- Letter to the Editor
- Open Access
Hedgehog pathway inhibitors – current status and future prospects
© Sheikh et al.; licensee BioMed Central Ltd. 2012
- Received: 2 September 2012
- Accepted: 31 October 2012
- Published: 1 November 2012
The Hedgehog (Hh) proteins comprise a group of secreted proteins that regulate cell growth, differentiation and survival. Inappropriate activation of the Hh signaling pathway has been implicated in the development of a variety of cancers. Hedgehog pathway inhibitors are a relatively new class of therapeutic agents that act by targeting the proteins involved in the regulation of Hh pathway (PTCH, SMO and Gli). Together, they serve as exciting new prospects, with a bright future, both alone or as an adjuvant to the more traditional anti-cancer drugs.
- Basal Cell Carcinoma
- Regulate Cell Growth
- Snail Expression
The Hedgehog (Hh) proteins comprise a group of secreted proteins that regulate cell growth, differentiation and survival . They are involved in organogenesis, and have been shown to promote adult stem cell proliferation [2, 3]. Inappropriate activation of the Hh signaling pathway has been implicated in the development of several types of cancers including prostate, lung, pancreas, breast, brain and skin [4–9].
Sonic Hedgehog (Shh) is the best studied ligand of Hh pathway in vertebrates. In the absence of the ligand, the Patched (PTCH) receptor inhibits Smoothened (SMO), a downstream protein in the pathway. Binding of Shh to PTCH alleviates this inhibition, thus regulating the expression of Gli transcription factors . Loss-of-function mutations of PTCH, gain-of-function mutations of SMO and misexpression of the Gli2 and Gli3 have been associated with tumor formation and maintenance in animal models of medulloblastoma and basal cell carcinoma of the skin [11–14]. Other studies have pointed towards Hedgehog signaling having an important role in angiogenesis (by increasing angiopoietin-1 and angiopoietin-2), metastasis (by increasing Snail expression) and suppression of apoptosis (by increasing Cyclins and anti-apoptotic factors and decreasing pro-apoptotic genes such as Fas) [15–18].
Hedgehog pathway inhibitors are a relatively new class of therapeutic agents that act by targeting the proteins involved in the regulation of Hh pathway. Cyclopamine is the prototype inhibitor of the Shh pathway that inactivates SMO by binding to its hepta-helical bundle . It is currently undergoing preclinical and clinical studies as an anticancer agent in basal cell carcinoma, medulloblastoma and rhabdomyosarcoma [20, 21]. Saridegib (IPI-926), a synthetic analog of cyclopamine, has shown positive results in Phase I clinical trial of advanced solid tumors . Similarly, itraconazole, an antifungal drug, has also been shown to suppress growth of medulloblastoma in mice allograft models . This compound acts as an SMO antagonist, in a manner distinct from its anti-lanosterol activity in fungi (other azole drugs have not been found to have this effect). Other candidates for future trials include Novartis’ LDE-225, Millennium Pharmaceuticals' TAK-441, Exelixis/Bristol-Myers Squibb's BMS-833923 (XL139) and Pfizer's PF-04449913 [24, 25].
Vismodegib (IPI-926; Erivedge: Genentech, South St Francisco, CA, USA) has been recently approved by the FDA for treatment of advanced basal cell carcinoma . However, like other drugs in the category, it also has an adverse effect profile. Due to its mechanism of action, it is contraindicated during pregnancy, as it is teratogenic, embryotoxic and fetotoxic . Other adverse reactions include alopecia, muscle spasms, weight loss, fatigue, GIT disturbances and arthralgias .
The approval of Vismodegib by the FDA can prove to be the beginning of a new era in anti-cancer therapeutics. Other drugs targeting the Hh pathway are likely to follow. Together, they serve as exciting new prospects, with a bright future, both alone or as an adjuvant to the more traditional anti-cancer drugs.
- Varjosalo M, Taipale J: Hedgehog: functions and mechanisms. Genes Dev. 2008, 22 (18): 2454-2472. 10.1101/gad.1693608.PubMedView ArticleGoogle Scholar
- Ingham PW, McMahon AP: Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 2001, 15 (23): 3059-10.1101/gad.938601.PubMedView ArticleGoogle Scholar
- Bhardwaj G, Murdoch B, Wu D, Baker D, Williams K, Chadwick K, Ling L, Karanu F, Bhatia M: Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nat Immunol. 2001, 2 (2): 172-180. 10.1038/84282.PubMedView ArticleGoogle Scholar
- Sheng T, Li C, Zhang X, Chi S, He N, Chen K, McCormick F, Gatalica Z, Xie J: Activation of the hedgehog pathway in advanced prostate cancer. Mol Cancer. 2004, 3 (1): 29-10.1186/1476-4598-3-29.PubMedPubMed CentralView ArticleGoogle Scholar
- Watkins DN, Berman DM, Burkholder SG, Wang B, Beachy PA, Baylin SB: Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature. 2003, 422 (6929): 313-317. 10.1038/nature01493.PubMedView ArticleGoogle Scholar
