"Thalidomide and its analogues ; How molecules selected for anti-TNFa activity affect so many different pathways with direct binding with Cereblon mediating both anti proliferative and Immunomodulatory functions"

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• Jerome B. Zeldis CEO of Celgene Global Health & Angus Dalgleish, St George's Hospital London
• Tuesday 20 March 2012, 12:00-13:00
• CRI Lecture Theatre.

If you have a question about this talk, please contact Mala Jayasundera.

Individuals who are interested in meeting with any of the speakers should contact me asap. Thanks, Jonathan (jlh66@cam.ac.uk)

Thalidomide was resurrected due to its marked clinical activity in the skin manifestations of leprosy and leshmaniasis. This activity also extended to steroid resistant auto-immune conditions. Clinical trials in HIV and, cachexia and myeloma have led to its registration. Together with lenalidomide and pomalidomide (analogues selected for having high anti TNFa activity) they are therapeutically active in a number of hematological malignant and premalignant conditions including myelodysplastic syndromes, multiple myeloma, and lymphomas. They have been shown to have widespread activities including anti-inflammatory, anti-proliferative, anti-angiogenic as well as being co-stimulatory and in the case of the analogues only able to inhibit suppressor T cell function. Clinical efficacy is ascribed to a complement of overlapping activities including direct antitumor effects, immune system activation and inhibition of stromal support of tumor growth. The dominant actyivity has until recently not been clear . However, Thalidomide has previously been shown to bind cereblon (CRBN) a protein required for the teratogenic effects of thalidomide in zebrafish and chicken embryos (Ito et al). CRBN forms an ubiquitin E3 ligase complex with DNA damage-binding protein 1 (DDB1), cullin 4 (CUL4) and protein Rbx1 and thalidomide treatment has been shown to inhibit the ubiquitin ligase activity of the complex (Ito et al).

Lenalidomide and pomalidomide have now been shown to bind to the CRBN DDB1 complex. CRBN expression is reduced in activated human T cells using CRBN siRNAs. After T cell activation, incubation with lenalidomide (1 µM) or pomalidomide (1 µM) results in an 11 to 14 fold-increase in IL-2 and a 5 to 10-fold increase in TNF -α. This increase is reduced ~60% in the presence of siCRBN. Since IL-2 and TNF -α are important cytokines for tumor surveillance by activated T cells, our results indicate that some of the immunomodulatory effects of lenalidomide and pomalidomide are mediated via CRBN . The antiproliferative effect of lenalidomide and pomalidomide in myeloma cells has been demonstrated using multiple siRNAs w to silence the expression of CRBN in U266B1 cells resulting in the absence of CRBN protein as determined by immunoblot analysis.The results of these and activities with other new analogues will be presented..

This talk is part of the Cambridge Oncology Seminar Series series.

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