Quantcast


CURATOR
A pinboard by
Mohamed Saad

PhD student, Hudson Institute of Medical Research - Monash University

PINBOARD SUMMARY

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.

4 ITEMS PINNED

IL6 Trans-signaling Promotes KRAS-Driven Lung Carcinogenesis.

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