View clinical trials related to Prolactinomas.
Filter by:There are no available medical treatment options for patients with non-functioning pituitary adenomas (NFPA) or with resistant prolactinomas to dopamine agonists (DA) who are not cured by surgery. The study of the receptors by quantitative mRNA expression levels and immunohistochemistry analysis might end with a better understanding of these tumors. Besides that, it will be assessed the in vitro and in vivo responses to pasireotide (for NFPA and prolactinomas) and cabergoline (for NFPA). These responses will be compared with the receptor expressions which may be a tool as a predicting element of the response to these compounds.
This study focuses on new therapies for a challenging disease in pituitary medicine, that of aggressive pituitary tumors which have limited therapeutic options beyond standard surgical, radiotherapy, and select medical therapies, each incurring significant morbidity and mortality, and each not optimally effective. To improve this gap in knowledge, we seek to translate findings from the laboratory into clinical practice and hone in on therapies directed at pituitary molecular targets, namely ErbB receptors. We have shown that human prolactinomas express nuclear EGFR and membranous ErbB2, ErbB3 and ErbB4, and expression correlates with tumor invasion. Pituitary tumor cell lines transfected with EGFR and ErbB2 translated to downstream effects on prolactin (PRL) gene expression and secretion,as well as cell proliferation. Animal models implanted with these cell lines developed larger tumors and PRL elevations. Treatment with ErbB tyrosine kinase inhibitors (TKIs) led to regression of tumors xenografted into these animals and attenuated PRL secretion. Primary culture of human prolactinomas confirmed expression of ErbB receptors and inhibitory effects of TKIs on PRL secretion and cell proliferation. Based on these exciting preliminary data, the objective of this new proposal is to conduct a Phase IIa clinical trial as a trenchant test of our translational hypothesis that tyrosine kinase inhibition constitutes highly effective targeted biologic therapy for these hitherto refractory pituitary adenomas. Specifically, our aims are to test the: 1) efficacy of TKI therapy with a clinical trial; 2) threshold level of tumor receptor expression to achieve TKI clinical response. Nineteen subjects will be treated with lapatinib for 6 months in combination with their current dopamine agonist therapy, with monthly measurements of PRL levels and MRI imaging every 3 months to evaluate the primary endpoints of achieving 40% reduction in tumor size and 50% reduction in PRL and secondary endpoints of radiologic stabilization and/or reduction and PRL normalization. Mean ErbB receptor protein expression will be compared between responders to lapatinib and non-responders by immunohistochemistry in pituitary tumor samples of these subjects collected from prior surgeries.
Dopamine agonists are first-line agents for the treatment of prolactinomas (1) and Parkinson's disease (2). There is evidence supporting a causal relationship between the occurrence of drug-induced "restrictive" valvular heart disease and treatment with pergolide (3): in several cases, the valvulopathy improved when pergolide was discontinued (4). Valvular heart damage has also been reported with the ergot-derived dopamine agonists bromocriptine and cabergoline (5,6). Two recent studies (7,8) have further demonstrated that both pergolide and cabergoline are associated with an increased risk of new cardiac valve regurgitation in patients treated for Parkinson's disease. The valvular abnormalities seen with ergot-derived dopamine agonists are similar to those observed in patients receiving ergot alkaloid agents (such as ergotamine and methysergide) in the treatment of migraine, or fenfluramine and dexfenfluramine in the treatment of obesity. These abnormalities also closely resemble carcinoid-related valvulopathies (9). Cardiac valve disease has never been reported in patients with prolactinomas who require treatment with dopamine-agonists even life-long (1). At variance with patients with Parkinson's disease, patients with prolactinomas are younger and are treated with an average dose of dopamine-agonists that is significantly lower (median bromocriptine dose 5 mg/day and median cabergoline dose 1 mg/week). Because of the young age of treatment beginning (most patients with microprolactinomas start dopamine-agonist treatment in early adulthood), treatment might be continued for over 3 decades: the cumulative risk of low doses of dopamine agonists for such a long period of treatment is currently unknown. To assess the prevalence of cardiac valve disease in patients treated with cabergoline, we wish to perform an echocardiography screening in a large representative sample of patients with prolactinoma who were treated with cabergoline for at least 12 months and in a group of control subjects recruited prospectively. We wish to evaluate the severity of regurgitation for the mitral, aortic, and tricuspid valves. Changes in cardiac valve apparatus was compared with treatment duration and cumulative cabergoline dose.