Advancing Treatment of Pituitary Adenomas through Targeted Molecular Therapies: The Acromegaly and Cushing Disease Paradigms

Mooney, Michael A.; Simón, Elías; Little, Andrew S.

doi:10.3389/fsurg.2016.00045

Cited by 6 publications

(3 citation statements)

References 71 publications

(70 reference statements)

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“…Pituitary adenomas (PAs) are tumorous growth in the pituitary marked by an abnormal increase in the cells, mainly from the anterior pituitary gland and account for approximately 15% of all primary brain tumors. 1 These PAs, based on their hormone secretion, can be classified as functional PAs (FPAs) such as acromegaly and Cushing's (ability to secrete hormone) and nonfunctional pituitary adenomas (NFPAs), 2 which are majorly benign with slower growth and are detected once they grow to a detectable size, beyond which they exert an intracranial pressure known as the "mass effect". 1 Understanding the nature of PAs has played a vital role in various treatment strategies.…”

Section: ■ Introductionmentioning

confidence: 99%

Metabolomics Profiling of Pituitary Adenomas by Raman Spectroscopy, Attenuated Total Reflection-Fourier Transform Infrared Spectroscopy, and Mass Spectrometry of Serum Samples

et al. 2022

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To date, no studies are available in which pituitary adenomas (PAs) have been studied using techniques like confocal Raman spectroscopy, attenuated total reflection-Fourier transform infrared (FT-IR), and liquid chromatography–tandem mass spectrometry (LC–MS/MS) in the same serum samples. To understand the metabolomics fingerprint, Raman spectra of 16 acromegaly, 19 Cushing’s, and 33 nonfunctional PA (NFPA) and ATR-FTIR spectral acquisition of 16 acromegaly, 18 Cushing’s, and 22 NFPA patient’s serum samples were acquired. Next, Principal component-based linear discriminant analysis (PC-LDA) models were developed, Raman spectral analysis classified acromegaly with an accuracy of 79.17%, sensitivity of 75%, and specificity of 81.25%, Cushing’s with an accuracy of 66.67%, sensitivity of 100%, and specificity of 52.63%, and NFPA with an accuracy of 73.17%, sensitivity of 75%, and specificity of 72.73%. ATR-FTIR spectral analysis classified acromegaly with an accuracy of 95.83%, sensitivity of 100%, and specificity of 93.75%, Cushing’s with an accuracy of 65.38%, sensitivity of 87.5%, and specificity of 55.56%, and NFPA with an accuracy of 70%, sensitivity of 87.5%, and specificity of 43.75%. In either of the cases, healthy individual cohorts were clearly segregated from the disease cohort, which identified differential regulated regions of nucleic acids, lipids, amides, phosphates, and polysaccharide/C–C residue α helix regions. Furthermore, LC–MS/MS-based analysis of sera samples resulted in the identification of various sphingosine, lipids, acylcarnitines, amino acids, ethanolamine, choline, and their derivatives that differentially regulated in each tumor cohort. We believe cues obtained from the study may be used to generate the metabolite-based test to diagnose PAs from serum in addition to conventional techniques and also to understand disease biology for better disease management, point of care, and improving quality of life in PA patients.

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Section: ■ Introductionmentioning

confidence: 99%

Metabolomics Profiling of Pituitary Adenomas by Raman Spectroscopy, Attenuated Total Reflection-Fourier Transform Infrared Spectroscopy, and Mass Spectrometry of Serum Samples

et al. 2022

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“…Therapies aiming to reduce the circulating cortisol mainly act directly on the adrenal cortex by either blocking the synthesis of, or antagonizing peripheral glucocorticoid receptors, thus inhibiting glucocorticoid action or modulating ACTH pituitary hormone secretion (Pedroncelli 2010, Fleseriu & Castinetti 2016, Fuertes et al 2018, Grossman 2018, Langlois et al 2018. Despite the ample variety of current available therapies (Fuertes et al 2018), none has proven to be effective and to reliably provide a good, recurrencefree quality of life to the patient (Mooney et al 2016, Bertagna 2018. The genetic and cellular mechanisms that underlie corticotrophinomas are poorly understood (Newell-Price et al 2006), partially explaining the lack of effective treatments (Pivonello et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Crosstalk of BMP-4 and RA signaling pathways on Pomc gene regulation in corticotrophs

