Serendipity versus planning - cancer drugs of the future?
Mar 27, 2006 - 4:28:37 AM
New anticancer drugs are usually developed specially for the job, but occasionally they are borrowed from another field of medicine, and applied speculatively in cancer. Tamoxifen was designed as an anti-oestrogen, based on the observation that at least a third of breast cancers depend on female sex hormones such as oestrogen for survival. Tamoxifen has shown to be an exceptionally effective molecule in cancer treatment; It was never planned to be a preventive agent, but so it has proved to be! It is now licensed to be used to prevent breast cancer in certain women at high risk of the disease.
Contrast this with raloxifene, a drug first developed to treat osteoporosis in women. A selective benzothiophene oestrogen receptor modulator (SERM), raloxifene binds to oestrogen receptors as a mixed oestrogen and anti-oestrogen effect. It functions as an oestrogen sometimes (in bones and on lipid metabolism) and as an anti-oestrogen in other target tissues (endometrium and breast). So, it has the potential for producing some of oestrogen's beneficial effects without producing its adverse effects. In a trial of its use in osteoporosis, it appeared to have another completely different effect, namely prevention of new hormone dependant breast cancers.
Results from the MORE (The Multiple Outcomes of Raloxifene Evaluation) study of 7,705 women that were randomised to raloxifene or placebo demonstrated that among postmenopausal women with osteoporosis, the risk of invasive breast cancer was decreased by 76% during three years of treatment with raloxifene.
Stronger evidence on the safety and efficacy of raloxifene is awaited from the STAR Trial. This trial includes almost 20,000 postmenopausal women in the US who are at increased risk of breast cancer to determine whether raloxifene is as effective in reducing the chance of developing breast cancer as tamoxifen. Women taking raloxifene demonstrated some side effects and in clinical trials have about three times the chance of developing a deep vein thrombosis or pulmonary embolism as women on a placebo, however there is less risk of cancer of the uterus (a serious side effect of tamoxifen).
An example of a molecule causing much interest in breast cancer treatment is lapatinib, which administered orally. It was designed to hit a subset of the popular Epidermal Growth Factor Receptors (EGFR), which are targeted by other successful agents such as trastuzamab (Herceptin), cetuximab (Erbitux) and gefitinib (Iressa). The first two are monoclonal antibodies, against ErbB2 and ErbB1 respectively, the third is a 'designer' drug. Trials of the combination of antibodies have been promising, so the development of lapatinib to block both receptors via their tyrosine kinase portions is giving rise to optimism. It is a small molecule, like gefitinib, and may have pharmacological advantages over the antibody formulations, such as penetrating the blood-brain barrier.
Early clinical trials with lapatinib suggest that it may hit cancer cells, resistant to other commonly used breast cancer drugs, and to the other EGFR targeting agents, including trastuzamab. Its activity as a single agent is modest, but combination trials already underway are looking promising enough to start randomised comparative large scale investigation. Side effects reported so far suggest a good safety profile, though skin rash, lung and heart effects seen with other members of the drug class will be monitored carefully in the next generation of trials. And, following the example of tamoxifen, it is being tested as a chemo-preventive too.
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