Signifor Shrinks Tumors in Cushing’s by Reducing Number of Specific Proteins, Study Suggests

Signifor (pasireotide) — a treatment approved for Cushing’s disease patients who are not cured by surgery — reduces the growth of pituitary tumor cells by lowering the amount of activated ERK1/2 proteins, a study finds.

The treatment also induces programmed cell death, the scientists discovered.

The study, “Somatostatin analogs regulate tumor corticotrophs growth by reducing ERK1/2 activity,” was published in Molecular and Cellular Endocrinology. 

Cushing’s disease, a condition characterized by excess cortisol in the bloodstream, is caused by a pituitary gland tumor that produces too much of the adrenocorticotrophic hormone (ACTH). This hormone acts on the adrenal glands and makes them produce additional cortisol.

Nearly all Cushing’s patients undergo pituitary surgery, but up to half will require more treatment in the ensuing 10 years. Novartis‘ Signifor is a therapy approved for patients who were not eligible for, or cured by, surgery.

Signifor is an analog of somatostatin, and reduces ACTH production by activating the somatostatin receptors, and lowering hormone levels.  The treatment also seems to shrink the growth of ACTH-releasing tumor cells, but the molecular mechanisms remain unknown.

In pituitary tumors, somatostatin analogs like Signifor affect cell proliferation by reducing the activation of the MAPK pathway. This signaling pathway plays an important role in complex cellular programs like proliferation, differentiation, maturation, and cell death.

Researchers explored not just if, but also how Signifor affected this pathway in ACTH-producing pituitary tumors.

While Signifor binds to several somatostatin receptors, investigators found that its effects were mostly caused by the activation of the somatostatin receptor type 5 (SST5) and, to a lesser extent, the activation of the SST2.

However, only SST5 activation had an impact on the high levels of activated ERK1/2 — a part of the MAPK signaling pathway — suggesting that, at least in part, Signifor reduces cell proliferation in ACTH-producing pituitary tumors by inhibiting these proteins.

Researchers also found for the first time that Signifor caused the cells to enter into programmed cell death. However, this effect was not seen with selective activators of SST5 or SST2, suggesting that other receptors might be in play.

“This data suggests that [Signifor] may play a crucial role in the treatment of tumors where the MAPK pathway is overactivated,” they concluded. “Furthermore, we unveil that other SSTs may be involved in the pro-apoptotic [programmed cell death] effect mediated by such broader-spectrum SS analog.”