Candidate Drug Starves Cancer Cells of Energy Source

Amato Giaccia (Stanford University)

Researchers from the U.S., Canada, and New Zealand have identified a compound that deprives some cancer cells of their energy source, the sugar glucose. The compound is packaged in a drug candidate licensed for pre-clinical testing to a company founded by one of the study’s senior authors. The findings appear in the 3 August issue of the journal Science Translational Medicine (paid subscription required).

An evolving strategy for cancer drug development is to focus on properties unique to cancer cells, to develop therapies that target the cancer cells themselves. Current chemotherapies attack cancerous and non-cancer cells that divide rapidly, often causing severe side effects to patients already suffering with cancer.

In this study, Stanford’s Amato Giaccia, professor of radiation oncology (pictured right), the study’s senior author aimed to inhibit the ability of cancer cells to take up glucose, which Giaccia says “is a pretty powerful way of killing those cells.” He and his study colleagues investigated renal cell carcinomas, a form of kidney cancer that is resistant to typical chemotherapies.

Most renal cell carcinomas produce energy through aerobic glycolysis, a biochemical process that healthy cells do not typically require. This energy-making process depends on the cells’ ability to take up glucose from their environment.

Nearly 90 percent of renal cell carcinomas carry a genetic mutation that leads to uncontrolled cell growth. Since most normal tissues in the body do not have this mutation, says Giaccia, “a drug that targets this vulnerability should be very specific for cancer cells.”

Using a high-throughput screening facility at Stanford, the team tested a library of 64,000 synthetic chemical compounds on tumor cells with that mutation and then looked for signs of cell death.

The screen produced two drug candidates that killed cancer cells, one already in pre-clinical testing, and the other, labeled STF-31. Using PET scanning of injected radioactively-labeled glucose, the team found that STF-31 reduced the amount of glucose the cancer cells could ingest, thus robbing them of their energy source.

The researchers then tested the compound in mice with kidney cancer and found that STF-31 reduced by nearly half the amount of glucose imported by tumors and slowed tumor growth, with few side effects. Mice treated with the compound for 14 days had no apparent damage to their normal tissues, maintaining a normal immune system and normal numbers of blood cells. Further experiments using computational modeling indicate that STF-31 binds directly to a glucose transporter, probably blocking the pore of the channel-like molecule.

Ruga Corp., a biotechnology company in Palo Alto, California that Giaccia co-founded has licensed STF-31 from Stanford for preclinical testing. Giaccia serves on the company’s scientific advisory board. A co-author of the study, Denise Chan, a former Stanford postdoc now at University of California in San Francisco, serves as a consultant to Ruga.

Read more: Diagnostic Company to Partner with Scripps on Drug Discovery

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