Unraveling the Therapeutic Potential of the Hedgehog Pathway in Cancer

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2013 Nov 9

PMID 24202394

Citations 281

Authors

Dereck Amakye

Zainab Jagani

Marion Dorsch

Affiliations

Soon will be listed here.

Abstract

Major progress has been made in recent years in the development of Hedgehog (Hh) pathway inhibitors for the treatment of patients with cancer. Promising clinical trial results have been obtained in cancers that harbor activating mutations of the Hh pathway, such as basal cell carcinoma and medulloblastoma. However, for many cancers, in which Hh ligand overexpression is thought to drive tumor growth, results have been disappointing. Here we review the preclinical data that continue to shape our understanding of the Hh pathway in tumorigenesis and the emerging clinical experience with smoothened inhibitors.

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References

Buonamici S, Williams J, Morrissey M, Wang A, Guo R, Vattay A . Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci Transl Med. 2010; 2(51):51ra70. PMC: 3422576. DOI: 10.1126/scitranslmed.3001599. View

Chang Q, Foltz W, Chaudary N, Hill R, Hedley D . Tumor-stroma interaction in orthotopic primary pancreatic cancer xenografts during hedgehog pathway inhibition. Int J Cancer. 2013; 133(1):225-34. DOI: 10.1002/ijc.28006. View

Yauch R, Dijkgraaf G, Alicke B, Januario T, Ahn C, Holcomb T . Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science. 2009; 326(5952):572-4. PMC: 5310713. DOI: 10.1126/science.1179386. View

Kim J, Lee J, Kim J, Gardner D, Beachy P . Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector. Proc Natl Acad Sci U S A. 2010; 107(30):13432-7. PMC: 2922148. DOI: 10.1073/pnas.1006822107. View

Karamboulas C, Ailles L . Developmental signaling pathways in cancer stem cells of solid tumors. Biochim Biophys Acta. 2012; 1830(2):2481-95. DOI: 10.1016/j.bbagen.2012.11.008. View

Cooper M, Porter J, Young K, Beachy P . Teratogen-mediated inhibition of target tissue response to Shh signaling. Science. 1998; 280(5369):1603-7. DOI: 10.1126/science.280.5369.1603. View

GORLIN R . Nevoid basal cell carcinoma syndrome. Dermatol Clin. 1995; 13(1):113-25. View

Jimeno A, Weiss G, Miller Jr W, Gettinger S, Eigl B, Chang A . Phase I study of the Hedgehog pathway inhibitor IPI-926 in adult patients with solid tumors. Clin Cancer Res. 2013; 19(10):2766-74. PMC: 3694426. DOI: 10.1158/1078-0432.CCR-12-3654. View

Mangelberger D, Kern D, Loipetzberger A, Eberl M, Aberger F . Cooperative Hedgehog-EGFR signaling. Front Biosci (Landmark Ed). 2011; 17(1):90-9. PMC: 3284771. DOI: 10.2741/3917. View

10.

Tian H, Callahan C, DuPree K, Darbonne W, Ahn C, Scales S . Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc Natl Acad Sci U S A. 2009; 106(11):4254-9. PMC: 2647977. DOI: 10.1073/pnas.0813203106. View

11.

Tang J, Mackay-Wiggan J, Aszterbaum M, Yauch R, Lindgren J, Chang K . Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med. 2012; 366(23):2180-8. PMC: 4362529. DOI: 10.1056/NEJMoa1113538. View

12.

Rudin C, Hann C, Laterra J, Yauch R, Callahan C, Fu L . Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med. 2009; 361(12):1173-8. PMC: 5317279. DOI: 10.1056/NEJMoa0902903. View

13.

Gailani M, Leffell D, Glynn M, Zaphiropoulos P, Pressman C, Unden A . The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet. 1996; 14(1):78-81. DOI: 10.1038/ng0996-78. View

14.

Hahn H, Wicking C, Zaphiropoulous P, Gailani M, Shanley S, Chidambaram A . Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996; 85(6):841-51. DOI: 10.1016/s0092-8674(00)81268-4. View

15.

Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, Mullendore M . Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res. 2007; 67(5):2187-96. PMC: 3073370. DOI: 10.1158/0008-5472.CAN-06-3281. View

16.

Gurney J, Severson R, Davis S, Robison L . Incidence of cancer in children in the United States. Sex-, race-, and 1-year age-specific rates by histologic type. Cancer. 1995; 75(8):2186-95. DOI: 10.1002/1097-0142(19950415)75:8<2186::aid-cncr2820750825>3.0.co;2-f. View

17.

Reifenberger J, Wolter M, Weber R, Megahed M, Ruzicka T, Lichter P . Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res. 1998; 58(9):1798-803. View

18.

Jagani Z, Mora-Blanco E, Sansam C, McKenna E, Wilson B, Chen D . Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog-Gli pathway. Nat Med. 2010; 16(12):1429-33. PMC: 3859448. DOI: 10.1038/nm.2251. View

19.

Dierks C, Beigi R, Guo G, Zirlik K, Stegert M, Manley P . Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell. 2008; 14(3):238-49. DOI: 10.1016/j.ccr.2008.08.003. View

20.

Wang Y, Zhou Z, Walsh C, McMahon A . Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation. Proc Natl Acad Sci U S A. 2009; 106(8):2623-8. PMC: 2650314. DOI: 10.1073/pnas.0812110106. View