Caroline Springer - Drug Discovery Unit
Molecular probes for imaging lysyl oxidase with potential application to the detection of metastasis
Tumour metastases are responsible for over 90% of cancer patient deaths, but treatment options for these late-stage patients are still very limited. Lysyl oxidase (LOX) regulates cross-linking of structural proteins in the extracellular matrix such as collagens and elastin. LOX is produced and secreted into the circulation by cancer cells in response to hypoxia1,2 and is a critical mediator of tumour growth and metastatic tumour spread1-5. Expression of LOX is elevated in > 70 % of breast cancer patients with ER negative disease, in 80 % of head & neck cancer patients,6 in 33 % of primary colorectal carcinomas (CRC) and 48 % of metastatic tissues from patients with CRC,7 and in cirrhotic hepatocellular carcinoma (HCC) patients with a history of alcoholism8. Elevated LOX expression is associated with metastasis and decreased patient survival. We have shown that LOX is upregulated in PDAC and plays a fundamental role in the primary growth and metastasis of this cancer9 [Miller et al, 2015]. Furthermore, LOX appears to be required to condition the pre-metastatic niche in breast cancer by modifying the extracellular matrix, which then prepares the environment for the recruitment of bone marrow derived cells, and subsequently the cancer cells themselves1,2,4.
We have designed and discovered new LOX inhibitors for the treatment of primary and metastatic cancers and have shown effective inhibition of primary tumour growth in several tumour models and potent inhibition of lung metastases in a breast model10.
The aim of this project is to design and synthesise molecular imaging probes, with an emphasis on optical imaging, based on our potent LOX inhibitors, for the detection of LOX in biological samples and in vivo. Near infrared (NIR) fluorescence has been used for in vivo imaging due to its deeper tissue penetrance compared to usual fluorophores of lower wavelength11. The student will design NIR probes based on our LOX inhibitors or through de novo design. These probes are designed for applications in tumour detection, detection of early metastases and understanding the role of LOX in tumour growth and formation of metastases. Additionally these probes will be useful as companion biomarkers to assess the efficacy of our LOX inhibitors. This project will involve close collaboration between the Drug Discovery Unit led by Prof Caroline Springer, and the Molecular Oncology group led by Prof. Richard Marais.
The successful candidate will learn synthetic and medicinal chemistry in the Drug Discovery Unit and will become familiar with analytical chemistry, including the use of nuclear magnetic resonance, mass spectrometry and high performance liquid chromatography. The student will gain an understanding of medicinal chemistry and drug design approaches and is expected to contribute to the design of new molecular probes The student will have the opportunity to learn biochemical and biological techniques such as enzymatic assays, cell culture and cell based assays.
- Erler, J. T.; Bennewith, K. L.; Nicolau, M.; Dornhofer, N.; Kong, C.; Le, Q.-T.; Chi, J.-T. A.; Jeffrey, S. S.; Giaccia, A. J. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 2006, 440, 1222-1226.
- Erler, J. T.; Bennewith, K. L.; Cox, T. R.; Lang, G.; Bird, D.; Koong, A.; Le, Q. T.; Giaccia, A. J. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer cell 2009, 15, 35-44.
- Gao, Y.; Xiao, Q.; Ma, H.; Li, L.; Liu, J.; Feng, Y.; Fang, Z.; Wu, J.; Han, X.; Zhang, J.; Sun, Y.; Wu, G.; Padera, R.; Chen, H.; Wong, K.-k.; Ge, G.; Ji, H. LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling. Proceedings of the National Academy of Sciences 2010, 107, 18892-18897.
- Bondareva, A.; Downey, C. M.; Ayres, F.; Liu, W.; Boyd, S. K.; Hallgrimsson, B.; Jirik, F. R. The lysyl oxidase inhibitor, beta-aminopropionitrile, diminishes the metastatic colonization potential of circulating breast cancer cells. PloS one 2009, 4, e5620.
- Levental, K. R.; Yu, H.; Kass, L.; Lakins, J. N.; Egeblad, M.; Erler, J. T.; Fong, S. F.; Csiszar, K.; Giaccia, A.; Weninger, W.; Yamauchi, M.; Gasser, D. L.; Weaver, V. M. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 2009, 139, 891-906.
- Barker, H. E.; Cox, T. R.; Erler, J. T. The rationale for targeting the LOX family in cancer. Nat Rev Cancer 2012, 12, 540-552.
- Baker, A.-M.; Cox, T. R.; Bird, D.; Lang, G.; Murray, G. I.; Sun, X.-F.; Southall, S. M.; Wilson, J. R.; Erler, J. T. The role of lysyl oxidase in SRC-dependent proliferation and metastasis of colorectal cancer. J Natl Cancer Inst 2011, 103, 407-424.
- Huang, C. S.; Ho, C. T.; Tu, S. H.; Pan, M. H.; Chuang, C. H.; Chang, H. W.; Chang, C. H.; Wu, C. H.; Ho, Y. S. Long-Term Ethanol Exposure-Induced Hepatocellular Carcinoma Cell Migration and Invasion through Lysyl Oxidase Activation Are Attenuated by Combined Treatment with Pterostilbene and Curcumin Analogues. J Agric Food Chem 2013, 61, 4326-4335.
- Miller BW, Morton JP, Pinese M, Saturno G, Jamieson NB, McGhee E, Timpson P, Leach J, McGarry L, Shanks E, Bailey P, Chang D, Oien K, Karim S, Au A, Steele C, Carter CR, McKay C, Anderson K, Evans TR, Marais R, Springer C, Biankin A, Erler JT, Sansom OJ (2015). Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy. EMBO Mol Med. 7(8): 1063-1076
- H. Tang et al, Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface, Nature Communications, 8:14909 (2017).
- Hong G. et al, Near-infrared fluorophores for biomedical imaging. Nature Biomed. Eng. (2017)