Abstract
The Hedgehog (Hh) pathway is a developmental signaling pathway involved in numerous developmental processes, including determination of cell fate, patterning, proliferation, survival, and differentiation. While this pathway is silenced in most adult tissues, aberrant activation of it has been documented in a variety of malignancies. In cancers such as basal cell carcinoma (BCC), ligand-independent mechanisms lead to constitutive Hh pathway activation through mutations in components of the pathway, including patched-1 (PTCH1) or smoothened (SMO). On the contrary, numerous other solid and hematologic tumors have been shown to harbor ligand-dependent activation of the Hh pathway by autocrine or paracrine mechanisms. Given that aberrant Hh pathway signaling has been seen in a number of malignancies, this pathway has been an attractive target for drug development. While the best-characterized approach is to target the SMO receptor, other rational approaches for inhibiting the Hh pathway include inhibiting downstream components or directly binding Hh ligands. In January of 2012, vismodegib, a SMO antagonist, became the first agent to target the Hh pathway to receive approval by the United States Food and Drug Administration (FDA) after this agent showed remarkable activity in phase I and II trials for the treatment of BCC. Despite promising preclinical studies with Hh pathway inhibitors in other malignancies that have suggested a potential role for these agents, attempts to translate this potential to clinical benefit has been disappointing. Future efforts will require further careful interpretation and analysis to determine the potential determinants and predictors of efficacy. Currently, several phase I and II trials evaluating Hh inhibitors in a variety of tumor settings are underway.
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Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783–92.
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659–72.
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673–84.
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–57.
Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239–46.
Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735–42.
Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):809–19.
Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 2001;15(23):3059–87.
Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature. 1980;287(5785):795–801.
Gupta S, Takebe N, Lorusso P. Targeting the Hedgehog pathway in cancer. Ther Adv Med Oncol. 2010;2(4):237–50.
Palma V, Lim DA, Dahmane N, et al. Sonic hedgehog controls stem cell behavior in the postnatal and adult brain. Development. 2005;132(2):335–44.
van den Brink GR, Bleuming SA, Hardwick JC, et al. Indian Hedgehog is an antagonist of Wnt signaling in colonic epithelial cell differentiation. Nat Genet. 2004;36(3):277–82.
Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis. Nature. 2004;432(7015):324–31.
McMillan R, Matsui W. Molecular pathways: the Hedgehog signaling pathway in cancer. Clin Cancer Res. 2012;18:4883–8.
Hui CC, Angers S. Gli proteins in development and disease. Annu Rev Cell Dev Biol. 2011;27:513–37.
Corbit KC, Aanstad P, Singla V, et al. Vertebrate smoothened functions at the primary cilium. Nature. 2005;437(7061):1018–21.
Scales SJ, de Sauvage FJ. Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci. 2009;30(6):303–12.
Kinzler KW, Bigner SH, Bigner DD, et al. Identification of an amplified, highly expressed gene in a human glioma. Science. 1987;236(4797):70–3.
Gorlin RJ, Goltz RW. Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib. A syndrome. N Engl J Med. 1960;262:908–12.
Hahn H, Wicking C, Zaphiropoulous PG, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996;85(6):841–51.
Johnson RL, Rothman AL, Xie J, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 1996;272(5268):1668–71.
Dahmane N, Lee J, Robins P, et al. Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours. Nature. 1997;389(6653):876–81.
Xie J, Murone M, Luoh SM, et al. Activating smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998;391(6662):90–2.
Kool M, Koster J, Bunt J, et al. Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS One. 2008;3(8):e3088.
Taylor MD, Liu L, Raffel C, et al. Mutations in SUFU predispose to medulloblastoma. Nat Genet. 2002;31(3):306–10.
Tostar U, Malm CJ, Meis-Kindblom JM, et al. Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development. J Pathol. 2006;208(1):17–25.
Berman DM, Karhadkar SS, Maitra A, et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature. 2003;425(6960):846–51.
Varnat F, Duquet A, Malerba M, et al. Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion. EMBO Mol Med. 2009;1(6–7):338–51.
Bar EE, Chaudhry A, Lin A, et al. Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells. 2007;25(10):2524–33.
Stecca B, Mas C, Clement V, et al. Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proc Natl Acad Sci USA. 2007;104(14):5895–900.
Yuan Z, Goetz JA, Singh S, et al. Frequent requirement of hedgehog signaling in non-small cell lung carcinoma. Oncogene. 2007;26(7):1046–55.
Thayer SP, di Magliano MP, Heiser PW, et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 2003;425(6960):851–6.
Karhadkar SS, Bova GS, Abdallah N, et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature. 2004;431(7009):707–12.
Watkins DN, Berman DM, Burkholder SG, et al. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature. 2003;422(6929):313–7.
Theunissen JW, de Sauvage FJ. Paracrine Hedgehog signaling in cancer. Cancer Res. 2009;69(15):6007–10.
Yauch RL, Gould SE, Scales SJ, et al. A paracrine requirement for hedgehog signalling in cancer. Nature. 2008;455(7211):406–10.
