Targeting the PI3K/Akt pathway to overcome somatostatin analogue treatment resistance in pituitary adenomas
Final Report Abstract
This study had two major key findings: the rise of the tumor suppressor ZAC1 as a marker, and potentially a predictor, of somatostatin analogue response in acromegalic patients and the potential of somatostatin analogues in improving the anticancer action of rapamycin analogues. The first is of high clinical importance for the identification of patients that will respond successfully to standard depot somatostatin analogues and will help to direct the ones that will not benefit from this treatment to alternative treatments using new generation multiligand somatostatin analogues or other pharmaceutical compounds. Furthermore it sheds new light in the physiology of somatostatin receptors. Somatostatin analogues constitute the primary pharmaceutical treatment not only for acromegalic tumors but also for other neuroendocrine cancers including gastrointestinal tumors and carcinoids. Many of these cancers have a bad prognosis, so better understanding of the mechanism of action of somatostatin receptors will eventually lead to better design of somatostatin analogue treatment. The second demonstrates that a pharmacological protein receptor agonist is able not only to enhance the antiproliferative action of the cytostatic, anticancer drug rapamycin, but also to reverse the resistance seen in many tumors. Rapamycin analogues (rapalogs) are very promising for the treatment of tumors in which the PI3K survival pathway, one of the most important pathways in cancer, is overactivated. Unfortunately many tumors that initially responded to rapalog’s antiproliferative treatment get resistant after a time. This was found to be due to a previously unsuspected overactivation of the PI3K pathway originating from the drug itself which eventually cancels its cytostatic beneficial effects. The present study demonstrates a novel way to bypass this deleterious side effect by targeting the PI3K pathway upstreams using somatostatin receptor ligands. This intervention facilitated tumors expressing somatostatin receptors to overcome their resistance to rapalog treatment and to show better antiproliferative response. The promising results derived from this study reveal a novel way to improve rapalog treatment in somatostatin receptor expressing cancers.
Publications
- The mTOR Inhibitors Rapamycin and RAD001 (Everolimus) Induce Antiproliferative effects in GH-secreting pituitary tumor cells in vitro. Endocr Relat Cancer
Gorshtein A, Rubinfeld H, Kendler E, Theodoropoulou M, Cerovac V, Stalla GK, Cohen Z, Hadani M, Shimon I
- Tumor ZAC1 Expression is Associated with the Response to Somatostatin Analog Therapy in Patients with Acromegaly. Int J Cancer. 2009
Theodoropoulou M, Tichomirowa MA, Sievers C, Yassouridis A, Arzberger T, Hougrand O, Deprez M, Daly AF, Petrossians P, Pagotto U, Beckers A, Stalla GK
