PhD student, Hudson Institute of Medical Research - Monash University
My research is focusing on identifying new and effective therapeutic targets to combat lung cancer.
Lung cancer is the leading cause of cancer-related death among men and the second leading cause of cancer mortality among women worldwide, accounting for approximately 19% of all cancer deaths. It is estimated that 1.8 million cases are diagnosed with lung cancer each year. The association between lung cancer and cigarette smoking is unequivocal, and in a given country, the trend of lung cancer incidence rate is shaped by its tobacco epidemic.
Current treatment options for lung cancer patients are surgery, chemotherapy, and/or radiotherapy, which remain associated with a high risk of tumor reoccurrence and poor patient survival rates.
A disintegrin and metalloproteinase 17 (ADAM17), also known as the tumor necrosis factor-α (TNFα)-converting enzyme (TACE), is a membrane protein, which acts as a molecular scissors to liberate other membrane proteins, releasing their active form. TNFα, soluble interleukin 6 receptor (sIL-6R), epidermal growth factor receptor (EGFR) ligands and Notch ligands are important targets for ADAM17 and are implicated in the development of lung cancer.
Using well-established animal models, biopsies from human lung cancer patients following surgery and human cancer cell lines, we are investigating the role of ADAM17 in promoting lung cancer. Furthermore, we have shown that blocking of ADAM17 reduces tumour growth significantly. Therefore, our research suggests that blocking of ADAM17 may represent an attractive therapeutic strategy for tackling lung cancer.
Abstract: Over the last few years disintegrin metalloproteinases of the Adam (a disintegrin and metalloproteinase) family have been associated with the process of proteolytic 'shedding' of membrane-associated proteins and hence the rapid modulation of key cell signalling pathways in the tumour microenvironment. Furthermore, numerous members of the Adam family have been associated with tumorigenesis and tumour progression. The question now arises of whether pharmacological manipulation of their functions would be a useful adjunct to therapies targeting intercellular communications. To learn from the lessons of matrix metalloproteinase inhibitors as anticancer agents, there are many facets of the biological and clinical relevance of the ADAMs that need to be understood before embarking with confidence on such an approach.
Pub.: 14 Nov '08, Pinned: 24 Aug '17
Abstract: IL-6 binds to IL-6R and the complex of IL-6 and IL-6R associates with the receptor subunit gp130, which initiates signaling. gp130 is expressed on all cells. The IL-6R is cleaved by the ADAM17 generating a soluble IL-6R (sIL-6R). The sIL-6R binds IL-6 and the complex of IL-6 and sIL-6R binds to gp130 even on cells, which do not express IL-6R. This process, which has been called IL-6 trans-signaling, increases the spectrum of target cells for IL-6. We generated a protein, sgp130Fc, which inhibits IL-6 trans-signaling without affecting IL-6 classic signaling. Using the sgp130Fc protein we demonstrated that IL-6 classic signaling is anti-inflammatory and protective whereas IL-6 trans-signaling is pro-inflammatory. Blocking IL-6 trans-signaling does not compromise the defense of the body against bacterial infections. We suggest that sgp130Fc is a superior agent as compared to IL-6 or IL-6R antibodies to block IL-6. The sgp130Fc protein is in phase II clinical trials. This article is protected by copyright. All rights reserved.
Pub.: 05 Jul '17, Pinned: 24 Aug '17
Abstract: The fibroblast growth factor receptor 2-IIIb (FGFR2b) and the vascular endothelial growth factor receptor 2 (VEGFR2) are tyrosine kinases that can promote cell migration and proliferation and have important roles in embryonic development and cancer. Here we show that FGF7/FGFR2b-dependent activation of epidermal growth factor receptor (EGFR)/ERK1/2 signalling and cell migration in epithelial cells require stimulation of the membrane-anchored metalloproteinase ADAM17 and release of heparin-binding epidermal growth factor (HB-EGF). Moreover, VEGF-A/VEGFR2-induced migration of human umbilical vein endothelial cells also depends on EGFR/ERK1/2 signalling and shedding of the ADAM17 substrate HB-EGF. The pathway used by the FGF7/FGFR2b signalling axis to stimulate shedding of substrates of ADAM17, including ligands of the EGFR, involves Src, p38 mitogen-activated protein-kinase and PI3K, but does not require the cytoplasmic domain of ADAM17. Based on these findings, ADAM17 emerges as a central component in a triple membrane-spanning pathway between FGFR2b or VEGFR2 and EGFR/ERK1/2 that is required for cell migration in keratinocytes and presumably also in endothelial cells.
Pub.: 17 Mar '11, Pinned: 24 Aug '17
Abstract: Oncogenic KRAS mutations occur frequently in lung adenocarcinoma. The signaling pathways activated by IL6 promote Kras-driven lung tumorigenesis, but the basis for this cooperation is uncertain. In this study, we used the gp130(F/F) (Il6st) knock-in mouse model to examine the pathogenic contribution of hyperactivation of the STAT3 arm of IL6 signaling on KRAS-driven lung tumorigenesis. Malignant growths in the gp130(F/F):Kras(G12D) model displayed features of atypical adenomatous hyperplasia, adenocarcinoma in situ, and invasive adenocarcinoma throughout the lung, as compared with parental Kras(G12D) mice, where STAT3 was not hyperactivated. Among IL6 family cytokines, only IL6 was upregulated in the lung. Accordingly, normalization of pulmonary STAT3 activity, by genetic ablation of either Il6 or Stat3, suppressed the extent of lung cancer in the model. Mechanistic investigations revealed elevation in the lung of soluble IL6 receptor (sIL6R), the key driver of IL6 trans-signaling, and blocking this mechanism via interventions with an anti-IL6R antibody or the inhibitor sgp130Fc ameliorated lung cancer pathogenesis. Clinically, expression of IL6 and sIL6R was increased significantly in human specimens of lung adenocarcinoma or patient serum. Our results offer a preclinical rationale to clinically evaluate IL6 trans-signaling as a therapeutic target for the treatment of KRAS-driven lung adenocarcinoma. Cancer Res; 76(4); 866-76. ©2016 AACR.
Pub.: 09 Jan '16, Pinned: 24 Aug '17