Seeley ES, Carriere C, Goetze T, et al. Pancreatic cancer and precursor pancreatic intraepithelial neoplasia lesions are devoid of primary cilia. Cancer Res. 2009;69(2):422–30.
Hegde GV, Peterson KJ, Emanuel K, et al. Hedgehog-induced survival of B-cell chronic lymphocytic leukemia cells in a stromal cell microenvironment: a potential new therapeutic target. Mol Cancer Res. 2008;6(12):1928–36.
Dierks C, Grbic J, Zirlik K, et al. Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nat Med. 2007;13(8):944–51.
Taipale J, Beachy PA. The Hedgehog and Wnt signalling pathways in cancer. Nature. 2001;411(6835):349–54.
Zhang Y, Kalderon D. Hedgehog acts as a somatic stem cell factor in the Drosophila ovary. Nature. 2001;410(6828):599–604.
Dierks C, Beigi R, Guo GR, et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell. 2008;14(3):238–49.
Zhao C, Chen A, Jamieson CH, et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature. 2009;458(7239):776–9.
Li C, Heidt DG, Dalerba P, et al. Identification of pancreatic cancer stem cells. Cancer Res. 2007;67(3):1030–7.
Liu S, Dontu G, Mantle ID, et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 2006;66(12):6063–71.
Peacock CD, Wang Q, Gesell GS, et al. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci USA. 2007;104(10):4048–53.
Chen JK, Taipale J, Cooper MK, et al. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev. 2002;16(21):2743–8.
Cooper MK, Porter JA, Young KE, et al. Teratogen-mediated inhibition of target tissue response to Shh signaling. Science. 1998;280(5369):1603–7.
Tremblay MR, Nevalainen M, Nair SJ, et al. Semisynthetic cyclopamine analogues as potent and orally bioavailable hedgehog pathway antagonists. J Med Chem. 2008;51(21):6646–9.
Maun HR, Wen X, Lingel A, et al. Hedgehog pathway antagonist 5E1 binds hedgehog at the pseudo-active site. J Biol Chem. 2010;285(34):26570–80.
Stanton BZ, Peng LF, Maloof N, et al. A small molecule that binds Hedgehog and blocks its signaling in human cells. Nat Chem Biol. 2009;5(3):154–6.
Metcalfe C, de Sauvage FJ. Hedgehog fights back: mechanisms of acquired resistance against Smoothened antagonists. Cancer Res. 2011;71(15):5057–61.
Yauch RL, Dijkgraaf GJ, Alicke B, et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science. 2009;326(5952):572–4.
Buonamici S, Williams J, Morrissey M, et al. Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci Transl Med. 2010;2(51):51ra70.
Dijkgraaf GJ, Alicke B, Weinmann L, et al. Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance. Cancer Res. 2011;71(2):435–44.
Hyman JM, Firestone AJ, Heine VM, et al. Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade. Proc Natl Acad Sci USA. 2009;106(33):14132–7.
Lauth M, Bergstrom A, Shimokawa T, et al. Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc Natl Acad Sci USA. 2007;104(20):8455–60.
Mazumdar T, Devecchio J, Agyeman A, et al. Blocking Hedgehog survival signaling at the level of the GLI genes induces DNA damage and extensive cell death in human colon carcinoma cells. Cancer Res. 2011;71(17):5904–14.
Mazumdar T, DeVecchio J, Shi T, et al. Hedgehog signaling drives cellular survival in human colon carcinoma cells. Cancer Res. 2011;71(3):1092–102.
Kim J, Lee JJ, Gardner D, et al. Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector. Proc Natl Acad Sci USA. 2010;107(30):13432–7.
Beauchamp EM, Ringer L, Bulut G, et al. Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. J Clin Invest. 2011;121(1):148–60.
LoRusso PM, Rudin CM, Reddy JC, et al. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clinical Cancer Res. 2011;17(8):2502–11.
Von Hoff DD, LoRusso PM, Rudin CM, et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med. 2009;361(12):1164–72.
Lorusso PM, Jimeno A, Dy G, et al. Pharmacokinetic dose-scheduling study of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors. Clin Cancer Res. 2011;17(17):5774–82.
Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171–9.
Tang JY, Mackay-Wiggan JM, Aszterbaum M, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med. 2012;366(23):2180–8.
Skvara H, Kalthoff F, Meingassner JG, et al. Topical treatment of basal cell carcinomas in nevoid basal cell carcinoma syndrome with a smoothened inhibitor. J Invest Dermatol. 2011;131(8):1735–44.
Siu LL, Papadopoulos K, Alberts SR, et al. A first-in-human, phase I study of an oral hedgehog (HH) pathway antagonist, BMS-833923 (XL139), in subjects with advanced or metastatic solid tumors. J Clin Oncol. 2010;25(15s):abstr2501.
Rudin CM, Jimeno A, Miller WH, et al. A phase I study of IPI-926, a novel hedgehog pathway inhibitor, in patients (pts) with advanced or metastatic solid tumors. J Clin Oncol. 2011;29(Suppl):Abstr3014.
Rudin CM, Hann CL, Laterra J, et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med. 2009;361(12):1173–8.
