Researchers at the Institute of Cancer Research (ICR) in the UK have identified a new drug target that opens up two more potential avenues for treatment of advanced bowel cancer.
The discovery by Dr Janine Erler and colleagues that the enzyme lysyl oxidase (LOX) plays an important role in the growth and metastasis of bowel cancer builds on previous research by Erler and others on LOX as a critical mediator in the spread of breast cancer.
Those findings were published by Erler and researchers from the ICR, Stanford University School of Medicine in the US and British Columbia Cancer Research Centre in Canada in the journal Cancer Cell in January 2009.
Now Erler and her ICR colleagues have described their study on “The Role of Lysyl Oxidase in SRC-dependent Proliferation and Metastasis of Colorectal Cancer” in the Journal of the National Cancer Institute. Erler is leader of the hypoxia and metastasis team within the ICR’s Cell and Molecular Biology Section,
The researchers found that cell growth increased in tumour cells with high levels of the LOX enzyme, while low levels of LOX led to limited cell growth. The ICR team further showed that LOX was activating SRC, a tyrosine kinase that plays a role in oncogenic, invasive and bone-metastatic processes, to promote cancer growth and spread.
One of a number of SRC inhibitors in development, the compound dasatinib (Bristol-Myers Squibb’s Sprycel) is known to block SRC function and is already approved as a treatment for adults with myeloid and lymphoblastic leukaemia. BMS is also looking at Sprycel in a range of solid tumours.
In laboratory tests, Erler’s team discovered that dasatinib reduced bowel cancer cell growth by inhibiting the effects of LOX. “Our findings have revealed two potential new avenues for combating advanced bowel cancer – either with existing SRC inhibitor treatments or with drugs currently being developed to target LOX,” Erler commented.
The research also showed that a test for levels of LOX expression could be used to recognise cancers whose SRC molecules are highly activated, thereby identifying patients most likely to benefit from treatment with dasatinib.
The study was supported by the Medical Research Council, the ICR, Cancer Research UK and a Seeding Drug Discovery award from the Wellcome Trust.
Bowel cancer is the third most common cancer worldwide, causing 529,000 deaths a year, the ICR pointed out. Currently metastatic bowel cancer has few treatment options and a poor prognosis.