sonic hedgehog pathway and small molecule therapies
DESCRIPTION
Ten-minute presentation about the history of the discovery of the Sonic hedgehog pathway, its role in development, and current efforts to develop small molecule inhibitors for various cancers.TRANSCRIPT
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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
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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
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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
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Hedgehog signalingcyclopamineIPI-926LDE225LEQ506XL 139PF-04449913GDC-0449TAK-441Itraconazole
Arsenic trioxide
upregulation of independent pathways
January 30, 2012:VismodegibErivedge™
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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
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Future directions
p38 inhibition in mouse models of medulloblastoma and BCC
Combination therapies with p38 and hedgehog inhibitors
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Dr. Anna KenneyDr. Alex Joyner
Members of the Kenney and Joyner Labs
Dr. Alexia-Ileana ZaromytidouDr. Praveen Raju
Thanks to…