The exact mechanisms and targets through which these therapies work to enhance immune response or kill cancer cells has been largely unknown; therefore, it has been challenging to understand which patients to treat and to distinguish the positive properties of these drugs from the side effects. After recent research identified a specific protein known as cereblon as a primary mediator of the birth defects caused by thalidomide, a hypothesis emerged that cereblon may also be responsible for the anti-tumor properties of IMiDs.
To test whether the presence of cereblon in myeloma cells might be partly responsible for resistance or response to MM treatment, and thus may potentially serve as a target for therapeutic intervention, researchers examined MM cell lines resistant to IMiDs and found that expression of the cereblon gene was either low or entirely absent, suggesting a possible link between resistance to IMiDs and presence of the protein.
The team then lowered the level of cereblon expression in five human-derived MM cell lines, which caused the cell lines to become almost completely resistant to lenalidomide (compared with control cell lines) yet remain sensitive to other myeloma therapies such as melphalan, dexamethasone, and bortezomib. The investigators then examined the DNA of 10 MM patients who were resistant to IMiD therapy and found low levels of cereblon expression in eight of those 10 patients, further emphasizing that cereblon expression appears necessary for IMiDs to work properly. Interestingly, some resistant patients had normal cereblon levels, suggesting that while cereblon may be an absolute requirement for response, there are likely other mechanisms present that play a role in drug resistance.
"These findings help us understand which patients may be more or less likely to respond to therapy and will allow us to focus on other ways we can target cereblo
|SOURCE American Society of Hematology|
Copyright©2010 PR Newswire.
All rights reserved