Preclinical Targeting of the Type I Insulin-Like Growth Factor Receptor in Adrenocortical Carcinoma

Barlaskar, Ferdous; Spalding, Aaron C.; Heaton, Joanne H.; Kuick, Rork; Kim, Alex C.; Thomas, Dafydd G.; Giordano, Thomas J.; Ben‐Josef, Edgar; Hammer, Gary D.

doi:10.1210/jc.2008-1456

Cited by 168 publications

(167 citation statements)

References 29 publications

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“…For example, while Ciresi et al reported that patients with poorly controlled acromegaly show an increased volume of all adrenal segments (13), Scaroni et al and Pappa et al conversely found no significant associations between adrenal alterations and the activity of acromegaly (8,14). Although an increased protein level of IGF-1 receptor has been reported in patients with adrenocortical cancer (15), no such phenomena have been observed in cases of adrenocortical adenoma (16,17). In the present case, slight growth of the adrenal tumor was identified when retrospectively compared with the results of an abdominal CT scan performed two years before the first consultation at our hospital to screen for breast cancer metastasis.…”

Section: Discussionmentioning

confidence: 99%

Poorly-controlled Acromegaly Accompanied by Subclinical Adrenal Cushing's Syndrome after Surgery for Multiple Endocrine Tumors

et al. 2015

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A 48-year-old woman diagnosed with acromegaly 21 years earlier presented at our hospital with a left adrenal tumor. Her medical history included breast cancer, thyroid cancer and an incompletely resected growth hormone (GH)-producing pituitary adenoma. Endocrinological and radiological examinations revealed subclinical adrenal Cushing's syndrome. She subsequently underwent left adrenalectomy, followed by glucocorticoid replacement therapy. Her GH and insulin-like growth factor-1 levels were insufficiently controlled, and pegvisomant was administered in addition to octreotide acetate. Following adrenalectomy, a giant hepatic hemangioma and papillary thyroid carcinoma in the residual right lobe developed, indicating the high risk of tumor development in patients with acromegaly.

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Section: Discussionmentioning

confidence: 99%

Poorly-controlled Acromegaly Accompanied by Subclinical Adrenal Cushing's Syndrome after Surgery for Multiple Endocrine Tumors

et al. 2015

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“…Studies have demonstrated that antagonizing the IGF signaling pathway with pharmacological agents results in the inhibition of in vitro and in vivo tumor cell growth. This raises the prospect of using target disruption of the IGF1R signaling pathway as a therapeutic agent since this targeted inhibition was apparently more potent than the use of mitotane in xenograft growth (10,15).…”

Section: Discussionmentioning

confidence: 99%

Clinical and molecular aspects of a pediatric metachronous adrenocortical tumor

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et al. 2011

Arq Bras Endocrinol Metab

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SUMMARYThe occurrence of metachronous adrenocortical carcinoma has rarely been described. We report a case of a child with virilizing adrenocortical metachronous tumors that, despite several metastases, presented long-term survival (15 years). We analyzed in this tumor IGF2, IGF1R and FGFR4 gene expression, and evaluated the presence of p.R337H germline p53 mutation and somatic CTNNB1 mutation. IGF2 gene was over-expressed in both left (Weiss score 5) and right (Weiss 7) adrenocortical tumors. IGF1R expression levels were higher in the right adrenocortical tumor. FGFR4 over-expression was also detected in the right adrenocortical tumor. In addition, this patient harbors the germline p.R337H p53 mutation and loss of heterozygosity (LOH) was detected in the tumors. No somatic CTNNB1 mutations were found in both tumors.In conclusion, we demonstrated in this unusual case the over-expression of growth signaling pathways, which are molecular mechanisms previously related to adrenocortical tumorigenesis. Furthermore, the absence of somatic CTNNB1 mutations, which is a molecular marker of poor prognosis in adults, might be related to the long-term survival of this patient. Arq Bras Endocrinol Metab. 2011;55(1):72-7 SUMÁRIO A ocorrência de carcinomas adrenocorticais metacrônicos é raramente relatada. Descrevemos o caso de uma criança portadora de tumor adrenocortical virilizante metacrônico que, apesar das inúmeras metástases, apresentou uma longa sobrevida (15 anos). Analisamos nesse tumor a expressão gênica de IGF2, IGF1R e FGFR4 e avaliamos a presença da mutação germinativa R337H no p53 e mutação somática no gene CTNNB1. O gene IGF2 foi hiperexpresso nos tumores adrenocorticais esquerdo (Weiss 5) e direito (Weiss 7). Os níveis de expressão de IGF1R foram maiores no tumor direito. Hiperexpressão do gene FGFR4 também foi observada no tumor adrenocortical direito. Esse paciente é portador da mutação germinativa R337H no p53, e perda de heterozigose (LOH) foi observada em ambos os tumores. Não foram encontradas mutações no gene CTNNB1 nos tumores. Em conclusão, demonstramos neste caso a hiperexpressão de vias moleculares de crescimento, que são mecanismos previamente relacionados à tumorigê-nese adrenocortical. Além disso, não encontramos mutações somáticas no gene CTNNB1, que é um marcador molecular de mau prognóstico em adultos e poderia estar relacionado à longa sobrevida desse paciente. Arq Bras Endocrinol Metab. 2011;55(1):72-7

