Emerging drugs for Cushing’s disease

Guelho, Daniela; Grossman, Ashley

doi:10.1517/14728214.2015.1047762

Cited by 14 publications

(9 citation statements)

References 90 publications

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“…This receptor subtype is highly expressed in GH-secreting tumors and is the most expressed SSTRs in ACTH-secreting tumors. Since the multi-ligand SSA pasireotide represents the only pituitary-directed drug approved by regulatory authorities to treat Cushing's disease, at least in Europe, it would be of great interest to evaluate a possible FLNA role in molecular mechanisms underlying the resistance to pasireotide, occurring in 50-70% of patients with Cushing's disease (Guelho & Grossman 2015).…”

Section: Flna Role In Gh-secreting Tumor Responsiveness To Ssasmentioning

confidence: 99%

Cytoskeleton actin-binding proteins in clinical behavior of pituitary tumors

Mantovani

Treppiedi

Giardino

et al. 2019

Endocrine-Related Cancer

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Although generally benign, pituitary tumors are frequently locally invasive, with reduced success of neurosurgery and unresponsive to pharmacological treatment with somatostatin or dopamine analogues. The molecular basis of the different biological behavior of pituitary tumors are still poorly identified, but a body of work now suggests that the activity of specific cytoskeleton proteins is a key factor regulating both the invasiveness and drug resistance of these tumors. This review recapitulates the experimental evidence supporting a role for the actin-binding protein filamin A (FLNA) in the regulation of somatostatin and dopamine receptors expression and signaling in pituitary tumors, thus in determining the responsiveness to currently used drugs, somatostatin analogues and dopamine receptor type 2 agonists. Regarding the regulation of invasive behavior of pituitary tumoral cells, we bring evidence to the role of the actin-severing protein cofilin, whose activation status may be modulated by dopaminergic and somatostatinergic drugs, through FLNA involvement. Molecular mechanisms involved in the regulation of FLNA expression and function in pituitary tumors will also be discussed.

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Section: Flna Role In Gh-secreting Tumor Responsiveness To Ssasmentioning

confidence: 99%

Cytoskeleton actin-binding proteins in clinical behavior of pituitary tumors

Mantovani

Treppiedi

Giardino

et al. 2019

Endocrine-Related Cancer

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“…Over time, both corticotroph tumor progression and regression occurred, with possible significant increases in ACTH levels without evidence of tumor growth [81]. However, reported side effects include nausea, fatigue, hypokalemia, headaches, arthralgia, vomiting, endometrial thickening and peripheral edema [82]. A limitation of mifepristone is the fact that there is no biochemical marker for its effect; the patient should be substituted with hydrocortisone for safety reasons.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

“The Adrenal Gland: Central Relay in Health and Disease - Current Challenges and Perspectives 2018” – Cushing’s Disease

Stalla

Ciato

Dimopoulou

2018

Exp Clin Endocrinol Diabetes

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CD is associated to a significant clinical burden, since numerous comorbidities persist after long-term biochemical control. These chronically ill patients show an increased mortality despite disease remission. Clinicians should treat comorbidities aggressively and seek for appropriate consultations. Structured consultation hours and expert excellence networks are needed in order to allow optimal, individualized care for affected patients, reverse increased morbidity and mortality and identify tumor recurrence early.

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“…However, it is significantly more potent, having a 3-fold higher affinity to 11 beta-hydroxylase than metyrapone, as demonstrated in preclinical studies (in vitro half maximal inhibitory concentration (IC 50 ) of 7.5 nM vs 2.5 nM for metyrapone) [103]. In addition, its longer half-life allows twice daily oral administration, conferring an advantage over metyrapone, which may require administration up to 6 times daily [103, 104]. In a 10-week, proof of concept study (LINC-1; NCT01331239), osilodrostat demonstrated good efficacy, normalizing UFC in 11 of 12 patients with CD.…”

Section: Novel Medical Treatments For Cushing’s Disease In Clinical Tmentioning

confidence: 99%

“…Improvement was noted in weight and body mass index (BMI) [106]. Based on these results, osilodrostat shows promise as an alternative treatment in CD [104] and two phase III studies (LINC-3 and LINC-4) are currently underway.…”

Section: Novel Medical Treatments For Cushing’s Disease In Clinical Tmentioning

confidence: 99%

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Update on medical treatment for Cushing’s disease

Cuevas‐Ramos

Lim

Fleseriu

2016

Clin Diabetes Endocrinol

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Cushing’s disease (CD) is the most common cause of endogenous Cushing’s syndrome (CS). The goal of treatment is to rapidly control cortisol excess and achieve long-term remission, to reverse the clinical features and reduce long-term complications associated with increased mortality.While pituitary surgery remains first line therapy, pituitary radiotherapy and bilateral adrenalectomy have traditionally been seen as second-line therapies for persistent hypercortisolism. Medical therapy is now recognized to play a key role in the control of cortisol excess. In this review, all currently available medical therapies are summarized, and novel medical therapies in phase 3 clinical trials, such as osilodrostat and levoketoconazole are discussed, with an emphasis on indications, efficacy and safety. Emerging data suggests increased efficacy and better tolerability with these novel therapies and combination treatment strategies, and potentially increases the therapeutic options for treatment of CD. New insights into the pathophysiology of CD are highlighted, along with potential therapeutic applications. Future treatments on the horizon such as R-roscovitine, retinoic acid, epidermal growth factor receptor inhibitors and somatostatin-dopamine chimeric compounds are also described, with a focus on potential clinical utility.

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Emerging drugs for Cushing’s disease

Cited by 14 publications

References 90 publications

Cytoskeleton actin-binding proteins in clinical behavior of pituitary tumors

Cytoskeleton actin-binding proteins in clinical behavior of pituitary tumors

“The Adrenal Gland: Central Relay in Health and Disease - Current Challenges and Perspectives 2018” – Cushing’s Disease

Update on medical treatment for Cushing’s disease

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