BEGIN:VCALENDAR VERSION:2.0 PRODID:-//Talks.cam//talks.cam.ac.uk// X-WR-CALNAME:Talks.cam BEGIN:VEVENT SUMMARY:"\;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 funct ions"\; - Jerome B. Zeldis CEO of Celgene Global Health &\; Angus D algleish\, St George's Hospital London DTSTART:20120320T120000Z DTEND:20120320T130000Z UID:TALK36933@talks.cam.ac.uk CONTACT:Mala Jayasundera DESCRIPTION:Thalidomide was resurrected due to its marked clinical activit y in the skin manifestations of leprosy and leshmaniasis. This activity al so extended to steroid resistant auto-immune conditions. Clinical trials i n HIV and\, cachexia and myeloma have led to its registration. Together wi th lenalidomide and pomalidomide (analogues selected for having high anti TNFa activity) they are therapeutically active in a number of hematologic al malignant and premalignant conditions including myelodysplastic syndrom es\, multiple myeloma\, and lymphomas. They have been shown to have widesp read activities including anti-inflammatory\, anti-proliferative\, anti-an giogenic as well as being co-stimulatory and in the case of the analogues only able to inhibit suppressor T cell function. Clinical efficacy is ascr ibed to a complement of overlapping activities including direct antitumor effects\, immune system activation and inhibition of stromal support of tu mor growth. The dominant actyivity has until recently not been clear . How ever\, Thalidomide has previously been shown to bind cereblon (CRBN) a pro tein required for the teratogenic effects of thalidomide in zebrafish and chicken embryos (Ito et al). CRBN forms an ubiquitin E3 ligase complex wit h DNA damage-binding protein 1 (DDB1)\, cullin 4 (CUL4) and protein Rbx1 a nd thalidomide treatment has been shown to inhibit the ubiquitin ligase ac tivity of the complex (Ito et al).\n\nLenalidomide and pomalidomide have n ow 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\, i ncubation 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. Thi s 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\, o ur results indicate that some of the immunomodulatory effects of lenalidom ide and pomalidomide are mediated via CRBN . The antiproliferative effect of lenalidomide and pomalidomide in myeloma cells has been demonstrated us ing multiple siRNAs w to silence the expression of CRBN in U266B1 cells re sulting in the absence of CRBN protein as determined by immunoblot analysi s.The results of these and activities with other new analogues will be pre sented.. LOCATION:CRI Lecture Theatre END:VEVENT END:VCALENDAR