Is receptor profiling useful for predicting pituitary therapy?

Abstract

Medical treatment of pituitary tumours may present important challenges in the presence of resistance to first line therapy. In this setting, the availability of specific markers of responsiveness/resistance could be helpful to provide tailored patients' treatment. Pituitary receptor profiling has emerged as a potentially useful tool for predicting the response to specific pituitary-directed medical therapy, mainly somatostatin analogues and dopamine agonists. However, its utility is not always straightforward. In fact, agonist-receptor coupling to the consequent biological response is complex and sometimes jeopardizes the understanding of the molecular basis of pharmacological resistance. Defective expression of pituitary receptors, genetic alterations, truncated variants, impaired signal transduction or involvement of other proteins, such as cytoskeleton proteins or the Aryl hydrocarbon receptor interacting protein amongst others, have been linked to differential tumour phenotype or treatment responsiveness with conflicting results, keeping the debate on the utility of pituitary receptor profiling open. Why does this occur? How can we overcome the difficulties? Is there a true role for pituitary receptor profiling in the near future? All authors of this debate article agree on the need of prospective studies using standardized methods in order to assess the efficacy of receptor profiling as a reliable clinical predictive factor.

Role of Receptor Profiling for Personalized Therapy in a Patient with a Growth Hormone-Secreting Macroadenoma Resistant to First-Generation Somatostatin Analogues

“…A number of factors might predict a poor response to lanreotide Autogel in the present patient which could have been considered before treatment, thus obviating the need and additional cost of a non-efficacious treatment. Young age at presentation, male gender, high baseline hormonal levels, high signal intensity on T2-weighted MRI, and the histopathology of a sparsely-granulated pattern [13,27] with intense expression of SSTR5 and low expression of E-cadherin [13,14,18,28], are all markers pointing to an expected poor response to a predominant SSTR2 agonist such as lanreotide. Pasireotide is a second-generation SSA with higher affinity for SSTR5 (besides SSTR1,-2,-3) [24,28].…”

“…Immunohistochemistry of somatotroph tumors has been problematic, with heterogeneity in tumoral SSTR expression in different studies, variability of techniques to detect SSTR status, and the pre-operative treatment of tumors, all contributing to highly variable results [13,14]. In cases where both SSTR2/5 are intensively positive on IHC, an additional factor such as E-cadherin may guide further treatment [13,27]. It has been suggested that additional biomarkers could be used to predict the biological behavior of the tumor and its response to treatment.…”

“…At present, first-generation SSAs [6] remain the preferred first-line pharmacological treatment. However, some 55% of patients do not obtain biochemical and/or tumor volume control [10][11][12][13], although this is usually only established after a 'trial-and-error' approach. Recently, it has been suggested that a more personalized approach to treatment may be established using a number of current and evolving biomarkers, such that we may be able to identify patients who could benefit from a particular drug or therapy, thus increasing the success rates of the available pharmacologic agents in acromegaly [6,9,[13][14][15][16].…”

“…We describe here a patient where immunoreceptor profiling of somatostatin receptor type (SSTR) 2, SSTR5 [13,14,17] and cadherin E [18][19][20] were found to be useful to guide towards a more personalized therapeutic plan [3,13].…”

MANAGEMENT OF ENDOCRINE DISEASE: Individualised management of acromegaly

“…Molecular profiling has become an emerging method to characterise a large variety of molecular markers. qPCR is widely used in research settings, but has not yet been established in a daily clinical diagnostic routine setting and validation in well characterised cohorts undergoing standardised SRLs treatment, with well-defined outcome parameters is warranted (38,80).…”