Scientists Find Drug Scrambles Signals of CLL and Its Food Source

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JanBurgerimage.jpgAs cozy as it looks, the scene pictured here is one that oncologists prefer to break up. The  purple cells are chronic lymphocytic leukemia cells and they are being nourished by the green cell, appropriately called a nurse-like cell.

Jan Burger, M.D., assistant professor in Leukemia at MD Anderson, discovered nurse-like cells as a post-doctoral fellow.  Now he, graduate student Julia Hoellenriegel and colleagues have shown that an experimental drug called CAL-101 interferes with this connection and also directly attacks the abnormal B cells that cause CLL.

(B cells are white blood cells that fight infection. CLL is the most common form of leukemia.)

The drug works by jamming chemical signals -- chemokines and cytokines -- produced by B cells, including those that communicate with nurse-like cells. The nurse-like cells are part of CLL's microenvironment -- external factors that support cancer and need to be suppressed. In this case, external signaling is transmitted by PI3Kδ, part of a signaling pathway often involved in cancer development, and the drug's target.

CAL-101, developed by Calistoga Pharmaceuticals, also kills malignant cells by forcing them to commit suicide -- a process called apoptosis.

"We've identified a central mechanism of action of this drug," Burger says. "It blocks B cell antigen receptor signaling and BCR-derived survival signals."

Hoellenriegel presented their findings at the 52nd American Society of Hematology Meeting in Orlando Sunday evening. Only involved in this field for a year, Hoellenriegel held her own in a room full of CLL experts.

In a series of lab experiments, the researchers found that the drug reduced CLL cell viability and steeply cut the production of a number of important chemokines. They then treated CLL cell cultures with either CAL-101, the chemotherapy drug bendamustine, or a combination of both. By itself, CA-101 produced a 20% reduction in cells compared to untreated controls. Bendamustine alone cut the cells by 30%. Together, they pushed the cell count down by more than 40%.

Separately, plasma samples from 14 patients treated with the drug also showed sharp reductions in cytokine levels. For example, one of these, CCL3, fell from 186 picograms per milliliter to 29 pg/mL 28 days after treatment.

Burger is co-principal investigator on a soon-to-open Phase II study at MD Anderson of CAL-101 and rituximab in elderly patients with no previous treatment. "We will further explore the drug's activity in CLL patients," Burger says.

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