Sonic hedgehog pathway and small molecule therapies
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Transcript of Sonic hedgehog pathway and small molecule therapies
From the mountains of Idaho to the bedside: A story basic science, drug discovery, and clinical research
Cemile “Blue” Guldal, Ph.D.
02/14/2012
From the mountains of Idaho to human clinical trials…
Corn lily
1950s: In Idaho newborn lambs with severe craniofacial defects, including cyclopia
1968: Cyclopamine isolated. (Odysseus escapes the cyclops with the help of a sheep!)
1993: Mammalian Shh gene cloned
1980s and ‘90s: Three hedgehog homologs:
Sonic Indian Desert
1998: cyclopamine inhibits hh signaling2002: mechanism of hh inhibition by cyclopamine
1996: Gorlin’s syndrome linked to mutations in the hh pathway
1970s: Classic Heidelberg mutant screens in fruit flies, published in 1978; 1995 Nobel prize for Nüsslein-Volhard and Weischaus
Gorlin’s Syndrome (1 in 57,000 people)Basal cell carcinoma (most common skin cancer)skeletal abnormalitiesmedulloblastoma (5%)
Medulloblastoma1,000 new cases each year18% of pediatric brain tumorsthe most common malignant pediatric brain tumor
RabdomyosarcomaPancreatic cancer (ductal adenocarcinoma) Breast cancerOvarian cancerColorectal cancerSmall cell lung cancerChronic Myelogenous Leukemia…
Human disease and Hedgehog pathway
IPI-926, LDE225, GDC-0449
LDE225, PF-04449913
LDE225, XL 139, GDC-0449, LEQ506TAK-441
LDE225, LEQ506, GDC-0449, PF-04449913
LDE225
GDC-0449, XL 139
GDC-0449
cyclopamine - poor solubility, low potency, rapid clearance, nonspecific toxicity, and chemical instability
IPI-926 – Infinity, 6 trialsLDE225 – Novartis, 12 trialsXL 139– Exelixis+BMS, 7 trialsGDC-0449 – Curis+Genentech, 30 trialsTAK-441 – Millenium, 1 trialPF-04449913 – Pfizer, 2 trialsLEQ506 – Novartis, 1 trial
Hedgehog signalingcyclopamineIPI-926LDE225LEQ506XL 139PF-04449913GDC-0449TAK-441Itraconazole
Arsenic trioxide
upregulation of independent pathways
January 30, 2012:VismodegibErivedge™
p-p38α
cyclin D2
β-tubulin
A.n-T1 MB1 A.n-T2 MB2
p38 MAPK is active in mouse medulloblastoma
p-p38-low p-p38-high (four representative tumor samples)
10x
40x
p38 MAPK is active in pediatric medulloblastoma
Pharmacological inhibition of p38 activity inhibits HH pathway
Future directions
p38 inhibition in mouse models of medulloblastoma and BCC
Combination therapies with p38 and hedgehog inhibitors
Dr. Anna KenneyDr. Alex Joyner
Members of the Kenney and Joyner Labs
Dr. Alexia-Ileana ZaromytidouDr. Praveen Raju
Thanks to…