Exploring cancer therapies based on p53-reactivating drugs using shRNA barcode screening
Summary:
p53 is one of our most efficient tumor suppressor genes, but in about 50% of all cancer patients functionally blocked by Mdm2.
Since the p53 gene is still wild-type in sequence, it can be reactivated by small molecules, which release p53 from the
inhibitory interaction with Mdm2. These Mdm2 inhibitors are therefore promising novel anti-cancer drugs that are currently in
preclinical and early clinical trials. In response to Mdm2 inhibitors, p53 becomes stabilized and activates a tumor suppressive
program, which ranges from a transient cell cycle arrest to the killing of cells in a drug- and cell-specific manner.
The response to Mdm2 inhibitors is therefore modified by genetic alterations in tumors that affect signaling pathways downstream,
upstream or in parallel to p53. As clinical trials of other molecular targeted drugs have shown, typically only a small fraction
of the treated cancer patients show a therapeutic benefit. Many patients are therefore treated with costly drugs and exposed to
side effects without having a survival benefit. It is therefore necessary to stratify patients in advance according to their
genetic setup as the major determinant of the drug response. In this project we plan to identify the genetic factors, which
determine the cellular fate in response to reactivation of wild-type p53 by Mdm2 inhibitors, using unbiased, genome-wide RNAi
screening techniques.
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KLINISCHE FORSCHERGRUPPE 210 |
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