Combination of somatostatin analogues with rapamycin analogues as a potential pharmaceutical treatment for non-functioning pituitary adenomas

Abstract

There is increasing evidence of an antiproliferative action of somatostatin analogues in many tumor types in vitro. We have previously shown that the somatostatin analogue octreotide decreases cell growth by blocking components of the PI3K/Akt pathway. Immortalized pituitary tumor cells, which are known to respond to this kind of treatment by decreasing cell proliferation, transfected with an Akt overexpressing vector do not respond to octreotide's antiproliferative treatment, indicating the importance of Akt in octreotide treatment resistance. Non-functioning pituitary adenomas (NFPA) cannot benefit from the antiproliferative action of somatostatin analogues despite the fact that they express somatostatin receptors. Recently it was shown that the Akt pathway is overactivated in this type of tumors, suggesting that blocking this pathway could facilitate their response to octreotide treatment. NFPA (n=26) were cultured and treated with the mTOR inhibitor rapamycin alone or in combination with octreotide. Treatment with rapamycin decreased cell proliferation in immortalized pituitary tumor cells by 50%, but had variable efficiency in most NFPA in primary cell culture (13%±17). Combined octreotide and rapamycin treatment decreased cell viability in all 26 tumors examined (40%±13), while octreotide alone had little effect (12%±9). Western blot analysis on immortalized pituitary tumor cell lysates revealed that the combined treatment dramatically reduced cyclin D1/3 and CDK4/6 protein levels when compared to octreotide alone. Furthermore the combined treatment almost completely blocked the colony formation ability of pituitary tumor cells. Summarizing, these data show that combining somatostatin analogues with mTOR inhibitors may be more effective to reduce growth than either substance alone and may constitute a therapy for NFPA for which there is no successful pharmaceutical treatment so far.