Temozolomide Treatment for Aggressive Pituitary Tumors: Correlation of Clinical Outcome with O<sup>6</sup>-Methylguanine Methyltransferase (MGMT) Promoter Methylation and Expression

Bush, Zachary M.; Longtine, Janina A.; Cunningham, Tracy; Schiff, David; Jane, John A.; Vance, Mary Lee; Thorner, Michael O.; Laws, Edward R.; Lopes, M. Beatriz S.

doi:10.1210/jc.2010-0441

Cited by 146 publications

(164 citation statements)

References 39 publications

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“…The alkylating compound, temozolomide, recently demonstrated a significant response against aggressive pituitary adenomas and carcinomas (19,37,38). A recent relatively large cohort study (nZ24) (19) demonstrated that immunohistochemically low MGMT expression predicts a better response to temozolomide.…”

Section: Discussionmentioning

confidence: 99%

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The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease

Hayashi

Inoshita

Kawaguchi

et al. 2016

European Journal of Endocrinology

136

156

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Context: Somatic mutations in the ubiquitin-specific peptidase USP8 gene were recently detected in one-to two-third(s) of corticotroph adenomas of Cushing's disease (CD). These mutations may lead to the deubiquitination of EGFR, thereby increasing EGFR signaling, which has been implicated in ACTH hypersecretion. Objective: Our objective was to determine the impact of USP8 mutations on the clinicopathological features of CD. Subjects and methods: USP8 mutations as well as clinicopathological characteristics were examined in 60 corticotroph adenomas including 15 Crooke's cell adenomas (CCAs), a rare histological variant presenting with generally aggressive behavior, using qRT-PCR and/or immunohistochemistry. Results: USP8 mutations were exclusively detected in women, except for one case, with a prevalence of 42.2% in non-CCA and 13.3% in CCA (overall 35%). Clinically well-behaved presentations including microadenoma and curative resection were more common in mutated cases. The expression of EGFR was not associated with the mutation status. In contrast, mutated tumors expressed significantly higher levels of POMC, SSTR5, and MGMT. Conclusions: Microadenomas that strongly express POMC were common among mutated tumors, which may lead to the mechanisms by which very small adenomas secrete excess ACTH to present overt CD. While USP8 mutations were less likely to enhance tumorous ACTH hypersecretion via EGFR-mediated activation, the presence of USP8 mutations may predict favorable responses to the somatostatin analog pasireotide, which exhibits high affinity for SSTR5. In contrast, non-mutated aggressive tumors such as CCA may respond better to the alkylating agent temozolomide because of their significantly weak expression of MGMT.

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Section: Discussionmentioning

confidence: 99%

“…Several studies have argued that an immunohistochemical MGMT expression analysis is not clinically useful in predicting tumor responses to temozolomide therapy (20,37,38). One possible explanation of the controversy is the acquisition of temozolomide resistance due to the loss of MSH6 expression during temozolomide treatments (19,20,39).…”

Section: Discussionmentioning

confidence: 99%

The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease

Hayashi

Inoshita

Kawaguchi

et al. 2016

European Journal of Endocrinology

136

156

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“…More studies of temozolomide in NS treatment involving larger populations is needed. [18][19][20][21] …”

Section: Discussionmentioning

confidence: 99%

Tan Without the Sun: A Case of Nelson’s Syndrome

Darmawan

Pagsisihan

Andag-Silva

2012

JAFES

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“…Despite these encouraging results with temozolomide showing longterm control in 40% of patients (Bush et al 2010, Raverot et al 2010, some tumours develop secondary resistance during the follow-up (McCormack et al 2009, Raverot et al 2010. The development of new therapeutic options is particularly necessary for pituitary carcinomas resistant to temozolomide .…”

Section: :6mentioning

confidence: 99%

Molecular targeted therapies in adrenal, pituitary and parathyroid malignancies

Angelousi¹,

Dimitriadis²,

Zografos³

et al. 2017

Endocrine-Related Cancer

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Tumourigenesis is a relatively common event in endocrine tissues. Currently, specific guidelines have been developed for common malignant endocrine tumours, which also incorporate advances in molecular targeted therapies (MTT), as in thyroid cancer and in gastrointestinal neuroendocrine malignancies. However, there is little information regarding the role and efficacy of MTT in the relatively rare malignant endocrine tumours mainly involving the adrenal medulla, adrenal cortex, pituitary, and parathyroid glands. Due to the rarity of these tumours and the lack of prospective studies, current guidelines are mostly based on retrospective data derived from surgical, locoregional and ablative therapies, and studies with systemic chemotherapy. In addition, in many of these malignancies the prognosis remains poor with individual patients responding differently to currently available treatments, necessitating the development of new personalised therapeutic strategies. Recently, major advances in the molecular understanding of endocrine tumours based on genomic, epigenomic, and transcriptome analysis have emerged, resulting in new insights into their pathogenesis and molecular pathology. This in turn has led to the use of novel MTTs in increasing numbers of patients. In this review, we aim to present currently existing and evolving data using MTT in the treatment of adrenal, pituitary and malignant parathyroid tumours, and explore the current utility and effectiveness of such therapies and their future evolution.

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Temozolomide Treatment for Aggressive Pituitary Tumors: Correlation of Clinical Outcome with O⁶-Methylguanine Methyltransferase (MGMT) Promoter Methylation and Expression

Cited by 146 publications

References 39 publications

The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease

The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease

Tan Without the Sun: A Case of Nelson’s Syndrome

Molecular targeted therapies in adrenal, pituitary and parathyroid malignancies

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Temozolomide Treatment for Aggressive Pituitary Tumors: Correlation of Clinical Outcome with O6-Methylguanine Methyltransferase (MGMT) Promoter Methylation and Expression

Cited by 146 publications

References 39 publications

The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease

The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease

Tan Without the Sun: A Case of Nelson’s Syndrome

Molecular targeted therapies in adrenal, pituitary and parathyroid malignancies

Contact Info

Product

Resources

About

Temozolomide Treatment for Aggressive Pituitary Tumors: Correlation of Clinical Outcome with O⁶-Methylguanine Methyltransferase (MGMT) Promoter Methylation and Expression