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Exploring a glycolytic inhibitor for the treatment of an FH-deficient type-2 papillary RCC

Nature Reviews Urology volume 8, pages 165–171 (2011)Cite this article

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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.

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Figure 1: CT and 18FDG-PET/CT imaging throughout treatment.
Figure 2: Representative photomicrographs of tumor sections, showing fibrovascular papillae lined by stratified, large, pleomorphic cells with eosinophilic cytoplasm and large, prominent nucleoli.
Figure 3: FH gene sequencing and enzymatic activity analyses.
Figure 4: Characterization of the mutant FHAsp341Asn protein.
Figure 5: The effect of 2DG on the proliferation of UOK262 cells.
Figure 6: The effect of 2DG treatment on ECAR, OCR and ATP levels in UOK262 cells and two control cell lines: 786-O and the extensively characterized C2C12 myoblast cell line.
Figure 7: Western blot of UOK262 cells treated with 1 mM 2DG for the indicated periods of time in the presence of compound C (an AMPK inhibitor) or DMSO (vehicle).

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Acknowledgements

This manuscript is dedicated to the memory of the patient and to her family whose request it was that the findings be reported so that others may potentially benefit. pBabe–FH–flag was a gift from Dr. Sunil Sudarshan (University of Texas Health Science Center, San Antonio, TX) and UOK262 cells were a gift from Dr. Youfeng Yang and Dr. W. Marston Linehan (National Cancer Institute, Bethesda, MD). We are grateful to Dr. Samuel Peña-Llopis, Sharanya Sivanand and Jessica Gillen for tissue collection and processing, Dr. Virginia Langmuir and Stew Kroll at Threshold Pharmaceuticals for providing the drug and for advice, Capt. Frank H. Cross Jr at the FDA, the Simmons Cancer Center pharmacy and nursing staff, and the Brugarolas lab. T. A. T. Tran was supported by a T32CA124334 grant, and R. J. DeBerardinis was supported by NIH (DK072565) and CPRIT (HIRP100437) grants. This research was supported by the following grants to J. Brugarolas: Clinical Scientist Development Award from the Doris Duke Charitable Foundation (2007062), K08NS051843, RO1CA129387 and CPRIT (RP101075). J. Brugarolas is a Virginia Murchison Linthicum Scholar in Medical Research at UT Southwestern.

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Authors and Affiliations

  1. Department of Internal Medicine, Hematology–Oncology division, University of Texas Southwestern Medical Center, Dallas, 75390, TX, USA

    Toshinari Yamasaki, Tram Anh T. Tran & James Brugarolas

  2. Department of Radiology, University of Texas Southwestern Medical Center, Dallas, 75390, TX, USA

    Orhan K. Oz

  3. Department of Urology, University of Texas Southwestern Medical Center, Dallas, 75390, TX, USA

    Ganesh V. Raj

  4. Department of Surgery, University of Texas Southwestern Medical Center, Dallas, 75390, TX, USA

    Roderich E. Schwarz

  5. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, 75390, TX, USA

    Ralph J. DeBerardinis

  6. Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, 75390, TX, USA

    Xuewu Zhang

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Contributions

T. Yamasaki designed and carried out most experiments. T. A. T. Tran was responsible for the site-directed mutagenesis and the native gel electrophoresis. O. K. Oz evaluated the PET scans, X. Zhang performed the crystallographic analyses, and R. J. DeBerardinis was involved in discussions. G. V. Raj and R. E. Schwarz contributed to the care of the patient and were responsible for the initial and subsequent surgeries, respectively. J. Brugarolas was the patient's primary oncologist, directed the project, and wrote the manuscript. T. Yamasaki and all the authors reviewed and made suggestions to the manuscript.

Corresponding author

Correspondence to James Brugarolas.

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The authors declare no competing financial interests.

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Yamasaki, T., Tran, T., Oz, O. et al. Exploring a glycolytic inhibitor for the treatment of an FH-deficient type-2 papillary RCC. Nat Rev Urol 8, 165–171 (2011). https://doi.org/10.1038/nrurol.2010.234

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