Seeking better cancer treatments

EUREKA project E! 1948 SASTEREC and its follow-up E! 2705 SAMARDES carried out essential research with the human androgen receptor to understand the mechanism of the mode of action of androgens. The human androgen receptor (hAR) binds the male sex steroids and regulates genes for male differentiation and development.

The lengthy and meticulous research began in 1998 with E! 1948 SASTEREC. Structural evidence was found for fine-tuning ligand specificity in the binding domain of the human androgen receptor. This project identified and categorised the critical hormone binding sites through crystallisation and X ray determination of the 3D structure, and studied how they docked and acted. The researchers then tested the sites with agonists and antagonists to assess their possible use as hormone-based drugs to control tumours.

In E! 2705 SAMARDES, the research was extended to include investigations into mutated forms of the human androgen receptor (hAR). This work is important as 14 known mutations of hAR are known to be associated with either prostate cancer or partial or complete androgen receptor insensitivity syndrome. A double mutant of this receptor derived from an independent cancer line that had been shown to have glucocorticoid activity was structurally characterized.

"The two projects form a continuous sequence of research aiming to understand the mode of action of androgens. With the structural data in hand, the development of drugs that bind to the ligand binding domain of these receptors could become easier and lead to more effective treatments with fewer side effects," explains Professor Maria Armnia Carrondo of the Portuguese Instituto de Biologia Experimental e Tecnolgica (IBET).

These two EUREKA projects have forged an eight-year partnership between the leading pharmaceutical company in steroid hormones (Schering, Germany) and IBET.

"Schering has had an extremely fruitful collaboration with Professor Carrondo

Contact: Julie Sors

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