title: Exploring a glycolytic inhibitor for the treatment of an FH-deficient type-2 papillary RCC.
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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
authors.affiliation: Department of Internal Medicine, Hematology-Oncology Division, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Toshinari
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Tram Anh T
authors.initials: TA
authors.lastname: Tran
authors.forename: Orhan K
authors.initials: OK
authors.lastname: Oz
authors.forename: Ganesh V
authors.initials: GV
authors.lastname: Raj
authors.forename: Roderich E
authors.initials: RE
authors.lastname: Schwarz
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: Deberardinis
authors.forename: Xuewu
authors.initials: X
authors.lastname: Zhang
authors.forename: James
authors.initials: J
authors.lastname: Brugarolas
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002291:Carcinoma, Papillary / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D005649:Fumarate Hydratase / Q000172:deficiency* / Q000235:genetics; D006019:Glycolysis / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D046912:Multiprotein Complexes; D011506:Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D005649:Fumarate Hydratase