Scientists develop new drug to combat tamoxifen-resistant tumours

An anti-oestrogen compound, discovered only four years ago, has been found to inhibit the growth of breast cancer cells using a unique mechanism which enables it to work against tumours that are resistant to other anti-oestrogens, the 3rd European Breast Cancer Conference in Barcelona heard today (Thursday 21 March).

Yasuji Yamamoto, from the Institute of Molecular and Cellular Biosciences at the University of Tokyo in Japan, said the compound, known as TAS-108, was being assessed in phase l clinical trials at the M.D. Anderson Cancer Center, Houston, USA.

Dr Tetsuji Asao, product director of Taiho Pharmaceutical Co. Ltd – the company that developed TAS-108 – said: “We believe that TAS-108 is a promising anti-oestrogen for the treatment of breast cancer patients. In particular, it appears to inhibit the growth of tamoxifen-resistant tumours. We plan to confirm its efficacy in breast cancer patients who have become resistant to tamoxifen and/or aromatase inhibitors by clinical phase ll and lll trial. We would welcome collaborating in clinical trials with a partner in the States and Europe.”

TAS-108 is a steroidal anti-oestrogen which was discovered in 1998 by scientists at two institutions: SRI International in California, USA, and Taiho Pharmaceutical Co. Ltd, based in Tokyo, Japan. As well as inhibiting the growth of oestrogen-dependent breast tumours it also appears to exert a protective effect on the skeleton and the cardiovascular system. Since its discovery Mr Yamamoto and colleagues have been investigating how the compound works at the molecular level.

They compared TAS-108 with other leading anti-oestrogens: tamoxifen, raloxifene and faslodex. They found that only faslodex matched TAS-108 in its ability to inhibit the activities of the oestrogen receptors on the tumour cells, while tamoxifen and raloxifene were only partially successful. In addition, TAS-108 and faslodex were both able to overcome tamoxifen resistance caused by a mutated oestrogen receptor, ERaD351Y. However TAS-108 differed from faslodex in one crucial area which made it far more effective than any of the other anti-oestrogens. Mr Yamamoto discovered that it recruited another molecular signal, a co-repressor, to help it inhibit the activities of the oestrogen receptors. The co-repressor, SMRT (Silencing Mediator for Retinoid and Thyroid hormone receptor), was known to be active when tamoxifen or raloxifene was used, but the scientists found that it swung into action far more vigorously when recruited to help TAS-108. (Faslodex did not recruit SMRT at all).

Therefore, TAS-108 appears to be a more effective anti-oestrogen that any of the other compounds. Mr Yamamoto said: “Based on these findings, we conclude that TAS-108 could be classified as a unique anti-oestrogen, successfully inhibiting the growth of oestrogen-dependent breast tumours, including tamoxifen-resistant tumours. It operates against oestrogen receptors by recruiting the co-repressor SMRT to help it. These unique properties of TAS-108 are also shared by its active metabolite already found in animals and humans.”

In related studies at Taiho Pharmaceutical Co. Ltd., Dr Jiro Shibata, from the Cancer Research Laboratory, and Hidetoshi Yamaya, from the Pharmacokinetics Research Laboratory, investigated the anti-cancer activity of TAS-108 and of its metabolite, DeET-TAS-108, which is what TAS-108 metabolises into in the liver.

Dr Shibata found that, unlike tamoxifen, TAS-108 and DeET-TAS-108 inhibited breast tumours in rats without any effect on the uterus. (One of the side-effects of tamoxifen can be a slightly increased risk of endometrial cancer). Furthermore, he found that TAS-108 and DeET-TAS-108 accumulated in the tumour tissue, thereby boosting the anti-cancer effect of TAS-108.

Meanwhile Mr Yamaya carried out work to establish the safety and correct dosage of TAS-108 for use in clinical trials. He used radioactive-labeled TAS-108 to track the progress of the drug and its metabolite DeET-TAS-108 in the body of a rat with a breast tumour. He found high concentrations of both compounds in the tumour, and also in the liver, lungs, ovaries, adrenal and pituitary glands and in the bone marrow, but extremely low amounts in the brain. This means that neither TAS-108 nor its metabolite would damage the brain of patients.

Mr Yamaya said: “TAS-108 accumulates well in tumour tissues and these preclinical results suggest that it would be well tolerated by breast cancer patients, and at a range of effective doses.”

Dr Asao said: “We are extremely excited by the potential of TAS-108. Obviously we need to continue to test its efficacy and safety in phase ll and lll clinical trials, but if these prove successful, we believe we have a new tool for combating oestrogen-dependent breast cancers which have proved to be resistant to other anti-oestrogen drugs.”