Apart from a handful of hormonal agents, virtually all anticancer drugs in current clinical use produce their therapeutic effects by interfering with the replication and transcription of DNA. However, as knowledge of the biology of normal and cancer cells has increased, a variety of new therapeutic targets have emerged. People attending the ASCO meeting were able to learn about several of these and to hear the early results from clinical trials with drugs designed to interact with them.
Speaking during one of the conference education sessions, Dr Janet Dancey (National Cancer Institute, Rockville, USA) described how study of the immunosuppressant drug rapamycin has led to the identification of one possible target for anticancer drug therapy.
As well as its immunomodulatory activity, rapamycin has antiproliferative properties. Dr Dancey explained that these had been shown to be the result of the drug forming a complex with the intracellular protein FKBP-12, which then inhibited an enzyme known as mTOR (mammalian target of rapamycin). mTOR appeared to have a key role in regulating the burst of protein synthesis that followed stimulation of cell growth by the activation of cell surface growth factor receptors. By inhibiting mTOR, the transduction of the growth signal could be blocked, preventing cell proliferation.
Dr Dancey said that rapamycin itself was not an ideal candidate for development as an anticancer drug, both because of its physicochemical properties - poor water solubility and poor stability in solution - and also because of its immunosuppressant character.
She added that this had led to a search for rapamycin derivatives with similar effects on protein translation but fewer undesirable characteristics.
One such compound was CCI-779 (National Cancer Institute; Wyeth-Ayerst), which had been found to inhibit the growth of some tumour cell lines when present at nanomolar concentrations in tissue culture media.
Dr Dancey added that phase I clinical trials with this compound were now in progress and that it appeared to be well tolerated, with skin reactions and mucositis the most common side effects to date. Encouragingly, even in the phase I trials some objective antitumour responses had been seen during CCI-779 treatment although, as she explained, since the compound was cytostatic rather than cytotoxic in vitro, objective tumour regression might not be the most appropriate end-point for clinical trials.
During her presentation, Dr Dancey made it clear that, although mTOR was known to be "downstream" of growth factor receptors and "upstream" of protein translation, the steps linking these three features of growth factor signalling had yet to be fully elucidated. However, because the processes of growth factor control and signal transduction are known to be aberrant in many tumours, they are the subject of an intensive research effort which has identified several other targets for therapeutic intervention.
For example, as Dr J. Baselga (Barcelona, Spain) explained during his conference presentation, many tumours have an excessive number of cell surface receptors to polypeptide growth factors, such as epidermal growth factor (EGF). He said that these transmembrane receptors incorporated tyrosine kinase activity in their intracellular portion. During growth factor binding, this enzyme phosphorylated tyrosine residues incorporated into the intracytoplasmic part of the receptor. The phosphorylated receptor could then bind cytoplasmic signalling molecules which were vital in the transduction of the growth signal.
The increasing understanding of this process has led researchers to look for inhibitors of receptor tyrosine kinases. Results from phase I trials with one of these - ZD1839 (Iressa; Astra Zeneca), a relatively selective inhibitor of the EGF receptor-linked tyrosine kinase - were the main subject of Dr Baselga's presentation.
He said that 159 patients had now been entered into studies involving chronic oral administration of ZD1839 at doses ranging from 150-1000mg per day and that treatment had, generally, been well tolerated, with the most common side effects of treatment being acne, nausea, vomiting and diarrhoea, the last of these being dose-limiting.
Objective antitumour response, or disease stabilisation lasting three months or longer, was seen in 30 per cent of patients. As with CCI-779, ZD1839 was cytostatic in vitro and might be expected to produce disease stabilisation rather than regression. For this reason, Dr Baselga explained, early phase clinical trials with compounds like ZD1839 would need to establish their minimal effective dose as well as the more readily established maximum tolerated dose, which was the end-point of phase I trials with conventional cytotoxic agents.
One of the cytoplasmic signalling molecules which associates with the phosphorylated EGF receptor is the Ras protein. Ras requires the post-translational addition of a farnesyl group before it can function as a signalling molecule. Farnesylation is carried out by the enzyme farnesyl transferase (FT) and an alternative approach to interfering with EGF signal transduction is to develop inhibitors of this enzyme.
Early stage clinical trials with several such compounds were reported at the ASCO meeting. One of the more advanced agents is R115777 (Janssen-Cilag), which has already been the subject of a phase II trial in women with previously treated, advanced breast cancer. This was reported upon in New Orleans by Dr S. Johnston (Royal Marsden hospital, London). Women entering the study received chronic oral treatment with 400mg R115777 twice daily (reduced to 300mg twice daily after the first six patients because of unacceptable haematological toxicity). Of 26 women assessable for antitumour response at the time of this preliminary report, three (12 per cent) had had a partial antitumour response and a further nine (35 per cent) had experienced disease stabilisation lasting at least three months. Although the major toxicity of R115777 was myelosuppression, other side effects were observed, including parasthesias, skin rashes and fatigue.
Presenting the results of a phase I study with another FT inhibitor, L-778123 (Merck), Dr E. Rubin (Cancer Institute of New Jersey) explained that the FT inhibitors currently under development were not as selective in inhibiting Ras farnesylation as was first thought. They also inhibited the addition of a farnesyl group to a number of other proteins, which may account for some of their adverse effects. He gave as an example the eye changes seen after L-778123 treatment, which were believed to be a consequence of the inhibition of farnesylation of pigment proteins within the retina.
When growth factor receptors are known to be present on the cell surface in excessive numbers, an alternative to interfering with post-receptor signal transduction is to target the external, growth factor binding, portion of the receptor using an appropriate antibody. This approach has been followed with considerable success in the 25-30 per cent of women with breast cancer who overexpress the HER-2 receptor. The addition of the anti-HER2 antibody, trastuzumab (Herceptin; Roche, Genentech), to conventional chemotherapy for metastatic disease was reported, at last year's ASCO meeting, to improve tumour response rates and prolong survival.
This year, Dr C. Vogel (Aventura, Florida, US) presented the results of a clinical trial in which 114 women with breast cancer overexpressing HER-2 received trastuzumab alone as their first treatment for metastatic disease. Thirty-six and 40 per cent, respectively, of patients receiving conventional and high doses of the antibody experienced clinical benefit (objective tumour response or disease stabilisation lasting longer than six months). These results, and the median times to disease progression and death, were comparable to those seen following combination therapy with trastuzumab and chemotherapy given to similar patients in previous studies. This led Dr Vogel to conclude that trastuzumab monotherapy is a reasonable first-line treatment option for women with HER-2 positive metastatic breast cancer.
Dr Summerhayes is principal oncology pharmacist,Guy's and St Thomas's hospitals NHS trust. He attended the ASCO meeting as a guest of Roche Products