- Thayer SP, Di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, Qi YP, Gysin S, Fernández-del Castillo C, Yajnik V: Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 2003, 425 (6960): 851-856. 10.1038/nature02009.PubMedPubMed CentralView ArticleGoogle Scholar
- Liu S, Dontu G, Mantle ID, Patel S, Ahn N, Jackson KW, Suri P, Wicha MS: Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 2006, 66 (12): 6063-10.1158/0008-5472.CAN-06-0054.PubMedPubMed CentralView ArticleGoogle Scholar
- Dellovade T, Romer JT, Curran T, Rubin LL: The hedgehog pathway and neurological disorders. Annu Rev Neurosci. 2006, 29: 539-563. 10.1146/annurev.neuro.29.051605.112858.PubMedView ArticleGoogle Scholar
- Bale AE, Yu K: The hedgehog pathway and basal cell carcinomas. Hum Mol Genet. 2001, 10 (7): 757-762. 10.1093/hmg/10.7.757.PubMedView ArticleGoogle Scholar
- Michaud EJ, Yoder BK: The primary cilium in cell signaling and cancer. Cancer Res. 2006, 66 (13): 6463-10.1158/0008-5472.CAN-06-0462.PubMedView ArticleGoogle Scholar
- Oro AE, Higgins KM, Hu Z, Bonifas JM, Epstein EH, Scott MP: Basal cell carcinomas in mice overexpressing sonic hedgehog. Science. 1997, 276 (5313): 817-821. 10.1126/science.276.5313.817.PubMedView ArticleGoogle Scholar
- Xie J, Murone M, Luoh S-M, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam C-W, Hynes M, Goddard A, et al: Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998, 391 (6662): 90-92. 10.1038/34201.PubMedView ArticleGoogle Scholar
- Nilsson M, Undèn AB, Krause D, Malmqwist U, Raza K, Zaphiropoulos PG, Toftgård R: Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1. Proc Natl Acad Sci. 2000, 97 (7): 3438-3443. 10.1073/pnas.97.7.3438.PubMedPubMed CentralView ArticleGoogle Scholar
- Grachtchouk M, Mo R, Yu S, Zhang X, Sasaki H, Hui C, Dlugosz AA: Basal cell carcinomas in mice overexpressing Gli2 in skin. Nat Genet. 2000, 24 (3): 216-217. 10.1038/73417.PubMedView ArticleGoogle Scholar
- Lee SW, Moskowitz MA, Sims JR: Sonic hedgehog inversely regulates the expression of angiopoietin-1 and angiopoietin-2 in fibroblasts. Int J Mol Med. 2007, 19 (3): 445-PubMedGoogle Scholar
- Li X, Deng W, Nail CD, Bailey SK, Kraus MH, Ruppert JM, Lobo-Ruppert SM: Snail induction is an early response to Gli1 that determines the efficiency of epithelial transformation. Oncogene. 2005, 25 (4): 609-621.Google Scholar
- Adolphe C, Hetherington R, Ellis T, Wainwright B: Patched1 functions as a gatekeeper by promoting cell cycle progression. Cancer Res. 2006, 66 (4): 2081-2088. 10.1158/0008-5472.CAN-05-2146.PubMedView ArticleGoogle Scholar
- Athar M, Li C, Tang X, Chi S, Zhang X, Kim AL, Tyring SK, Kopelovich L, Hebert J, Epstein EH, et al: Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of fas expression and apoptosis. Cancer Res. 2004, 64 (20): 7545-7552. 10.1158/0008-5472.CAN-04-1393.PubMedView ArticleGoogle Scholar
- Chen JK, Taipale J, Cooper MK, Beachy PA: Inhibition of hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev. 2002, 16 (21): 2743-2748. 10.1101/gad.1025302.PubMedPubMed CentralView ArticleGoogle Scholar
- Kolterud Å, Toftgård R: Strategies for Hedgehog inhibition and its potential role in cancer treatment. Drug Discovery Today: Therapeutic Strategies. 2007, 4 (4): 229-235. 10.1016/j.ddstr.2008.03.002.Google Scholar
- Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, Scott MP, Beachy PA: Effects of oncogenic mutations in smoothened and patched can be reversed by cyclopamine. Nature. 2000, 406 (6799): 1005-1009. 10.1038/35023008.PubMedView ArticleGoogle Scholar
- Rudin C, Jimeno A, Miller W, Eigl B, Gettinger S, Chang A, Faia K, Sweeney J, Loewen G, Ross R: A phase 1 study of IPI-926, a novel hedgehog pathway inhibitor, in patients with advanced or metastatic solid tumors. Surgery. 2011, 32: 94-Google Scholar
- Kim J, Tang JY, Gong R, Kim J, Lee JJ, Clemons KV, Chong CR, Chang KS, Fereshteh M, Gardner D, et al: Itraconazole, a commonly used antifungal that inhibits hedgehog pathway activity and cancer growth. Cancer Cell. 2010, 17 (4): 388-399. 10.1016/j.ccr.2010.02.027.PubMedPubMed CentralView ArticleGoogle Scholar
- Tremblay MR, McGovern K, Read MA, Castro AC: New developments in the discovery of small molecule Hedgehog pathway antagonists. Curr Opin Chem Biol. 2010, 14 (3): 428-435. 10.1016/j.cbpa.2010.03.016.PubMedView ArticleGoogle Scholar
- McMillan R, Matsui W: Molecular Pathways: The Hedgehog Signaling Pathway in Cancer. Clinical Cancer Research. 2012, 18 (18): 4883-4888. 10.1158/1078-0432.CCR-11-2509.PubMedPubMed CentralView ArticleGoogle Scholar
- Dlugosz A, Agrawal S, Kirkpatrick P: Vismodegib. Nat Rev Drug Discov. 2012, 11 (6): 437-438. 10.1038/nrd3753.PubMedView ArticleGoogle Scholar
- Genentech: Erivedge [vismodegib; prescribing information]. 2012, Genentech, Inc, South San Francisco, CAGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.