title: SSTR3 is a putative target for the medical treatment of gonadotroph adenomas of the pituitary.
abstract: Gonadotroph pituitary adenomas (GPAs) often present as invasive macroadenomas not amenable to complete surgical resection. Radiotherapy is the only post-operative option for patients with large invasive or recurrent lesions. No medical treatment is available for these patients. The somatostatin analogs (SSAs) octreotide and lanreotide that preferentially target somatostatin receptor type 2 (SSTR2) have little effect on GPAs. It is widely accepted that the expression of specific SSTR subtypes determines the response to SSAs. Given that previous studies on mRNA and protein expression of SSTRs in GPAs have generated conflicting results, we investigated the expression of SSTR2, SSTR3, and SSTR5 (the main targets of available SSAs) in a clinically and pathologically well-characterized cohort of 108 patients with GPAs. A total of 118 samples were examined by immunohistochemistry using validated and specific MABs. Matched primary and recurrent tissues were available for ten patients. The results obtained were validated in an independent cohort of 27 GPAs. We observed that SSTR3 was significantly more abundant than SSTR2 (P<0.0001) in GPAs, while full-length SSTR5 was only expressed in few tumors. Expression of SSTR3 was similar in primary and recurrent adenomas, was high in potentially aggressive lesions, and did not change significantly in adenomas that recurred after irradiation. In conclusion, low levels of expression of SSTR2 may account for the limited response of GPAs to octreotide and lanreotide. Given the potent anti-proliferative, pro-apoptotic, and anti-angiogenic activities of SSTR3, targeting this receptor with a multireceptor ligand SSA such as pasireotide may be indicated for potentially aggressive GPAs.
authors.affiliation: Institute of PathologyHelmholtz Zentrum München, D-85764 Neuherberg, GermanyDepartment of Pharmacology and ToxicologyJena University Hospital, Friedrich Schiller University, Jena, GermanyDepartments of NeurosurgeryMedicineImperial College, St Dunstans Road, London W6 8RP, UKDepartment of NeuropathologyInstitute for Pathology and NeuropathologyDepartment of NeurosurgeryUniversity of Tübingen, Tübingen, GermanyInstitute of PathologyTechnical University of Munich, München, Germany.
authors.forename: Misu
authors.initials: M
authors.lastname: Lee
authors.affiliation: Institute of PathologyHelmholtz Zentrum München, D-85764 Neuherberg, GermanyDepartment of Pharmacology and ToxicologyJena University Hospital, Friedrich Schiller University, Jena, GermanyDepartments of NeurosurgeryMedicineImperial College, St Dunstans Road, London W6 8RP, UKDepartment of NeuropathologyInstitute for Pathology and NeuropathologyDepartment of NeurosurgeryUniversity of Tübingen, Tübingen, GermanyInstitute of PathologyTechnical University of Munich, München, Germany.
authors.forename: Amelie
authors.initials: A
authors.lastname: Lupp
authors.affiliation: Institute of PathologyHelmholtz Zentrum München, D-85764 Neuherberg, GermanyDepartment of Pharmacology and ToxicologyJena University Hospital, Friedrich Schiller University, Jena, GermanyDepartments of NeurosurgeryMedicineImperial College, St Dunstans Road, London W6 8RP, UKDepartment of NeuropathologyInstitute for Pathology and NeuropathologyDepartment of NeurosurgeryUniversity of Tübingen, Tübingen, GermanyInstitute of PathologyTechnical University of Munich, München, Germany.
authors.forename: Nigel
authors.initials: N
authors.lastname: Mendoza
authors.affiliation: Institute of PathologyHelmholtz Zentrum München, D-85764 Neuherberg, GermanyDepartment of Pharmacology and ToxicologyJena University Hospital, Friedrich Schiller University, Jena, GermanyDepartments of NeurosurgeryMedicineImperial College, St Dunstans Road, London W6 8RP, UKDepartment of NeuropathologyInstitute for Pathology and NeuropathologyDepartment of NeurosurgeryUniversity of Tübingen, Tübingen, GermanyInstitute of PathologyTechnical University of Munich, München, Germany.
authors.forename: Niamh
authors.initials: N
authors.lastname: Martin
authors.affiliation: Institute of PathologyHelmholtz Zentrum München, D-85764 Neuherberg, GermanyDepartment of Pharmacology and ToxicologyJena University Hospital, Friedrich Schiller University, Jena, GermanyDepartments of NeurosurgeryMedicineImperial College, St Dunstans Road, London W6 8RP, UKDepartment of NeuropathologyInstitute for Pathology and NeuropathologyDepartment of NeurosurgeryUniversity of Tübingen, Tübingen, GermanyInstitute of PathologyTechnical University of Munich, München, Germany.
