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SUMMARY:Babraham Lecture - Ras proteins as therapeutics targets - Dr Frank
  McCormick\; UCSF Helen Diller Family Comprehensive Cancer Center\, San Fr
 ancisco\, CA\, USA
DTSTART:20180713T130000Z
DTEND:20180713T140000Z
UID:TALK96742@talks.cam.ac.uk
CONTACT:Bobbie Claxton
DESCRIPTION:Ras proteins play important roles in human cancer\, and syndro
 mes such as neurofibromatosis type 1 and autism spectrum disorder. Their m
 ajor negative regulator is the Ras GAP neurofibromin\, which itself is reg
 ulated by the  Sprouty-related protein SPRED1.  Structural and biochemical
  features of neurofibromin and SPRED1 will be discussed.  Specifically\, t
 he critical interaction between these proteins is disrupted in cancer cell
 s expressing oncogenic receptor tyrosine kinases\, allowing Ras proteins t
 o exist in their active state without negative feedback.\nRas proteins are
  localized to the plasma membrane.  Biophysical and molecular dynamic simu
 lations suggest multiple points of contact between K-Ras and membrane comp
 onents which determine special organization of K-Ras in signaling complexe
 s and affect interaction of K-Ras with its major effectors\, Raf kinases. 
  Activation of Raf kinase by Ras proteins is a complex biochemical process
 \, involving translocation\, de-phosphorylation and dimerization. Active R
 af kinase promotes activation of MEK and ERK. Analysis of this cascade in 
 single cells reveals dramatic differences between signaling in normal cell
 s and in cells with mutant Ras\, suggesting the dynamics of the activation
  and inactivation process are significantly different in these cells. \nRa
 s proteins do not contain an active site that is amenable to therapeutic i
 ntervention\, but the surface of these proteins has a number of shallow po
 ckets to which small molecules can bind.  In the case of K-Ras\, a pocket 
 is formed by the C-terminal hypervariable region that folds back on the G-
 domain and makes contact residues near helix 4.  Compounds that bind this 
 pocket and bind covalently to the CAAX box cysteine of unprocessed K-Ras w
 ill be described. These compounds are effective at preventing K-Ras 4B pro
 cessing in cells\, and prevent proliferation of K-Ras dependent cells in c
 ulture.  Other approaches to targeting K-Ras directly will be described. \
 nH-Ras proteins are inhibited by farnesyl transferase inhibitors such as t
 ipifarnib. Kura Oncology recently initiated a  clinical trial of tipifarni
 b in patients suffering from H-Ras mutant cancers. Phase II analysis revea
 led significant clinical benefit\, showing for the first time that targeti
 ng Ras proteins can be an effective strategy for treating certain cancers.
   Future prospects for targeting these cancers will be discussed.\n
LOCATION:Babraham - The Cambridge Building\; Petersfield Lecture Theatre
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