Prolactinoma ErbB receptor expression and targeted therapy for aggressive tumors

Cooper, Odelia; Mamelak, Adam N.; Bannykh, Serguei; Carmichael, John D.; Bonert, Vivien; Lim, Stephen; Cook‐Wiens, Galen; Ben-Shlomo, Anat

doi:10.1007/s12020-013-0093-x

Cited by 70 publications

(61 citation statements)

References 56 publications

(51 reference statements)

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“…Identification of new molecular markers highly expressed or down-regulated in these giant tumours should help to better understand their origin and progression (27,120) and to find new therapeutic modalities, such as drugs interfering with angiogenesis or cell proliferation. An example of such strategy is the recent observation of specific expression of ErbB receptors in prolactinomas, which was associated with tumour invasion and response to DAs (121). Thus, targeting ErbB receptors might be a future effective therapy in patients with large aggressive prolactinomas.…”

Section: Perspectives In the Management Of Giant Prolactinomasmentioning

confidence: 99%

THERAPY OF ENDOCRINE DISEASE: The challenges in managing giant prolactinomas

Maiter

Delgrange

2014

European Journal of Endocrinology

158

166

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Giant prolactinomas are rare tumours, representing only 2-3% of all prolactin (PRL)-secreting tumours and raising special diagnostic and therapeutic challenges. Based on several considerations developed in this review, their definition should be restricted to pituitary adenomas with a diameter of 40 mm or more, significant extrasellar extension, very high PRL concentrations (usually above 1000 mg/l) and no concomitant GH or ACTH secretion. Giant prolactinomas are much more frequent in young to middle-aged men than in women, with a male to female ratio of about 9:1. Endocrine symptoms are often present but overlooked for a long period of time, and diagnosis is eventually made when neurologic complications arise from massive extension into the surrounding structures, leading to cranial nerve palsies, hydrocephalus, temporal epilepsy or exophthalmos. PRL concentrations are usually in the range of 1000-100 000 mg/l, but may be underestimated by the so-called 'high-dose hook effect'. As in every prolactinoma, dopamine agonists are the first-line treatment allowing rapid alleviation of neurologic symptoms in the majority of the cases, a significant reduction in tumour size in three-fourths of the patients and PRL normalization in 60-70%. These extensive tumours are usually not completely resectable and neurosurgery has significant morbidity and mortality. It should therefore be restricted to acute complications such as apoplexy or leakage of cerebrospinal fluid (often induced by medical treatment) or to patients with insufficient tumoural response or progression. Irradiation and temozolomide are useful adjuvant therapies in a subset of patients with aggressive/invasive tumours, which are not controlled despite combined medical and surgical treatments. Because of these various challenges, we advocate a multidisciplinary management of these giant tumours in expert centres.

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Section: Perspectives In the Management Of Giant Prolactinomasmentioning

confidence: 99%

THERAPY OF ENDOCRINE DISEASE: The challenges in managing giant prolactinomas

Maiter

Delgrange

2014

European Journal of Endocrinology

158

166

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“…More aggressive pituitary adenomas show higher EGFR and ErbB2 protein expression, with 40% of invasive adenomas staining positive for ErbB2 compared to 1.2% of noninvasive adenomas [19]. We demonstrated that approximately 80% of 28 human prolactinomas express ErbB receptors [20**], with EGFR positivity in 23/28 (82%), ErbB2 positivity in 24/26 (92%), ErbB3 positivity in 7/28 (25%), and ErbB4 positivity in 20/28 (71%). Higher ErbB3 expression was correlated with higher rates of optic chiasm compression, suprasellar extension, and encasement of the carotids compared to those without these radiologic findings.…”

