drug targeting – Drug Discovery Opinion

New Breast Cancer Subtype

Gene expression profiling is used to guide treatment options for women with breast cancer. Endocrine therapies – tamoxifen or aromatase inhibitors – are offered to women whose cancer is oestrogen receptor (ER) positive whilst the monoclonal antibody, trastuzumab (Herceptin®) and the small molecule, lapatinib (Tykerb®) are used to treat women whose cancer overexpresses the HER2 receptor. About 15% of breast cancers – the so-called triple negative breast cancers that don’t have receptors for oestrogen, progesterone or HER2 – don’t respond to hormone therapy or to HER2 blockers and the prognosis for women with these cancers is relatively poor.

Researchers at Washington University University School of Medicine in St. Louis have now identified a gene that is overexpressed mainly in ER-negative, HER2-negative and triple negative breast cancers, leading to the possibility of a new clinical biomarker and potential treatments. Upregulation of Wnt signalling coreceptor, LRP6 (low-density lipoprotein receptor-related protein 6), was found in about a quarter of the breast cancer samples that the researchers examined. Previous studies had shown that the protein Mesd (mesoderm development) blocks LRP6 and was able to slow the growth of cultured breast cancer cells. Mesd also inhibits the development of mammary tumours in mice, without producing known pathway-dependent side-effects such as bone lesions, skin disorders or intestinal malfunctions. A smaller fragment of Mesd was found to be as effective as full length Mesd and to have improved stability.

The study is published in the Proceedings of the National Academy of Sciences.

Although the study offers the prospect of targeted therapy for women with breast cancer that is currently difficult to treat, both screening and prescribing practices need to improve for such discoveries to realise their full potential. A recent news feature in Nature Biotechnology highlights differing views on testing as well as the problems associated with diagnostic tests for HER2 – both of which may be compromising women’s access to appropriate and effective treatment.

Engineering New Cancer Treatments

Metastasis, the spread of cancer cells to new organs, generally signals a poor prognosis but detecting circulating tumour cells is both difficult and time consuming. US and Russian scientists have now described a way to magnetically capture circulating tumour cells in the bloodstream that has potential for the early diagnosis of cancer and the prevention of metastasis. Magnetic nanoparticles, which were functionalised to target a receptor commonly found on breast cancer cells, were shown to bind and capture circulating tumour cells in the bloodstream when injected into mice. To improve detection sensitivity and specificity, gold-plated carbon nanotubes conjugated with folic acid were used as a second contrast agent for photoacoustic imaging. The approach allows cancer cells from a large volume of blood to be concentrated in peripheral blood vessels by a magnet attached to the skin, potentially increasing specificity and sensitivity up to 1,000-fold compared to existing technology. The cells can then be removed by microsurgery for genetic analysis, or can be noninvasively eradicated directly in blood vessels by laser irradiation through the skin, which is safe for normal blood cells.

The study is published in Nature Nanotechnology.

In a separate study, published in the British Journal of Cancer, a non-pathogenic strain of Salmonella typhimurium has been used to deliver the cytotoxic protein, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) directly to solid tumours. S. typhimurium were engineered to secrete murine TRAIL under control of the radiation-inducible RecA promoter which activates when cells experience DNA damage. Common bacteria such as Salmonella and Escherichia favour the microenvironment of solid tumours over normal tissue and when the modified S. typhimurium were injected into mice with mammary tumours they localized to the tumour. After 48 hours, the bacteria had multiplied to about 10 million per tumour and the mice were exposed to a very low dose of γ-radiation. The resulting mild DNA damage (single-stranded breaks) activated RecA and initiated synthesis of TRAIL which is highly toxic to cancer cells. Mice that received two low dose radiation treatments had the best result since TRAIL clears quickly and its release must be regularly re-stimulated for best effect; repeated dosing with modified S. typhimurium in conjunction with low dose radiation improved the 30-day survival from 0 to 100%.

The researchers hope that, once the technique is fully developed, spatial and temporal control of the release of cytotoxic agents will provide enhanced efficacy while limiting toxicity.

Making Light Work of Blood Clotting

The ability to selectively switch enzymes on and off in a particular tissue could offer many improved treatment options, and scientists at the University of Florida have now devised a way of achieving this goal. Writing in the journal PNAS, they describe a molecule consisting of a DNA aptamer attached by a polyethylene glycol linker to a complementary strand of DNA with azobenzene molecules attached. The aptamer was chosen to bind selectively to the enzyme thrombin and block its role in blood coagulation. In visible light, the azobenzene double bonds are in the trans-conformation and the aptamer is prevented from binding to thrombin by hybridisation with the complementary strand of DNA. When irradiated with ultraviolet light, however, the azobenzene molecules flip into the cis-conformation causing dissociation of the duplex and unveiling the aptamer which can then bind to thrombin and inhibit blood clotting.

The team hope that the technique could one day be used to cut off the blood supply to solid tumours or to produce controlled release versions of drugs which would be activated only in the target tissue, thus reducing the risk of side effects. Endoscopic lights could be used to activate the drugs or, in some cases, it may be sufficient to irradiate skin close to the target site with near-infrared light which penetrates the skin.