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.

antagonist ͉ cancer ͉ Gli ͉ medulloblastoma

We have functionally expressed the human cDNA encoding the putative lysophosphatidic acid (LPA) receptor Edg-2 (Vzg-1) in Saccharomyces cerevisiae in an attempt to determine the agonist specificity of this G-protein-coupled receptor. LPA activated the pheromone response pathway in S. cerevisiae expressing Edg-2 in a time-and dose-dependent manner as determined by induction of a pheromone-responsive FUS1::lacZ reporter gene. LPA-mediated activation of the pheromone response pathway was dependent on mutational inactivation of the SST2 gene, the GTPaseactivating protein for the yeast G ␣ protein (the GPA1 gene product). This indicates that, in sst2⌬ yeast cells, Edg-2 can efficiently couple to the yeast heterotrimeric G-protein in response to LPA and activate the yeast mitogen-activated protein kinase pathway. The Edg-2 receptor showed a high degree of specificity for LPA; other lyso-glycerophospholipids, sphingosine 1-phosphate, and diacyl-glycerophospholipids did not activate FUS1::lacZ. LPA analogs including a cyclic phosphoester form and ether-linked forms of LPA activated FUS1::lacZ, although fatty acid chains of 6 and 10 carbons did not activate FUS1::lacZ, suggesting a role for the side chain in ligand binding or receptor activation. These results indicate that Edg-2 encodes a highly specific LPA receptor.The lysophospholipid lysophosphatidic acid (LPA, 1 1-acyl-snglycero-3-phosphate) has been shown to be an important extracellular signaling molecule in a variety of systems (1). LPA has been shown to induce mitogenesis in certain cell types, exert an anti-mitogenic effect in other cells types, activate platelets, activate MAP kinase, stimulate ion transport, block apoptosis, and induce morphological changes (Refs. 2-14; for a recent review on these functions, see Refs. 1 and 15). Recently, two putative receptors for LPA have been identified, suggesting that functionally different LPA receptors may exist that dictate the particular cellular response of LPA (16 -19). Most cell types respond to LPA, making it difficult to characterize the receptor dependence of a particular response to LPA since the response cannot be solely attributed to a single LPA receptor. In particular, it is difficult to assess ligand binding specificity of an LPA receptor because other lipid receptors may exist with overlapping ligand specificity. We have therefore used the yeast Saccharomyces cerevisiae to study the human LPA receptor Edg-2 (also called Vzg-1). S. cerevisiae contains no endogenous LPA receptors and is therefore a potentially useful organism in which to functionally express LPA receptors and analyze their ligand specificity. Other mammalian receptors have been functionally expressed in S. cerevisiae including the somatostatin receptor, the A 2a adenosine receptor and the ␤ 2 -adrenergic receptor (20 -22).S. cerevisiae contains a heterotrimeric G-protein that is activated by mating factor binding to a specific receptor (23) (for review, see Ref. 24). Upon stimulation by an occupied receptor, the ␣ subunit of the heterotr...

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