Research Article: Prospects of Targeting the Gastrin Releasing Peptide Receptor and Somatostatin Receptor 2 for Nuclear Imaging and Therapy in Metastatic Breast Cancer

Date Published: January 20, 2017

Publisher: Public Library of Science

Author(s): Simone U. Dalm, Willemijne A. M. E. Schrijver, Anieta M. Sieuwerts, Maxime P. Look, Angelique C. J. Ziel – van der Made, Vanja de Weerd, John W. Martens, Paul J. van Diest, Marion de Jong, Carolien H. M. van Deurzen, Rajeev Samant.

http://doi.org/10.1371/journal.pone.0170536

Abstract

The gastrin releasing peptide receptor (GRPR) and the somatostatin receptor 2 (SSTR2) are overexpressed on primary breast cancer (BC), making them ideal candidates for receptor-mediated nuclear imaging and therapy. The aim of this study was to determine whether these receptors are also suitable targets for metastatic BC.

mRNA expression of human BC samples were studied by in vitro autoradiography and associated with radioligand binding. Next, GRPR and SSTR2 mRNA levels of 60 paired primary BCs and metastases from different sites were measured by quantitative reverse transcriptase polymerase chain reaction. Receptor mRNA expression levels were associated with clinico-pathological factors and expression levels of primary tumors and corresponding metastases were compared.

Binding of GRPR and SSTR radioligands to tumor tissue correlated significantly with receptor mRNA expression. High GRPR and SSTR2 mRNA levels were associated with estrogen receptor (ESR1)-positive tumors (p<0.001 for both receptors). There was no significant difference in GRPR mRNA expression of primary tumors versus paired metastases. Regarding SSTR2 mRNA expression, there was also no significant difference in the majority of cases, apart from liver and ovarian metastases which showed a significantly lower expression compared to the corresponding primary tumors (p = 0.02 and p = 0.03, respectively). Targeting the GRPR and SSTR2 for nuclear imaging and/or treatment has the potential to improve BC care in primary as well as metastatic disease.

Partial Text

Breast cancer (BC) is the second most common cancer found in women and the fifth cause of cancer related death [1]. The disease is very heterogeneous. Different subtypes with distinctive morphological and molecular characteristics exist. The four major intrinsic BC subtypes are luminal A, luminal B, human epidermal growth factor 2 (HER2, ERBB2)-driven and basal-like BC [2, 3]. Treatment and prognosis of the disease are highly dependent on these subtypes; luminal A and luminal B tumors have a better prognosis than basal-like BC [2, 3]. Although multiple therapy options for BC exist, 20–30% of BC patients experience relapse with metastatic disease [4].

Targeting of GRPR and SSTR2 overexpressed on BC cells with radioligands can offer novel imaging and therapy options for BC. Previous clinical and preclinical studies reported promising results. However, these studies were restricted to primary BC, while metastases are the main cause of BC-related death. In this study, we compared GRPR and SSTR2 mRNA expression levels in a unique dataset of primary BC and corresponding metastases to determine whether receptor-based imaging and/or therapy could also be useful for metastatic BC. For this purpose, we selected FFPE material of primary BCs and corresponding metastases from different sites, and compared mRNA receptor expression levels of the paired samples. Prior to this, we evaluated whether mRNA expression levels of tumor tissue properly represent radioligand binding, by correlating in vitro autoradiography results with mRNA expression levels of selected primary tumors and corresponding metastases with varying mRNA receptor expression. In line with previously published findings [10], we demonstrated that there was a high correlation between mRNA expression of the receptors and radiotracer binding, which suggests that mRNA expression levels can be used as a surrogate for radiotracer binding.

The presented data indicates that nuclear based imaging and therapy has the potential to improve BC patient care in primary as well as in metastatic disease, by targeting GRPR and SSTR2. Both GRPR and SSTR2 radioligands, but especially GRPR radioligands, are promising for imaging and treatment of ER-positive primary and metastatic BC.

 

Source:

http://doi.org/10.1371/journal.pone.0170536

 

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