Improved “Magic Bullet” Designed for Cancer Detection, Radiotherapy

Until recently, scientists accepted the idea that such an agent, an agonist, needed to enter and accumulate in the cancerous cells to act. An international research team has now shown in cancer patients that an investigational agent that sticks onto the surface of tumor cells without triggering internalization, an antagonist, may be safer and even more effective than agonists.

One of the Salk Institute’s (San Diego, CA, USA) leading researchers, Dr. Jean Rivier, professor in Salk’s Clayton Foundation Laboratories for Peptide Biology and his Swiss collaborator, Dr. Jean Claude Reubi, University of Berne (Switzerland) and adjunct professor at Salk, coauthored a pilot study, published in the September 2011 issue of the Journal of Nuclear Medicine, of five patients and demonstrated that their antagonist, ¹¹¹In-DOTA-BASS, outperformed the agonist agent, OctreoScan, that is widely used in the clinic to image neuroendocrine tumors bearing somatostatin receptors.

“This is the first proof of principle in humans that labeled peptide antagonists can effectively image tumors. Additional research suggests that we could one day use a different radioactive metal to effectively kill the tumors,” noted Dr. Rivier.

Dr. Reubi, a molecular pathologist, and Dr. Rivier, a chemist, collaborated in the design and selection of natIn-DOTA-BASS for human testing, and Dr. Helmut R. Maecke, a radiochemist, loaded DOTA-BASS with its radioactive marker and assessed the compound before use in human. Subsequently, the “first in man” study with the radioactive loaded DOTA-BASS was performed at the University Hospital in Freiburg (Germany), by Drs. Damian Wild, Melpomeni Fani, Martin Behe, Ingo Brink, Helmut R. Maecke, and Wolfgang A. Weber.

The basis for this study goes back to 1973, when a team of Salk researchers, which included Drs. Brazeau, Vale, Burgus, Rivier, and Roger Guillemin, a 1977 Nobel laureate, isolated and characterized somatostatin, a peptide produced by neuroendocrine glands. The scientists discovered that the normal function of somatostatin is to block the release of growth hormone throughout the body, which includes suppressing the release of thyroid-stimulating hormone (TSH) from the thyroid.

Drs. Rivier, Reubi and their colleagues from Germany showed that ¹¹¹In-DOTA-BASS bound to a greater number of somatostatin receptors on cancer cells than the agonist OctreoScan, and that it did accumulate in normal tissue (liver and kidney) to a lesser extent. The prototype antagonist therapy has been revamped, and the version studied in the Journal of Nuclear Medicine publication, ¹¹¹In-DOTA-BASS, detected 25 of 28 metastatic neuroendocrine tumors in the patients, whereas OctreoScan detected only 17.

In-DOTA-BASS has been licensed to a pharmaceutical company for clinical trial development, according to Dr. Rivier, who added that other researchers are exploring an antagonist approach for other G-protein coupled receptors that are amply expressed on cancer cells.

Related Links:
Salk Institute
University of Berne