BioWorld International Correspondent

BOSTON - The "exciting new biology" of cancer stem cells (CSC) shows why after 50 years of progress in understanding cancer, "we are not that much closer to a cure."

That was the sobering introduction by Bruce Cohen, president and CEO of Cellerant Therapeutics Inc., to the session "Cancer Stem Cells - Stem Cell Biology Meets Oncology," at the annual Biotechnology Industry Organization conference last week.

While some doubt the evidence for the existence of CSCs, and opinion is divided on their significance for existing therapies, new treatments are in development that target this specific type of tumor cell.

That could have a major impact on treatment outcomes, John Lewicki, senior vice president of R&D at OncoMed Pharmaceuticals told delegates.

He described CSCs as a rare subpopulation of cells in tumors, which self-renew and differentiate, driving tumor growth and metastasis, adding ominously, "CSCs are resistant to current therapies."

Redwood City, Calif.,-based OncoMed has uncovered evidence for that, developing techniques for separating out CSCs from solid tumors, showing they are a minor percentage of the tumor mass. When the CSCs are implanted in mice, tumors grow from as few as 40 cells. That contrasts with established cancer cell lines which may take millions of cells to prompt tumor growth.

Stripped of the CSCs, bulk tumor cells also are unable to grow tumors, even when a far higher volume of cells is implanted. When tumors grown from the CSCs are removed and analyzed, they show a similar phenotype to the tumor from which they were derived. "In other words, CSCs can self-renew and differentiate into the bulk tumor population," Lewicki said.

From this OncoMed has derived a gene signature, showing what genes are turned on as CSCs differentiate. Lewicki said that has been shown to predict patient response to treatment, with decreased survival and increased metastasis recorded in patients whose tumors showed a correlation with the gene signature.

The worse news is that OncoMed has shown that CSCs preferentially survive the chemotherapeutic cyclophosphamide. Meanwhile, another group has shown that radiation treatment increases survival of CSCs in gliomas. "In other words, you shrink the tumor, but you make it more aggressive," Lewicki said.

OncoMed's therapeutic approach to the problem is to impede a CSCs ability to self-renew. It is identifying monoclonal antibodies that bind to proteins in various differentiation pathways such as Notch and Hedgehog. The company hopes to advance two leads into the clinic in 2008. These would be used in combination with standard therapies to de-bulk the tumor and selectively target CSCs.

Similarly, Ivan Bergstein, chairman and CEO of Stemline Therapeutics Inc., of New York, said that in current therapies the tumor bulk is targeted but CSCs are not killed. The company's lead compound, SL-401 is targeted at the Interleukin-3 receptor, which is overexpressed on CSCs, as well as other tumor cells in hematological cancers.

The compound is currently in a Phase I trial in 27 patients with relapsed acute myeloid leukemia, one of whom has shown a durable eight month complete remission and two who have shown partial responses.

The trial is due to expand to two or three new centers and broaden the inclusion criteria to less-ill patients. It also is intended to measure percentages of CSCs in patients treated with SL-401 and those receiving standard therapy alone.

Looking forward, Bergstein said if there was an agent that was specific enough for destroying CSCs that should be sufficient treatment, since the bulk of the tumor could not be renewed and eventually would degrade away. However, the bulk of the tumor may be causing symptoms, and it might soak up the CSC drug, so combination therapies of existing treatments with CSC targeting agents would be needed.