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…