Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality

Denise A. Chan, Patrick D. Sutphin, Phuong Nguyen, Sandra Turcotte, Edwin W. Lai, Alice Banh, Gloria E. Reynolds, Jen Tsan Chi, Jason Wu, David E. Solow-Cordero, Muriel Bonnet, Jack U. Flanagan, Donna M. Bouley, Edward E. Graves, William A. Denny, Michael P. Hay, Amato J. Giaccia

Research output: Contribution to journalArticle

233 Citations (Scopus)

Abstract

Identifying new targeted therapies that kill tumor cells while sparing normal tissue is a major challenge of cancer research. Using a high-throughput chemical synthetic lethal screen, we sought to identify compounds that exploit the loss of the von Hippel-Lindau (VHL) tumor suppressor gene, which occurs in about 80% of renal cell carcinomas (RCCs). RCCs, like many other cancers, are dependent on aerobic glycolysis for ATP production, a phenomenon known as the Warburg effect. The dependence of RCCs on glycolysis is in part a result of induction of glucose transporter 1 (GLUT1). Here, we report the identification of a class of compounds, the 3-series, exemplified by STF-31, which selectively kills RCCs by specifically targeting glucose uptake through GLUT1 and exploiting the unique dependence of these cells on GLUT1 for survival. Treatment with these agents inhibits the growth of RCCs by binding GLUT1 directly and impeding glucose uptake in vivo without toxicity to normal tissue. Activity of STF-31 in these experimental renal tumors can be monitored by [18F] fluorodeoxyglucose uptake by micro-positron emission tomography imaging, and therefore, these agents may be readily tested clinically in human tumors. Our results show that the Warburg effect confers distinct characteristics on tumor cells that can be selectively targeted for therapy.

Original languageEnglish (US)
Article number94ra70
JournalScience Translational Medicine
Volume3
Issue number94
DOIs
StatePublished - Aug 3 2011

Fingerprint

Facilitative Glucose Transport Proteins
Renal Cell Carcinoma
Neoplasms
Glycolysis
Glucose
Fluorodeoxyglucose F18
Tumor Suppressor Genes
Positron-Emission Tomography
Synthetic Lethal Mutations
Adenosine Triphosphate
Kidney
Survival
Therapeutics
Growth
Research

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Chan, D. A., Sutphin, P. D., Nguyen, P., Turcotte, S., Lai, E. W., Banh, A., ... Giaccia, A. J. (2011). Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Science Translational Medicine, 3(94), [94ra70]. https://doi.org/10.1126/scitranslmed.3002394

Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. / Chan, Denise A.; Sutphin, Patrick D.; Nguyen, Phuong; Turcotte, Sandra; Lai, Edwin W.; Banh, Alice; Reynolds, Gloria E.; Chi, Jen Tsan; Wu, Jason; Solow-Cordero, David E.; Bonnet, Muriel; Flanagan, Jack U.; Bouley, Donna M.; Graves, Edward E.; Denny, William A.; Hay, Michael P.; Giaccia, Amato J.

In: Science Translational Medicine, Vol. 3, No. 94, 94ra70, 03.08.2011.

Research output: Contribution to journalArticle

Chan, DA, Sutphin, PD, Nguyen, P, Turcotte, S, Lai, EW, Banh, A, Reynolds, GE, Chi, JT, Wu, J, Solow-Cordero, DE, Bonnet, M, Flanagan, JU, Bouley, DM, Graves, EE, Denny, WA, Hay, MP & Giaccia, AJ 2011, 'Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality', Science Translational Medicine, vol. 3, no. 94, 94ra70. https://doi.org/10.1126/scitranslmed.3002394
Chan, Denise A. ; Sutphin, Patrick D. ; Nguyen, Phuong ; Turcotte, Sandra ; Lai, Edwin W. ; Banh, Alice ; Reynolds, Gloria E. ; Chi, Jen Tsan ; Wu, Jason ; Solow-Cordero, David E. ; Bonnet, Muriel ; Flanagan, Jack U. ; Bouley, Donna M. ; Graves, Edward E. ; Denny, William A. ; Hay, Michael P. ; Giaccia, Amato J. / Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. In: Science Translational Medicine. 2011 ; Vol. 3, No. 94.
@article{630a21b1c1b641d9976687d395ddd413,
title = "Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality",
abstract = "Identifying new targeted therapies that kill tumor cells while sparing normal tissue is a major challenge of cancer research. Using a high-throughput chemical synthetic lethal screen, we sought to identify compounds that exploit the loss of the von Hippel-Lindau (VHL) tumor suppressor gene, which occurs in about 80{\%} of renal cell carcinomas (RCCs). RCCs, like many other cancers, are dependent on aerobic glycolysis for ATP production, a phenomenon known as the Warburg effect. The dependence of RCCs on glycolysis is in part a result of induction of glucose transporter 1 (GLUT1). Here, we report the identification of a class of compounds, the 3-series, exemplified by STF-31, which selectively kills RCCs by specifically targeting glucose uptake through GLUT1 and exploiting the unique dependence of these cells on GLUT1 for survival. Treatment with these agents inhibits the growth of RCCs by binding GLUT1 directly and impeding glucose uptake in vivo without toxicity to normal tissue. Activity of STF-31 in these experimental renal tumors can be monitored by [18F] fluorodeoxyglucose uptake by micro-positron emission tomography imaging, and therefore, these agents may be readily tested clinically in human tumors. Our results show that the Warburg effect confers distinct characteristics on tumor cells that can be selectively targeted for therapy.",
author = "Chan, {Denise A.} and Sutphin, {Patrick D.} and Phuong Nguyen and Sandra Turcotte and Lai, {Edwin W.} and Alice Banh and Reynolds, {Gloria E.} and Chi, {Jen Tsan} and Jason Wu and Solow-Cordero, {David E.} and Muriel Bonnet and Flanagan, {Jack U.} and Bouley, {Donna M.} and Graves, {Edward E.} and Denny, {William A.} and Hay, {Michael P.} and Giaccia, {Amato J.}",
year = "2011",
month = "8",
day = "3",
doi = "10.1126/scitranslmed.3002394",
language = "English (US)",
volume = "3",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "94",

