Friday, July 25, 2014

Phenotypic screening in oncology drug discovery — Hosein Kouros-Mehr

A recent paper* summarized the history of oncology drug discovery and analyzes the contibutions of phenotypic drug discovery vs traditional target-based drug discovery. The authors analyze the development and mechanisms of all small molecule-based cancer drugs approved by the FDA over the past 15 years and those currently in clinical development.
The authors show that the majority of small molecule inhibitors for oncology originated in target-based discovery. However, a significant number of inhibitors were identified in phenotypic drug screening approaches. The authors suggest that the rate-limiting step in bringing compounds identified in phenotypic screenings into clinical development is the lack of mechanistically defined cellular models for the cancer phenotypes in question and also the reliance on traditional drug effects such as cytotoxicity and mitotic arrest, which are only a component of the hallmarks of cancer.
The authors suggest that mechanistically informed phenotypic models may better enable compounds identified in phenotypic screenings to successfully complete clinical development. These models would enable confirmation that the targeted agents have a molecular mechanism of action, which would enable PD biomarker development and development of diagnostic hypotheses and patient tailoring hypotheses.
* Moffat, et. al. (2014) Phenotypic screening in cancer drug discovery — past, present and future. Nat Rev Drug Discovery, doi:10.1038/nrd4366
Hosein Kouros-Mehr

Wednesday, July 23, 2014

Cholesterol, Wnt signaling, and Cancer - Hosein Kouros-Mehr

A recent paper* has reported a direct biological link between cholesterol and cancer.  The Wnt pathway plays an important role in cancer formation and metastasis, particularly in colorectal cancer in which the Wnt-related gene APC is frequently mutated.  In this report, the authors find that cholesterol is enriched around the Wnt-related Frizzled and LRP5/6 receptors in cancer cells.  This suggested to the authors that perhaps cholesterol itself could activate Wnt signaling.  The authors found that cholesterol directly recruits the Wnt-related Dishevelled (Dvl) scaffold protein to the cell membrane through interaction with its PDZ domain.  Dvl then activates the canonical Wnt signaling pathway.  In this way, cholesterol may directly regulate activation of canonical Wnt signaling and may regulate balance between canonical and non-canonical signaling.  Future studies will be needed to determine effects of anti-cholesterol medicines in silencing Wnt signaling and perhaps inhibiting Wnt-driven cancers.  


* ​Sheng, R., et. al. (2014).  Cholesterol selectively activates canonical Wnt signalling over non-canonical Wnt signalling.  Nature 5 (4393)

Hosein Kouros-Mehr