SONIC HEDGEHOG AND MEDULLOBLASTOMA

1. PHM142 Fall 2012 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson SONIC HEDGEHOG AND MEDULLOBLASTOMA BY: CHRISTINA WONG, EMILY TSE, DIR AL MUTAIR AND ANDREW GIRGIS

2. WHAT IS MEDULLOBLASTOMA?

3. MEDULLOBLASTOMA • TUMOR located mainly in the cerebellum and sometimes found in the brainstem • Most common malignant CNS tumor in children (age 3 - 8) • Also rarely seen in adults • 15-20% of all pediatric brain tumors • In children up to 15 years of age the incidence is 0.5 per 100,000 • Known as a PNET (Primative Neuro-Ectodermal Tumour)

4. WHAT CAUSES MEDULLOBLASTOMA? • Activation of expression in tumor-promoting genes • Associated with Wnt, Notch, and Shh signaling pathways

5. FOUR SUBGROUPS OF MEDULLOBLASTOMA ASSOCIATED WITH DISTINCT BIOCHEMISTRY

6. WHAT IS SONIC HEDGEHOG?

7. THE SONIC HEDGEHOG PATHWAY • Role in cell growth and differentiation (embryonic development) • Development of brain, spinal cord, eyes, limbs and other parts of the body • Required for developing the forebrain, establishing the midline and dividing the brain into the left and right hemisphere

8. THE SONIC HEDGEHOG PATHWAY Key Players Hedgehog = Initiate signal transduction of pathway Patched (PTCH) = Inhibitory receptor suppresses SMO activity Smoothened (SMO) = Signaling receptor activates GLI transcription factors

9. STEPS IN NORMAL SONIC HEDGEHOG PATHWAY • In resting state, PTCH remains on cell membrane and maintains SMO inside vesicle, thereby suppressing its activation. • Hedgehog ligand binds to PTCH, PTCH becomes internalized and degraded. • Without inhibition from PTCH, SMO moves from intracellular compartment to cell membrane of primary cilium • SMO activates GLI family of transcription factors • GLI enter nucleus  initiate transcription of Hedgehog target genes SHH GLI

10. SHH AND MEDULLOBLASTOMA MUTATION DRIVEN SIGNALING IN HEDGEHOG PATHWAY • Inactivating mutations in PTCH or • Activating mutations in SMO (less common) • Uncontrolled activation of SMO  activation of expression of tumor-promoting genes  uncontrolled proliferation of granule cells in the cerebellum  cause medulloblastoma

11. SIGNS & SYMPTOMS • Papilledema: swelling of the optic nerve as a consequence of increased intracranial pressure. • Morning Headache • Vomiting • Lethargy. • Truncal Ataxia: impairment in the synchronization of muscles movement in the trunk. • Abducens Palsy: a damage to the abducens nerve (the sixth cranial nerve) which impairs the lateral movement of eye muscles, possibly causing double vision. http://www.mayoclinic.org/medicalprofs/enlargeimage5586.html

12. PREDISPOSING FACTORS Genetic disorders such as: • Basal Cell Navus Syndrome • Li-Fraumeni Syndrome • Turcot’s Syndrome http://ghr.nlm.nih.gov/handbook/illustrations/dnastructure

13. CLINICAL EXAMPLE BASAL CELL NAVUS SYNDROME • Autosomal dominant disorder that results in skeletal abnormalities and susceptibility to various cancers. • 3-5 % of individuals with the Basal Cell Navus Syndrome potentially become afflicted with medulloblastoma. • In this syndrome, the Patched 1 allele (PTCH1) is inactivated through mutations. • PTCH1 is a shh receptor and is a tumor suppressor. • The active (non-mutated) PTCH1 only activates the shh pathway when shh binds to it. • The inactive (mutated) PTCH1 keeps the shh pathway activated constantly regardless of the binding of shh.

14. DIAGNOSIS • Magnetic Resonance Imaging of the neuroaxis. • Lumbar puncture: • Medulloblastoma can metastasize throughout the central nervous system. • The puncture involves obtaining a sample from the Cerebrospinal Fluid. • Cytological tests done on the sample to determine if neoplastic cells are present.

15. TREATMENT

16. TREATMENT Cyclopamine http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=442972#x332 • Natural alkaloid steroid found in False Helleborine (Veratrum californicum). • Results in teratogenicity if given during gestation because it interferes with the Shh pathway (inhibition). • Studies showed that it binds with and blocks Smo in the Shh pathway. • Heavily studied as a potential treatment of certain cancers such as medulloblastoma. • One of its analogs, IPI-926, is an oral form and is under phase I of clinical trials.

17. TREATMENT HhAntag691 http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=24776445 • Benzoimidazole derivative. • Inhibits Smo • Has more affinity to Smo than cyclopamine • Interferes with the tumor proliferation up to 10 times more effectively than cyclopamine. • Under clinical trials. • Research shows that it can also inhibit ABC (ATP-Binding Casettes) transporters which are proteins associated with drug efflux from cells.

