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Cyclopamine: A possible cancer treatment or the next Thalidomide?

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

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Cyclopamine: A possible cancer treatment or the next Thalidomide?

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  1. Cyclopamine: A possible cancer treatment or the next Thalidomide?

  2. Veratrum californicum • AKA: • Corn lily • False hellebore • Skunk cabbage • Family Liliaceae • Native to mountain meadows in the Sierra Nevadas and the Rockies

  3. Perennial monocot • Grows 1-2 meters tall • Stem/leaves resemble cornstalk

  4. Medicinal Uses • Used by native Americans to treat wounds • Contraceptive • Root is an analgesic and disinfectant • Also used to treat VD

  5. Sheep herds were plagued by unexplained birth defects • Intensive study by the USDA isolated cyclopamine as the causative agent

  6. Cyclopamine Method of Action

  7. But what about cells that have already differentiated? • Required for tissue maintenance and regeneration • T-cell activation • Can act as a mitogen • Tissue dependent

  8. Smoothened is a GPCR, no wonder your cells died! • GPCRs (G Protein Coupled Receptor) are responsible for a multitude of signal cascades : • Adenylate cyclase/cAMP pathway • Activates PKA, which activates ion channels • Phospholipase C pathway • Secretion and translocation of proteins from the ER • IP3 pathway: • Releases Ca+ from ER activating • Ca+/Calmodulin pathway • Glycogen pathway (via Adenylate cyclase)

  9. 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)

  10. 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)

  11. Why the comparison to thalidomide? If clinical trials are promising and the FDA is involved, what’s the problem?

  12. 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

  13. 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

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