Section: Targeting the Erbb Pathway In Lactotroph Adenomasmentioning

confidence: 99%

“…Higher ErbB4 was observed in tumors with sphenoid sinus invasion compared to those without invasion. Two subjects who experienced tumor shrinkage and PRL reduction on dopamine agonist therapy had tumors which were 100% percent positive for ErbB3 on their adenomas compared to 13 without tumor reduction who had 0-10% ErbB3 staining [20**]. …”

Section: Targeting the Erbb Pathway In Lactotroph Adenomasmentioning

confidence: 99%

Role of tyrosine kinase inhibitors in the treatment of pituitary tumours: from bench to bedside

Ben-Shlomo

Cooper

2017

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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Purpose of review Treatment of aggressive pituitary tumors often yields suboptimal control of the tumor and confers significant morbidity. Lactotroph and corticotroph derived tumors express ErbB receptors and ligands, and mutations in USP8, which alters EGFR degradation, have been implicated in Cushing disease (CD) pathogenesis. EGFR tyrosine kinase inhibitor (TKI) therapy has emerged as a potential new therapeutic approach for patients with aggressive prolactinomas and CD. Recent findings Using EGFR or HER2 driven PRL promoters, transgenic mice develop large tumors that respond to TKI inhibition. In human corticotroph primary cultures, treatment with the pan-ErbB TKI canertinib as well as the EGFR TKI gefitinib suppresses POMC mRNA, and USP8 mutations, detected in up to two-thirds of CD, may underlie the increase in EGFR signaling in these tumors. Human prolactinomas have differential ErbB receptor expression associated with aggressive behavior and data from an ongoing clinical trial suggest that resistant prolactinomas may respond to the EGFR TKI lapatinib. Summary Preclinical and clinical models substantiate the role of the EGFR pathway in corticotroph and lactotroph adenomas. Although further study is needed, results to date suggest targeting the ErbB pathway may be an effective therapeutic approach for patients with aggressive pituitary tumors.

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“…EGFR/HER2 signaling regulates tumor growth and hormone production in experimental lacto-somatotroph tumors and in an experimental Cushing disease model (24 -27). Moreover, targeted EGFR/HER2 therapy has also been shown to be effective in 2 dopamine agonist resistant prolactinomas (28).…”

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confidence: 99%

ErbB Receptor-Driven Prolactinomas Respond to Targeted Lapatinib Treatment in Female Transgenic Mice

et al. 2015

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As ErbB receptors are expressed in prolactinomas and exhibit downstream effects on prolactin (PRL) production and cell proliferation, we generated transgenic mice using a PRL enhancer/promoter expression system to restrict lactotroph-specific expression of human epidermal growth factor receptor (EGFR) or human EGFR2 (HER2). EGFR or HER2 transgenic mice developed prolactinomas between 13 and 15 months, and confocal immunofluorescence and Western blot analysis confirmed lactotroph-restricted PRL and EGFR or HER2 coexpression. Circulating PRL levels in EGFR and HER2 transgenic mice were increased 5-and 3.8-fold, respectively. Inhibiting EGFR or HER2 signaling with oral lapatinib (100 mg/kg), a dual tyrosine kinase inhibitor for both EGFR and HER2, suppressed circulating PRL by 72% and attenuated tumor PRL expression by 80% and also attenuated downstream tumor EGFR/HER2 signaling. This model demonstrates the role of ErbB receptors underlying prolactinoma tumorigenesis and the feasibility of targeting these receptors for translation to treatment of refractory prolactinomas. (Endocrinology 156: 71-79, 2015)

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Prolactinoma ErbB receptor expression and targeted therapy for aggressive tumors

Cited by 70 publications

References 56 publications

THERAPY OF ENDOCRINE DISEASE: The challenges in managing giant prolactinomas

THERAPY OF ENDOCRINE DISEASE: The challenges in managing giant prolactinomas

Role of tyrosine kinase inhibitors in the treatment of pituitary tumours: from bench to bedside

ErbB Receptor-Driven Prolactinomas Respond to Targeted Lapatinib Treatment in Female Transgenic Mice

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