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Efficacy of oral metformin in a patient with metastatic adrenocortical carcinoma: Examination of mechanisms and therapeutic implications.

ABSTRACT: Although rare, adrenocortical carcinoma is among the most common tumors found in children with Li-Fraumeni syndrome and Li-Fraumeni-like syndrome, associated with germ-line mutations in the TP53 gene. In southern Brazil, one form of Li-Fraumeni syndrome, associated with childhood adrenocortical carcinoma, is caused by a mutation in the R337H TP53 tetramerisation domain and is attributed to a familial founder effect. Adrenocortical carcinoma is considered an aggressive neoplasm, usually of poor prognosis and is generally unresponsive to systemic chemotherapy. Optimal treatment regimens remain to be established. We report the case of a young woman with metastatic adrenocortical carcinoma, who achieved stable disease with mitotane, cisplatin, doxorubicin, and etoposide as first-line therapy, but then had an objective response to oral metformin that lasted 9?months. The presence of the R337H TP53 mutation suggests a mechanism for the observed response to metformin.

SUBMITTER: Peixoto RD

PROVIDER: S-EPMC5811989 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Efficacy of oral metformin in a patient with metastatic adrenocortical carcinoma: Examination of mechanisms and therapeutic implications.

Peixoto R D RD Gomes L M LM Sousa T T TT Racy D J DJ Shigenaga M M Nagourney R A RA

Rare tumors 20180131

Although rare, adrenocortical carcinoma is among the most common tumors found in children with Li-Fraumeni syndrome and Li-Fraumeni-like syndrome, associated with germ-line mutations in the TP53 gene. In southern Brazil, one form of Li-Fraumeni syndrome, associated with childhood adrenocortical carcinoma, is caused by a mutation in the R337H TP53 tetramerisation domain and is attributed to a familial founder effect. Adrenocortical carcinoma is considered an aggressive neoplasm, usually of poor p ...[more]

PMID: 31508193

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Project description:BackgroundRenal medullary carcinoma (RMC) is a rare but aggressive tumor often complicated by early lung metastasis with few treatment options and very poor outcomes. There are currently no verified RMC patient-derived xenograft (PDX) mouse models established from metastatic pleural effusion (PE) available to study RMC and evaluate new therapeutic options.MethodsRenal tumor tissue and malignant PE cells from an RMC patient were successfully engrafted into 20 NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice. We evaluated the histopathological similarity of the renal tumor and PE PDXs with the original patient renal tumor and PE, respectively. We then evaluated the molecular integrity of the renal tumor PDXs between passages, as well as the PE PDX compared to two generations of renal tumor PDXs, by microarray analysis. The therapeutic efficacy of sunitinib and temsirolimus was tested in a serially-transplanted generation of 27 PE PDX mice.ResultsThe pathologic characteristics of the patient renal tumor and patient PE were retained in the PDXs. Gene expression profiling revealed high concordance between the two generations of renal tumor PDXs (RMC-P0 vs. RMC-P1, r=0.865), as well as between the first generation PE PDX and each generation of the renal tumor PDX (PE-P0 vs. RMC-P0, r=0.919 and PE-P0 vs. RMC-P1, r=0.843). A low number (626) of differentially-expressed genes (DEGs) was seen between the first generation PE PDX and the first generation renal tumor PDX. In the PE-P1 xenograft, sunitinib significantly reduced tumor growth (p<0.001) and prolonged survival (p=0.004) compared to the vehicle control.ConclusionsA metastatic PE-derived RMC PDX model was established and shown to maintain histologic features of the patient cancer. Molecular integrity of the PDX models was well maintained between renal tumor and PE PDX as well as between two successive renal tumor PDX generations. Using the PE PDX model, sunitinib demonstrated therapeutic efficacy for RMC. This model can serve as a foundation for future mechanistic and therapeutic studies for primary and metastatic RMC.

Dataset Information

Efficacy of oral metformin in a patient with metastatic adrenocortical carcinoma: Examination of mechanisms and therapeutic implications.

Publications

Efficacy of oral metformin in a patient with metastatic adrenocortical carcinoma: Examination of mechanisms and therapeutic implications.

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