24 Citations (Scopus)

Abstract

Background. A 24-year-old woman presented with a 45 cm complex cystic renal mass, which was resected. The tumor was a type-2 papillary renal cell carcinoma (pRCC-2), and several nodules remained. The patient was treated with mammalian target of rapamycin complex 1 (mTORC1) inhibitors, but after 5 months the tumor had progressed. Genetic testing of the patient revealed a novel heterozygous germline mutation in the gene encoding fumarate hydratase (FH), an enzyme of the tricarboxylic acid (TCA) cycle. As the tumor exhibited loss of heterozygosity for FH and markedly reduced FH activity, and in the absence of other established therapies, treatment with the glycolytic inhibitor 2DG (2-deoxy-D-glucose) was explored. Investigations. CT, histology, immunohistochemistry, genetic studies, 2-deoxy-2-( 18F)fluoro-D-glucose ( 18FDG)-PET/CT, FH enzymatic assays, reconstitution experiments and in vitro studies of the effects of 2DG on FH-deficient tumor cells. Diagnosis. pRCC-2 arising in a patient with a novel germline FH mutation and de novo hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome progressing after mTORC1 inhibitor therapy. Management. Surgical resection of the renal mass, treatment with mTORC1 inhibitors followed by 2DG. Unfortunately, 2DG was not effective, and the patient died several weeks later.

Original languageEnglish (US)
Pages (from-to)165-171
Number of pages7
JournalNature Reviews Urology
Volume8
Issue number3
DOIs
StatePublished - Apr 2011

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Fumarate Hydratase
Deoxyglucose
Neoplasms
Therapeutics
Kidney
Citric Acid Cycle
Germ-Line Mutation
Loss of Heterozygosity
Fluorodeoxyglucose F18
Enzyme Assays
Genetic Testing
Renal Cell Carcinoma
Histology
Immunohistochemistry
Mutation
Enzymes
Genes

ASJC Scopus subject areas

  • Urology

Cite this

Exploring a glycolytic inhibitor for the treatment of an FH-deficient type-2 papillary RCC. / Yamasaki, Toshinari; Tran, Tram Anh T; Oz, Orhan K.; Raj, Ganesh V.; Schwarz, Roderich E.; DeBerardinis, Ralph J.; Zhang, Xuewu; Brugarolas, James.

In: Nature Reviews Urology, Vol. 8, No. 3, 04.2011, p. 165-171.

Research output: Contribution to journalArticle

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abstract = "Background. A 24-year-old woman presented with a 45 cm complex cystic renal mass, which was resected. The tumor was a type-2 papillary renal cell carcinoma (pRCC-2), and several nodules remained. The patient was treated with mammalian target of rapamycin complex 1 (mTORC1) inhibitors, but after 5 months the tumor had progressed. Genetic testing of the patient revealed a novel heterozygous germline mutation in the gene encoding fumarate hydratase (FH), an enzyme of the tricarboxylic acid (TCA) cycle. As the tumor exhibited loss of heterozygosity for FH and markedly reduced FH activity, and in the absence of other established therapies, treatment with the glycolytic inhibitor 2DG (2-deoxy-D-glucose) was explored. Investigations. CT, histology, immunohistochemistry, genetic studies, 2-deoxy-2-( 18F)fluoro-D-glucose ( 18FDG)-PET/CT, FH enzymatic assays, reconstitution experiments and in vitro studies of the effects of 2DG on FH-deficient tumor cells. Diagnosis. pRCC-2 arising in a patient with a novel germline FH mutation and de novo hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome progressing after mTORC1 inhibitor therapy. Management. Surgical resection of the renal mass, treatment with mTORC1 inhibitors followed by 2DG. Unfortunately, 2DG was not effective, and the patient died several weeks later.",
author = "Toshinari Yamasaki and Tran, {Tram Anh T} and Oz, {Orhan K.} and Raj, {Ganesh V.} and Schwarz, {Roderich E.} and DeBerardinis, {Ralph J.} and Xuewu Zhang and James Brugarolas",
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AU - Tran, Tram Anh T

AU - Oz, Orhan K.

AU - Raj, Ganesh V.

AU - Schwarz, Roderich E.

AU - DeBerardinis, Ralph J.

AU - Zhang, Xuewu

AU - Brugarolas, James

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N2 - Background. A 24-year-old woman presented with a 45 cm complex cystic renal mass, which was resected. The tumor was a type-2 papillary renal cell carcinoma (pRCC-2), and several nodules remained. The patient was treated with mammalian target of rapamycin complex 1 (mTORC1) inhibitors, but after 5 months the tumor had progressed. Genetic testing of the patient revealed a novel heterozygous germline mutation in the gene encoding fumarate hydratase (FH), an enzyme of the tricarboxylic acid (TCA) cycle. As the tumor exhibited loss of heterozygosity for FH and markedly reduced FH activity, and in the absence of other established therapies, treatment with the glycolytic inhibitor 2DG (2-deoxy-D-glucose) was explored. Investigations. CT, histology, immunohistochemistry, genetic studies, 2-deoxy-2-( 18F)fluoro-D-glucose ( 18FDG)-PET/CT, FH enzymatic assays, reconstitution experiments and in vitro studies of the effects of 2DG on FH-deficient tumor cells. Diagnosis. pRCC-2 arising in a patient with a novel germline FH mutation and de novo hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome progressing after mTORC1 inhibitor therapy. Management. Surgical resection of the renal mass, treatment with mTORC1 inhibitors followed by 2DG. Unfortunately, 2DG was not effective, and the patient died several weeks later.

AB - Background. A 24-year-old woman presented with a 45 cm complex cystic renal mass, which was resected. The tumor was a type-2 papillary renal cell carcinoma (pRCC-2), and several nodules remained. The patient was treated with mammalian target of rapamycin complex 1 (mTORC1) inhibitors, but after 5 months the tumor had progressed. Genetic testing of the patient revealed a novel heterozygous germline mutation in the gene encoding fumarate hydratase (FH), an enzyme of the tricarboxylic acid (TCA) cycle. As the tumor exhibited loss of heterozygosity for FH and markedly reduced FH activity, and in the absence of other established therapies, treatment with the glycolytic inhibitor 2DG (2-deoxy-D-glucose) was explored. Investigations. CT, histology, immunohistochemistry, genetic studies, 2-deoxy-2-( 18F)fluoro-D-glucose ( 18FDG)-PET/CT, FH enzymatic assays, reconstitution experiments and in vitro studies of the effects of 2DG on FH-deficient tumor cells. Diagnosis. pRCC-2 arising in a patient with a novel germline FH mutation and de novo hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome progressing after mTORC1 inhibitor therapy. Management. Surgical resection of the renal mass, treatment with mTORC1 inhibitors followed by 2DG. Unfortunately, 2DG was not effective, and the patient died several weeks later.

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