Emerging therapy for adrenocortical carcinoma.
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ABSTRACT:
SUBMITTER: Aufforth RD
PROVIDER: S-EPMC4307842 | biostudies-literature | 2014
REPOSITORIES: biostudies-literature
Publications
Emerging therapy for adrenocortical carcinoma.
Aufforth Rachel D RD Nilubol Naris N
International journal of endocrine oncology 20140101 2
Adrenocortical carcinoma (ACC) is a very rare and aggressive tumor with dismal outcomes. Best current treatments include complete surgical resection for localized resectable disease and systemic therapy with mitotane alone or in combination for advanced ACC. Advances in molecular genetic profiling of ACC have created multiple new targets for potential treatment options in ACC. This article reviews the current treatment options available for ACC and discusses the potential new targets identified ...[more]
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Project description:Adrenocortical carcinoma (ACC) is a very rare endocrine tumour, with variable prognosis, depending on tumour stage and time of diagnosis. The overall survival is five years from detection. Radical surgery is considered the therapy of choice in the first stages of ACC. However postoperative disease-free survival at 5 years is only around 30% and recurrence rates are frequent. o,p'DDD (ortho-, para'-, dichloro-, diphenyl-, dichloroethane, or mitotane), an adrenolytic drug with significant toxicity and unpredictable therapeutic response, is used in the treatment of ACC. Unfortunately, treatment for this aggressive cancer is still ineffective. Over the past years, the growing interest in ACC has contributed to the development of therapeutic strategies in order to contrast the neoplastic spread. In this paper we discuss the most promising therapies which can be used in this endocrine neoplasia.
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Project description:PurposeClinical outcomes of adrenocortical carcinomas (ACC) could be improved by using novel treatment targets based on the recent advances of tumor biology knowledge. Insulin-like growth factor 2 (IGF2) protein expression is usually 8-80 fold higher in ACC when compared to normal adrenal glands (N-AG) or adrenocortical adenomas (ACA), despite the fact that the biological features of high vs. low IGF2 expressing ACC have not yet been well characterized. Our goal was to understand the IGF2 role in ACC biology by focusing in several cancer hallmarks, including cell proliferation, viability, invasion, and metabolism.MethodsIGF2 immunohistochemistry expression was evaluated in ACC (n = 13), non-functioning adrenocortical adenoma (ACAn) (n = 14), and N-AG (n = 9). The effects of IGF2 (50, 100 ng/mL) in cell proliferation, viability, invasion, and metabolism, as well as in MAPK/ERK and mTOR pathways activation and N-cadherin expression, were evaluated in the ACC human cell line H295R.ResultsIGF2 expression was increased in ACC compared to ACAn and N-AG. Exposure to 100 ng/mL of IGF2 increased H295R cell proliferation and viability. mTOR inhibition reverted IGF2 triggered cell proliferation and viability while MEK/MAPK/ERK inhibition only reverted IGF2 effects on cell proliferation. IGF2 at a 50 ng/mL concentration increased the glycolytic flux and decreased glutamine consumption.ConclusionsIGF2 is an excellent marker to differentiate ACC from ACAn. In addition, IGF2 was demonstrated to influence adrenocortical cancer cell proliferation, metabolism, and viability, but not the cell invasion. These data support that different IGF2 concentrations in ACC can be responsible for different biological behaviors of ACC.
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Project description:BackgroundIn a recently published retrospective case series, Temozolomide was found active as second line approach in advanced ACC patients. The disease control rate obtained, however, was short-lived. We report here an ACC patient with extensive metastatic disease who obtained a remarkable long lasting response with this alkylating agent.Case presentationa 22-year-old female patient with ACC presented at our Medical Oncology Department in poor general condition due the presence of extensive metastatic pulmonary involvement. The disease had progressed to etoposide, doxorubicin and cisplatin plus mitotane therapy. Second line temozolomide therapy was prescribed leading to a progressive improvement of patient general conditions. The disease restaging after 12 cycles revealed a complete response of lung lesions and the patient was free from progression for 14+ months.ConclusionTemozolomide therapy could be exceptionally efficacious in the management of ACC patients. The molecular mechanisms of sensitivity and resistance to this drug should be carefully studied, in order to select the patients destined to obtain a significant clinical benefit to the drug.
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