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“…Nevertheless, several investigators have initiated preclinical studies with pharmacological agents targeted to the IGF2 pathway, aimed at developing new treatments of ACC. This approach has already produced promising results showing that IGF1R antagonists induce a significant inhibition of growth in ACC cell lines (210).…”

Section: Factorsmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Autocrine/paracrine regulatory mechanisms in adrenocortical neoplasms responsible for primary adrenal hypercorticism

Lefebvre

Prévost

Louiset

2013

European Journal of Endocrinology

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A wide variety of autocrine/paracrine bioactive signals are able to modulate corticosteroid secretion in the human adrenal gland. These regulatory factors, released in the vicinity of adrenocortical cells by diverse cell types comprising chromaffin cells, nerve terminals, cells of the immune system, endothelial cells, and adipocytes, include neuropeptides, biogenic amines, and cytokines. A growing body of evidence now suggests that paracrine mechanisms may also play an important role in the physiopathology of adrenocortical hyperplasias and tumors responsible for primary adrenal steroid excess. These intra-adrenal regulatory systems, although globally involving the same actors as those observed in the normal gland, display alterations at different levels, which reinforce the capacity of paracrine factors to stimulate the activity of adrenocortical cells. The main modifications in the adrenal local control systems reported by now include hyperplasia of cells producing the paracrine factors and abnormal expression of the latter and their receptors. Because steroid-secreting adrenal neoplasms are independent of the classical endocrine regulatory factors angiotensin II and ACTH, which are respectively suppressed by hyperaldosteronism and hypercortisolism, these lesions have long been considered as autonomous tissues. However, the presence of stimulatory substances within the neoplastic tissues suggests that steroid hypersecretion is driven by autocrine/paracrine loops that should be regarded as promising targets for pharmacological treatments of primary adrenal disorders. This new potential therapeutic approach may constitute an alternative to surgical removal of the lesions that is classically recommended in order to cure steroid excess.European Journal of Endocrinology 169 R115-R138

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Preclinical Targeting of the Type I Insulin-Like Growth Factor Receptor in Adrenocortical Carcinoma

Abstract: These findings establish a critical role of IGF signaling in ACC pathophysiology and provide rationale for use of targeted IGF-1R antagonists to treat adrenocortical carcinoma in future clinical trials.

Cited by 168 publications

References 29 publications

Poorly-controlled Acromegaly Accompanied by Subclinical Adrenal Cushing's Syndrome after Surgery for Multiple Endocrine Tumors

Poorly-controlled Acromegaly Accompanied by Subclinical Adrenal Cushing's Syndrome after Surgery for Multiple Endocrine Tumors

Clinical and molecular aspects of a pediatric metachronous adrenocortical tumor

MECHANISMS IN ENDOCRINOLOGY: Autocrine/paracrine regulatory mechanisms in adrenocortical neoplasms responsible for primary adrenal hypercorticism

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