18. SUMMARY • Medulloblastoma is the most common malignant tumor located mainly in the cerebellum • It is commonly found in young children aged 3-8 • There are cases of medulloblastoma that are characterized as being mediated by SHH • SHH Pathway is important in cell growth and differentiation especially in the development of a fetus • Key Players of SHH: Hedgehog (HH), Patched (PTCH), Smoothened (SMO) • Normal Pathway: • PTCH inhibits SMO  HH binds to PTCH  PTCH is internalized  SMO is no longer inhibited and moves to primary cilium  SMO activates GLI  GLI enters nucleus  initiates transcription of HH target genes • Mutations in Pathway can cause Medulloblastoma • Inactivating mutations in PTCH • Activating mutations in SMO (less common) • Prominent Symptoms: Papilledema, vomiting, lethargy, Truncal Ataxia, Abducens Palsy • Treatments include: surgery, chemotherapy, radiotherapy • Potential Treatment: Small Molecule inhibitors of the Pathway • Cyclopamine • HhAntag691

19. REFERENCES • Cranial Mononeuopathy V. (2012). Retrieved from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001710/ • Dahmane, N., P. Sanchez, Y. Gitton, V. Palma, T. Sun, M. Beyna, H. Weiner, and A. Ruiz I Altaba. 2001. “The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis.” Development, 128: 5201-5212. • Epidemiology, treatment, and prognosis of medulloblastoma. (2012). Retrieved from http://www.uptodate.com.myaccess.library.utoronto.ca/contents/epidemiology-treatment-and-prognosis-of-medulloblastoma?source=search_result&search=medulloblastoma&selectedTitle=1~52 • Genentech. “What is the Hedgehog Pathway” <http://www.biooncology.com/research-education/hedgehog/overview/index.html> (25 Sept 2012) • Genetics Home Reference. “SHH” <http://ghr.nlm.nih.gov/gene/SHH> (25 Sept 2012) • Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Cell Surface Receptors and Their Signal Transduction Pathways. Available from: http://www.ncbi.nlm.nih.gov/books/NBK10043/ • Haldipur, P., U. Bharti , S. Govindan, C. Sarkar, S. Lyengar, P. Gressens, and S. Mani. 2012. “Expression of Sonic Hedgehog During Cell Proliferation in the Human Cerebellum.” Stem Cells and Development, 21(7) • Lee, M.J., B.A. Hatton, E.H. Villavicencio, P.C. Khanna, S.D. Friedman, S. Ditzler, B. Pullar, K. Robison, K.F. White, C. Tunkey, M. LeBlanc, J. Randolph-Habecker, S.E. Knoblaugh, S. Hansen, A. Richards, B.J. Wainwright, K. McGovern, and J.M. Olson. 2012. “Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse Medulloblastoma model.” Clin Cancer Res 109(20): 7859-7864.

20. REFERENCES • Macmillan Cancer Support. “Medulloblastoma” <http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Brain/Typesofbraintumours/Medulloblastoma.aspx#.UHngQ1GVwit> (25 Sept 2012) • Manoranjan, B., C. Venugopal, N. McFarlane, B.W. Doble, E.D. Sandra, K. Scheinemann, and S.K. Singh. 2012. “Medulloblastoma stem cells: where development and cancer cross pathways.” Pediatric Research. 71: 516-522. • Movement-Uncoordinated .(2012). Retrieved from http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003682/ • Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S, Bouffet E, Clifford SC, Hawkins CE, French P, Rutka JT, Pfister S, Taylor MD. 2011. “Medulloblastoma comprises four distinct molecular variants.” Journal of Clinical Oncology. 29(11):1408-14 • Papilledema. Retrieved from http://ovidsp.tx.ovid.com.myaccess.library.utoronto.ca/sp-3.6.0b/ovidweb.cgi • Pediatric Oncology Education Materials. (2012) Retrieved from http://www.pedsoncologyeducation.com/medulloblastoma.asp • Teglund, S., & Toftgård, R. (2010). Hedgehog beyond medulloblastoma and basal cell carcinoma. BBA - Reviews on Cancer, 1805(2), 181-208 • VCU Department of Pathology.(2012). Retrieved from http://www.pathology.vcu.edu/WirSelfInst/neuro_medStudents/tumor-2.html • Wechsler-Reya, R. and Scott, M.P. 2001. “The Developmental Biology of Brain Tumors” Annual Review of Neuroscience, 24(1):385-428. • Wlodarski, P. K., & Jozwiak, J. (2008). Therapeutic targets for medulloblastoma. Expert Opinion on Therapeutic Targets,12(4), 449-449. • Yoon, J.W, Fangusaro,J., Lannaccone, P., Walterhouse,D. (2011). Hedgehog Signaling in Pediatric Brain Tumors. In J. Xie (Ed.), HedgehogSignaling Activation in Human Cancer and its Clinical Implications (pp.115-120). New York: Springer. • Zhang, Y., Lattera, J., Pomper, M.J. (2009). Hedgehog Pathway Inhibitor HhAntag 691 Is a Potent Inhibitor of ABCG2/BRCP and ABCB1/PGP1. Neoplasia, 11(1), 96-101.