processing of hGH in the pituitary, leading to generation of hGH fragments. Our data suggest that KLKs 5, 6 and 14 might be involved in this process.
  Clinica Chimica Acta 03/2007; 377(1-2):228-36. · 2.54 Impact Factor
• Source

  Available from: utoronto.ca

  Article: Elevated human tissue kallikrein levels in the stratum corneum and serum of peeling skin syndrome-type B patients suggests an over-desquamation of corneocytes.

  Nahoko Komatsu, Yasushi Suga, Kiyofumi Saijoh, Amber C Liu, Saba Khan, Yuki Mizuno, Shigaku Ikeda, Hua-Kang Wu, Arumugam Jayakumar, Gary L Clayman, Fumiaki Shirasaki, Kazuhiko Takehara, Eleftherios P Diamandis
  Journal of Investigative Dermatology 11/2006; 126(10):2338-42. · 6.31 Impact Factor