authors.forename: Rudi
authors.initials: R
authors.lastname: Beschorner
authors.affiliation: Institute of PathologyHelmholtz Zentrum München, D-85764 Neuherberg, GermanyDepartment of Pharmacology and ToxicologyJena University Hospital, Friedrich Schiller University, Jena, GermanyDepartments of NeurosurgeryMedicineImperial College, St Dunstans Road, London W6 8RP, UKDepartment of NeuropathologyInstitute for Pathology and NeuropathologyDepartment of NeurosurgeryUniversity of Tübingen, Tübingen, GermanyInstitute of PathologyTechnical University of Munich, München, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Honegger
authors.affiliation: Institute of PathologyHelmholtz Zentrum München, D-85764 Neuherberg, GermanyDepartment of Pharmacology and ToxicologyJena University Hospital, Friedrich Schiller University, Jena, GermanyDepartments of NeurosurgeryMedicineImperial College, St Dunstans Road, London W6 8RP, UKDepartment of NeuropathologyInstitute for Pathology and NeuropathologyDepartment of NeurosurgeryUniversity of Tübingen, Tübingen, GermanyInstitute of PathologyTechnical University of Munich, München, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schlegel
authors.affiliation: Institute of PathologyHelmholtz Zentrum München, D-85764 Neuherberg, GermanyDepartment of Pharmacology and ToxicologyJena University Hospital, Friedrich Schiller University, Jena, GermanyDepartments of NeurosurgeryMedicineImperial College, St Dunstans Road, London W6 8RP, UKDepartment of NeuropathologyInstitute for Pathology and NeuropathologyDepartment of NeurosurgeryUniversity of Tübingen, Tübingen, GermanyInstitute of PathologyTechnical University of Munich, München, Germany.
authors.forename: Talia
authors.initials: T
authors.lastname: Shively
authors.affiliation: Institute of PathologyHelmholtz Zentrum München, D-85764 Neuherberg, GermanyDepartment of Pharmacology and ToxicologyJena University Hospital, Friedrich Schiller University, Jena, GermanyDepartments of NeurosurgeryMedicineImperial College, St Dunstans Road, London W6 8RP, UKDepartment of NeuropathologyInstitute for Pathology and NeuropathologyDepartment of NeurosurgeryUniversity of Tübingen, Tübingen, GermanyInstitute of PathologyTechnical University of Munich, München, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Pulz
authors.affiliation: Institute of PathologyHelmholtz Zentrum München, D-85764 Neuherberg, GermanyDepartment of Pharmacology and ToxicologyJena University Hospital, Friedrich Schiller University, Jena, GermanyDepartments of NeurosurgeryMedicineImperial College, St Dunstans Road, London W6 8RP, UKDepartment of NeuropathologyInstitute for Pathology and NeuropathologyDepartment of NeurosurgeryUniversity of Tübingen, Tübingen, GermanyInstitute of PathologyTechnical University of Munich, München, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schulz
authors.affiliation: Institute of PathologyHelmholtz Zentrum München, D-85764 Neuherberg, GermanyDepartment of Pharmacology and ToxicologyJena University Hospital, Friedrich Schiller University, Jena, GermanyDepartments of NeurosurgeryMedicineImperial College, St Dunstans Road, London W6 8RP, UKDepartment of NeuropathologyInstitute for Pathology and NeuropathologyDepartment of NeurosurgeryUniversity of Tübingen, Tübingen, GermanyInstitute of PathologyTechnical University of Munich, München, Germany natalia.pellegata@helmholtz-muenchen.de f.roncaroli@imperial.ac.uk.
authors.forename: Federico
authors.initials: F
authors.lastname: Roncaroli
authors.affiliation: Institute of PathologyHelmholtz Zentrum München, D-85764 Neuherberg, GermanyDepartment of Pharmacology and ToxicologyJena University Hospital, Friedrich Schiller University, Jena, GermanyDepartments of NeurosurgeryMedicineImperial College, St Dunstans Road, London W6 8RP, UKDepartment of NeuropathologyInstitute for Pathology and NeuropathologyDepartment of NeurosurgeryUniversity of Tübingen, Tübingen, GermanyInstitute of PathologyTechnical University of Munich, München, Germany natalia.pellegata@helmholtz-muenchen.de f.roncaroli@imperial.ac.uk.
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Pellegata
mesh_terms: D000236:Adenoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000378:metabolism*; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D017481:Receptors, Somatostatin; C103631:somatostatin receptor 3; D013004:Somatostatin; C517782:pasireotide
keywords: aggressive adenoma; gonadotroph adenoma; pasireotide; somatostatin receptors