Harvard Stem Cell Institute (HSCI) researchers have identified in the most aggressive forms of cancer a gene known to regulate embryonic stem cell self-renewal, beginning a creative search for a drug that can block its activity.
The gene, SALL4, gives stem cells their ability to continue dividing as stem cells rather than becoming mature cells. Typically, cells only express SALL4 during embryonic development, but the gene is re-expressed in nearly all cases of acute myeloid leukemia and 10 to 30 percent of liver, lung, gastric, ovarian, endometrial, and breast cancers, strongly suggesting it plays a role in tumor formation.
In work published in the New England Journal of Medicine, two HSCI-affiliated labs one in Singapore and the other in Boston show that knocking out the SALL4 gene in mouse liver tumors, or interfering with the activity of its protein product with a small inhibitor, treats the cancer.
"Our paper is about liver cancer, but it is likely true about lung cancer, breast cancer, ovarian cancer, many, many cancers," said HSCI Blood Diseases Program leader Daniel Tenen, who also heads a laboratory at the Cancer Science Institute of Singapore (CSI Singapore). "SALL4 is a marker, so if we had a small molecule drug blocking SALL4 function, we could also predict which patients would be responsive."
Studying the therapeutic potential of a transcription factor is unusual in the field of cancer research. Transcription factors are typically avoided because of the difficulty of developing drugs that safely interfere with genetic targets. Most cancer researchers focus their attention on kinases.
The HSCI researchers' inquiry into the basic biology of the SALL4 gene, however, revealed another way to interfere with its activity in cancer cells. The gene's protein product is responsible for turning off a tumor-suppressor gene, causing the cell to divide uncontrollably. Using this knowledge, the researchers demo
|Contact: B. D. Colen|