Cyclopamine: A possible cancer treatment or the next Thalidomide?

Veratrum californicum

AKA: Corn lily False hellebore Skunk cabbage

Family Liliaceae Native to mountain

meadows in the Sierra Nevadas and the Rockies

Perennial monocot

Grows 1-2 meters tall

Stem/leaves resemble cornstalk

Medicinal Uses

Used by native Americans to treat wounds

Contraceptive

Root is an analgesic and disinfectant

Also used to treat VD

Sheep herds were plagued by unexplained birth defects

Intensive study by the USDA isolated cyclopamine as the causative agent

Cyclopamine Method of Action

But what about cells that have already differentiated?

Required for tissue maintenance and regeneration

T-cell activation Can act as a

mitogen Tissue dependent

Smoothened is a GPCR, no wonder your cells died!

GPCRs (G Protein Coupled Receptor) are responsible for a multitude of signal cascades :1. Adenylate cyclase/cAMP pathway

Activates PKA, which activates ion channels

2. Phospholipase C pathway Secretion and translocation of proteins from the

ER

3. IP3 pathway: Releases Ca+ from ER activating

4. Ca+/Calmodulin pathway5. Glycogen pathway (via Adenylate cyclase)

Don’t worry, I’m a doctor!

Phase I clinical trials underway of a derivate

GDC-0449 (Genentech in collaboration with Curis)

Preliminary results were promising Side effects: loss of hair, weight loss,

otherwise mild toxicity reported Already being billed as “hav[ing] the

potential to become a blockbuster drug…for treating cancers.” (Wong, 2009)

But what type of cancer does it treat?

Glioblastoma multiforme (brain tumor) 2-3 cases per 100K Most often terminal Median survival = 15 months

(conventional chemotherapy) Without treatment = 4.5 months

(World Heath Organization)

Why the comparison to thalidomide? If clinical trials are promising and

the FDA is involved, what’s the problem?

What is Thalidomide?

Synthetic drug marketed as a sedative

Prescribed to pregnant women to help with morning sickness

Drug testing conducted on rats

Rats metabolized thalidomide

Late 1950’s children born with Pharcomelia

Later tests on monkeys produced same birth defects as seen in humans

References (excludes article screenshots)

Berry, L. (n.d.). Sierra Wild Flowers. Retrieved Oct 23, 2009, from Sierrawildflowers.org: http://www.sierrawildflowers.org/veratrum_californicum.htm

Binns, W. L. (1968). Effects of Teratogenic Agents in Range Plants. Cancer Research , 28, 2323-2326.

Keeley. (2002). Biology News. Retrieved Oct 23, 2009, from Bio-Medicine: http://news.bio-medicine.org/biology-news-2/Plant-compound-kills-brain-tumor-cells-6856-1/

Lingham, A. (2000, June). The First Appearance of Thalidomide. Retrieved Oct 23, 2009, from Thalidomide Isomerism and Optical Isomerism: http://www.chm.bris.ac.uk/motm/thalidomide/first.html

Wong, J. F. (2009). Genetic Engineering & Biotechnology News. Retrieved Oct 23, 2009, from GEN: http://www.genengnews.com/articles/chitem.aspx?aid=2518&chid=4