CANCER 3 - Shh and Everidge Flashcards
How was cyclopamine discovered?
Lambs were being born cyclopic because their mothers were eating corn lilies which contain CYCLOPAMINE
What is Hh, why is it important and what is it involved in?
Highly conserved ancient signalling pathway.
Hh mutants showed abnormal development – Hh involved in the devel of organs and tissues such as MUSCLE, BONE, PANCREAS & BRAIN
What is Shh and what protein mediates its effects?
What model was used to identify it?
Mouse, chick and zebrafish were used to identify Shh.
Shh is a homologue of Hh and mediates its effect via Smo.
What is happening when Shh is activated?
Hh is bound to Ptc and there is no repression of Smo therefore Smo initiates signalling
What is happening when Shh is inactivated
Hh isn’t bound to Ptc, so Smo is repressed by Ptc, stopping Smo from initiating signalling
How does Cyclopamine impact Shh?
ANTAGONISES SMO (works in same way as Ptc) - Smo is a Shh pathway componant
What is the purpose of the Shh pathway re. stem cells?
Involved in Stem cell renewal
How can dysreg of Shh result in cancers?
- Shh must be downregulated at developmental end stages and cancers can develop where this does not occur
- Shh is held in a careful balance and at particular levels throughout development (such as in stem cell niche) and cancer can develop where levels of Shh are not carefully regulated
SKIN STEM CELL NICHES - where is Shh expressed? What is the role of Shh here?
Skin cells develop from a crypt-like skin stem cell niche
Shh is expressed at the base of the crypt in proliferating cells of the deep dermis. Shh acts to regulate the balance of stem cells/progenitors/differentiating cells
What is GliA and what is its mechanism of action in relation to Smo?
What type of tumour is it abundant in?
GliA becomes activated downstream of the Shh pathway.
An activating Smo mutation causes upregulation of GliA.
Overactive GliA abundant in the deep dermis of a BASAL CELL CARCINOMA
Why is cyclopamine a potential cancer therapy?
Cyclopamine —l Smo therefore Gli1/Gli2 remain inactive and this prevents the expression of tumour mediating genes
What is EVERIDGE and how does it work?
- First licensed medicine for patients with B.C.Cs which was marketed as ‘Vismodegib’ and globally authorised in 2013
- Competitive antagonist of Smo
MAIN DISADVANTAGE of everidge?
very very costly - $250 per capsule and $7,500 per month!
It is no longer NHS funded as costs too much
Next steps in cancer treatments? WHat is the main problem?
- 25 year lag time between the first effects of the drug being observed and cost analysis for any cancer drug
- Field is moving swiftly to develop new drugs that also target the Shh pathway
What is a signal and signalling pathway
SIGNAL - produced by SIGNALLING cell
SIGNALLING PATHWAY - activated by RESPONDING cell
