Fight Aging!

The next generation of cancer therapies will involve ways to target and destroy cancer cells with far greater precision than is possible through presently available treatments, leading to highly effective therapies with few side effects. One branch of this research and development effort involves targeting cells by characteristic differences in surface chemistry, but there are many others. This is one recent example:

In a series of experiments in mice with cancer and in cancer cells, [researchers] have shown that they can block the process by which leukemia stem cells repair themselves by targeting a particular protein, RAD52, which the cells depend on to fix genetic mistakes. The findings may lead to a new strategy to help overcome drug resistance that hinges on cancer stem cells gone awry.

In chronic myeloid leukemia (CML), an enzyme called ABL1 goes into overdrive because of a chromosomal mix-up that occurs in bone marrow stem cells that are responsible for the generation of all blood components. The genes ABL1 and BCR become fused and produce a hybrid BCR-ABL1 enzyme that is always turned on. This overactive BCR-ABL1 protein drives the excessive production of white blood cells that is the hallmark of CML.

In CML cells, the BCR-ABL1 protein shuts down the main DNA repair system and leukemia cells have to rely on a backup pathway for repair. Previous experiments in mice bone marrow cells lacking RAD52, a key protein in the backup system, showed that its absence abrogated the development of CML, proving that CML DNA repair depended on RAD52.

[Researchers] then used an "aptamer," a peptide that mimicked the area where the RAD52 protein binds to DNA, to see the effects of blocking RAD52 from binding to DNA. The investigators found that when the aptamer was added to BCR-ABL1-positive bone marrow cells, RAD52 was prevented from binding to DNA and the leukemic bone marrow cells accumulated excessive double-strand breaks and eventually died. The aptamer had no effect on normal cells.

"With this treatment in hand, we eventually hope to generate a small molecule inhibitor with which we will be able to target leukemia patients based on their oncogenic profiles. We've started to use microarrays to look at the expression profiles of the DNA repair genes in other cancers, and based on these profiles, predicted if they would be sensitive to [this] approach."

Link: http://www.eurekalert.org/pub_releases/2012-12/tuhs-tst120612.php