}

TY - JOUR

T1 - Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality

AU - Chan, Denise A.

AU - Sutphin, Patrick D.

AU - Nguyen, Phuong

AU - Turcotte, Sandra

AU - Lai, Edwin W.

AU - Banh, Alice

AU - Reynolds, Gloria E.

AU - Chi, Jen Tsan

AU - Wu, Jason

AU - Solow-Cordero, David E.

AU - Bonnet, Muriel

AU - Flanagan, Jack U.

AU - Bouley, Donna M.

AU - Graves, Edward E.

AU - Denny, William A.

AU - Hay, Michael P.

AU - Giaccia, Amato J.

PY - 2011/8/3

Y1 - 2011/8/3

N2 - Identifying new targeted therapies that kill tumor cells while sparing normal tissue is a major challenge of cancer research. Using a high-throughput chemical synthetic lethal screen, we sought to identify compounds that exploit the loss of the von Hippel-Lindau (VHL) tumor suppressor gene, which occurs in about 80% of renal cell carcinomas (RCCs). RCCs, like many other cancers, are dependent on aerobic glycolysis for ATP production, a phenomenon known as the Warburg effect. The dependence of RCCs on glycolysis is in part a result of induction of glucose transporter 1 (GLUT1). Here, we report the identification of a class of compounds, the 3-series, exemplified by STF-31, which selectively kills RCCs by specifically targeting glucose uptake through GLUT1 and exploiting the unique dependence of these cells on GLUT1 for survival. Treatment with these agents inhibits the growth of RCCs by binding GLUT1 directly and impeding glucose uptake in vivo without toxicity to normal tissue. Activity of STF-31 in these experimental renal tumors can be monitored by [18F] fluorodeoxyglucose uptake by micro-positron emission tomography imaging, and therefore, these agents may be readily tested clinically in human tumors. Our results show that the Warburg effect confers distinct characteristics on tumor cells that can be selectively targeted for therapy.

AB - Identifying new targeted therapies that kill tumor cells while sparing normal tissue is a major challenge of cancer research. Using a high-throughput chemical synthetic lethal screen, we sought to identify compounds that exploit the loss of the von Hippel-Lindau (VHL) tumor suppressor gene, which occurs in about 80% of renal cell carcinomas (RCCs). RCCs, like many other cancers, are dependent on aerobic glycolysis for ATP production, a phenomenon known as the Warburg effect. The dependence of RCCs on glycolysis is in part a result of induction of glucose transporter 1 (GLUT1). Here, we report the identification of a class of compounds, the 3-series, exemplified by STF-31, which selectively kills RCCs by specifically targeting glucose uptake through GLUT1 and exploiting the unique dependence of these cells on GLUT1 for survival. Treatment with these agents inhibits the growth of RCCs by binding GLUT1 directly and impeding glucose uptake in vivo without toxicity to normal tissue. Activity of STF-31 in these experimental renal tumors can be monitored by [18F] fluorodeoxyglucose uptake by micro-positron emission tomography imaging, and therefore, these agents may be readily tested clinically in human tumors. Our results show that the Warburg effect confers distinct characteristics on tumor cells that can be selectively targeted for therapy.

UR - http://www.scopus.com/inward/record.url?scp=79961215490&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79961215490&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.3002394

DO - 10.1126/scitranslmed.3002394

M3 - Article

C2 - 21813754

AN - SCOPUS:79961215490

VL - 3

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 94

M1 - 94ra70

ER -