Nieto

Fuertes

Rosmino

et al. 2019

Journal of Molecular Endocrinology

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Retinoic acid (RA), an active metabolite of Vitamin A, and bone morphogenetic protein 4 (BMP-4) pathways control the transcription of pro-opiomelanocortin (Pomc), the precursor of ACTH. We describe a novel mechanism by which RA and BMP-4 act together in the context of pituitary corticotroph tumoral cells to regulate Pomc transcription. BMP-4 and RA exert a potentiated inhibition on Pomc gene expression. This potentiation of the inhibitory action on Pomc transcription was blocked by the inhibitory SMADs of the BMP-4 pathway (SMAD6 and SMAD7), a negative regulator of BMP-4 signaling (TOB1) and a blocker of RA pathway (COUP-TFI). AtT-20 corticotrophinoma cells express RA receptors (RARB, RXRA and RXRG) which associate with factors of BMP-4 (SMAD4 and SMAD1) signaling cascade in transcriptional complexes that block Pomc transcription. COUP-TFI and TOB1 disrupt these complexes. Deletions and mutations of the Pomc promoter and a specific DNA-binding assay show that the complexes bind to the RARE site in the Pomc promoter. The enhanced inhibitory interaction between RA and BMP-4 pathways occurs also in another relevant corticotroph gene promoter, the corticotropin-releasing hormone receptor 1 (Crh-r1). The understanding of the molecules that participate in the control of corticotroph gene expression contribute to define more precise targets for the treatment of corticotrophinomas.

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“…Signs and symptoms of pituitary tumor pressure may include vision loss, headaches, and loss of peripheral vision in particular. Hormone dysregulation induced symptoms can include: menstrual changes; sexual dysfunction; elevated blood sugar or pressure; body weight changes; adipose distribution changes (accumulation at the midsection and upper back); thinning of the extremities; diuresis; weakness; nausea; vomiting; feeling cold; weakening of bones; cardiac problems; exaggerated facial features; depression, anxiety, or irritability (adrenocorticotropic hormone-secreting tumors); acne; misaligned teeth; increased body hair (growth hormone-secreting tumors); excess sweating; enlarged hands and feet; stretch marks; propensity to bruising; joint pain; and other symptoms [2].…”

Section: Introductionmentioning

confidence: 99%

Analysis of pituitary adenoma expression patterns suggests a potential role for the NeuroD1 transcription factor in neuroendocrine tumor-targeting therapies

2019

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NeuroD1’s roles in the pathogenesis of pituitary adenomas and in the biology of the normal adult pituitary gland have been insufficiently researched. Much of the work investigating its expression patterns has yielded contradictory results. Objective: morphological study of NeuroD1 transcription factor expression in different types of pituitary adenomas and in normal adult human pituitary glands. Materials and methods: This study analyzed 48 pituitary adenomas and nine normal pituitary glands. In all cases, immunohistochemical study was performed with antibodies to NeuroD1, 6 hormones of adenohypophysis, Ki-67, and CK7. We used confocal laser scanning microscopy, electron microscopy and electron immunocytochemistry. Results: NeuroD1 expression was detected in all cases of plurihormonal adenomas, mammosomatotropinomas, corticotropinomas, prolactinomas, gonadotropinomas, null-cell pituitary adenomas, and in normal pituitary glands. The average numbers of NeuroD1 expressing cells in normal adenohypophysis specimens were significantly lower than in the adenomas overall (p=0.006). NeuroD1 expression was confirmed by several methods (in prolactinomas, by double stain immunohistochemistry; in mammosomatotropinomas, by double stain immunohistochemistry, confocal laser scanning microscopy, and electron immunocytochemistry; and in somatotropinomas, by electron immunocytochemistry). Conclusion: Immunohistochemistry, confocal microscopy, and double label electron immunocytochemistry confirmed NeuroD1’s key role in the pathogenesis of pituitary tumors, regardless of their hormonal state. Its expression level in pituitary adenomas is significantly higher than in the normal pituitary gland and has no reliable correlation with any studied hormones or Ki-67. These findings suggest that NeuroD1 should be investigated further as a potential molecular target in tumor-targeting therapies.

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Advancing Treatment of Pituitary Adenomas through Targeted Molecular Therapies: The Acromegaly and Cushing Disease Paradigms

Cited by 6 publications

References 71 publications

Metabolomics Profiling of Pituitary Adenomas by Raman Spectroscopy, Attenuated Total Reflection-Fourier Transform Infrared Spectroscopy, and Mass Spectrometry of Serum Samples

Metabolomics Profiling of Pituitary Adenomas by Raman Spectroscopy, Attenuated Total Reflection-Fourier Transform Infrared Spectroscopy, and Mass Spectrometry of Serum Samples

Crosstalk of BMP-4 and RA signaling pathways on Pomc gene regulation in corticotrophs

Analysis of pituitary adenoma expression patterns suggests a potential role for the NeuroD1 transcription factor in neuroendocrine tumor-targeting therapies

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