Preclinical validation of new combination therapies in xenograft mouse models of lung cancer
Project type
Honours and/or PhD
| Supervisor(s) | Division | |
| (Primary) | Stem Cells and Cancer | .(JavaScript must be enabled to view this email address) |
| (Co-supervisor) | Stem Cells and Cancer | .(JavaScript must be enabled to view this email address) |
Details of project
Two main types of lung cancer exist: non-small cell lung cancer (NSCLC), which comprise approximately 80 per cent of all lung cancers and small cell lung cancer (SCLC) comprising approximately 20 per cent of lung cancers.
Platinum-based chemotherapy (such as Cisplatin) constitutes standard first-line treatment for advanced lung cancer. These patients often show rapid emergence of chemo-resistant tumours with limited improvement in overall survival. EGFR tyrosine kinase inhibitors constitute efficient targeted therapy in NSCLC patient with EGFR mutation. However, many NSCLC patients develop resistance to these inhibitors within one year of treatment highlighting the need for new therapy for lung cancer.
Traditional preclinical investigations of new lung cancer therapies have relied on the use of human lung cancer cell lines grown subcutaneously in immunocompromised mice. It is now becoming clear that models that preserve the integrity of the tumour cells and their interaction with the microenvironment are critical to address treatment efficiency.
To study new treatments for lung cancer this project aims to establish orthotopic xenograft lung tumour models to more closely reflect the microenvironment of the original human tumours. Importantly, orthotopic xenografts readily exhibit metastatic behaviour, making them more clinically relevant. These xenografts phenocopy the tumour cell heterogeneity of the original tumour and will be exploited to determine the differential responsiveness of xenografted tumours to different therapeutic modalities.
Topical delivery of drugs to the lung through inhalation has been widely practiced for decades in the treatment of asthma and related respiratory diseases (e.g. cystic fibrosis and pulmonary hypertension). Delivery of cancer drugs to the lung for the treatment of lung cancer is less well developed, though a number of studies have demonstrated the utility of this approach. Whilst the benefits of lung delivery are self-evident (rapid delivery of a high dose of the active pharmaceutical to the target tissue), there are issues associated with inhaled drug delivery.
In collaboration with medicinal chemists who are developing new compounds for inhaled delivery, we will evaluate efficacy of these molecules in xenograft models of lung cancer.
Project references
- Oakes SR, Vaillant F, Lim E, Lee L, Breslin K, Feleppa F, Deb S, Ritchie ME, Takano E, Ward T, Fox SB, Generali D, Smyth GK, Strasser A, Huang DC, Visvader JE, Lindeman GJ. Breast Cancer Special Feature: Sensitization of BCL-2-expressing breast tumors to chemotherapy by the BH3 mimetic ABT-737. Proc Natl Acad Sci USA. 2011;Jul 18.
- Cappuzzo F. et al., Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 2010;11(6), 521-529 (2010).
- Garbuzenko OB, et al., Inhibition of lung tumor growth by complex pulmonary delivery of drugs with oligonucleotides as suppressors of cellular resistance. Proc Natl Acad Sci USA. 2010;107 (23), 10737-10742.
Research interests
Our laboratory is interested in studying the cellular and molecular mechanisms underlying lung development and lung cancer formation.
A prerequisite to identifying the cells of origin of lung cancers is the isolation and characterisation of the normal stem cell and the hierarchy of cells that exist in the lung.
We aim to identify master regulators of stem cells and tumour-initiating cells within the lung to identify new targets for the development of future lung cancer therapies.
Selected publications
- Yun CH, et al. Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell. 2007;11(3), 217-227.
- Curtis SJ, et al. Primary tumor genotype is an important determinant in identification of lung cancer propagating cells. Cell Stem Cell. 2010;7(1), 127-133.
Research theme
Cancer
Scientific discipline
- Cell Biology
- Genetics
- Molecular Biology
- Stem Cell Biology