Kaye S, Fehrenbacher L, Holloway R, et al. A phase 2, randomized, placebo-controlled study of Hedgehog (Hh) pathway inhibitor GDC-0449 as maintenance therapy in patients with ovarian cancer in 2nd or 3rd complete remission (CR). ESMO Meet Abstr. 2010;21(viii):11.
Berlin JD, Bendell J, Hart LL, et al. A phase 2, randomized, double-blind, placebo-controlled study of Hedgehog pathway inhibitor (Hpi) GDC-0449 in patients with previously untreated metastatic colorectal cancer (MCRC). ESMO Meet Abstr. 2010;21(viii):10.
Curis, Inc. Curis announces Genentech’s phase II clinical trial results of GDC-0449 in combination with avastin (R) and chemotherapy in first-line metastatic colorectal cancer. 2012. http://phx.corporate-ir.net/phoenix.zhtml?c=123198&p=irol-newsArticle&ID=1438731&highlight. Cited 18 Sept 2012.
Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324(5933):1457–61.
Richards DA, Stephenson J, Wolpin BM, et al. A phase Ib trial of IPI-926, a hedgehog pathway inhibitor, plus gemcitabine in patients with metastatic pancreatic cancer. J Clin Oncol. 2012;30(suppl 4):Abstract 213.
Infinity Pharmaceuticals, Inc. Infinity reports update from phase 2 study of saridegib plus gemcitabine in patients with metastatic pancreatic cancer. 2012. http://phx.corporate-ir.net/phoenix.zhtml?c=121941&p=irol-newsArticle&ID=1653550. Cited 18 Sept 2012.
Catenacci DVT, Bahary N, Edelman MJ, et al. A phase IB/randomized phase II study of gemcitabine (G) plus placebo (P) or vismodegib (V), a hedgehog (Hh) pathway inhibitor, in patients (pts) with metastatic pancreatic cancer (PC): interim analysis of a University of Chicago phase II consortium study. J Clin Oncol. 2012;30(suppl):Abstract 4022.
AACR. Inhibiting Hedgehog signaling pathway may improve pancreatic cancer treatment. 2012. http://www.aacr.org/home/public--media/aacr-press-releases.aspx?d=2830. Cited 18 Sept 2012.
AACR. News in brief: inhibiting Hedgehog pathway may aid in pancreatic cancer treatment. Cancer Discov. 2012;2:OF5.
Irvine DA, Copland M. Targeting hedgehog in hematologic malignancy. Blood. 2012;119(10):2196–204.
Jamieson C, Cortes JE, Oehler V, et al. Phase 1 dose-escalation study of PF-04449913, an oral Hedgehog (Hh) inhibitor, in patients with select hematologic malignancies. Blood (ASH Annu Meet Abstr) 2011;118:Abstract 424.
Lam CW, Xie J, To KF, et al. A frequent activated smoothened mutation in sporadic basal cell carcinomas. Oncogene. 1999;18(3):833–6.
Aszterbaum M, Rothman A, Johnson RL, et al. Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. J Invest Dermatol. 1998;110(6):885–8.
Wolter M, Reifenberger J, Sommer C, et al. Mutations in the human homologue of the Drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res. 1997;57(13):2581–5.
Raffel C, Jenkins RB, Frederick L, et al. Sporadic medulloblastomas contain PTCH mutations. Cancer Res. 1997;57(5):842–5.
Zwerner JP, Joo J, Warner KL, et al. The EWS/FLI1 oncogenic transcription factor deregulates GLI1. Oncogene. 2008;27(23):3282–91.
Nolan-Stevaux O, Lau J, Truitt ML, et al. GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev. 2009;23(1):24–36.
Rajurkar M, De Jesus-Monge WE, Driscoll DR, et al. The activity of Gli transcription factors is essential for Kras-induced pancreatic tumorigenesis. Proc Natl Acad Sci USA. 2012;109(17):E1038–47.
Tian H, Callahan CA, DuPree KJ, et al. Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc Natl Acad Sci USA. 2009;106(11):4254–9.
Queiroz KC, Ruela-de-Sousa RR, Fuhler GM, et al. Hedgehog signaling maintains chemoresistance in myeloid leukemic cells. Oncogene. 2010;29(48):6314–22.
Xu Y, Chenna V, Hu C, et al. Polymeric nanoparticle-encapsulated hedgehog pathway inhibitor HPI-1 (NanoHHI) inhibits systemic metastases in an orthotopic model of human hepatocellular carcinoma. Clin Cancer Res. 2012;18(5):1291–302.
Bhattacharya R, Kwon J, Ali B, et al. Role of hedgehog signaling in ovarian cancer. Clin Cancer Res. 2008;14(23):7659–66.
US National Institutes of Health. ClinicalTrials.gov. 2012. http://www.clinicaltrials.gov.
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Ruch, J.M., Kim, E.J. Hedgehog Signaling Pathway and Cancer Therapeutics: Progress to Date. Drugs 73, 613–623 (2013). https://doi.org/10.1007/s40265-013-0045-z
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DOI: https://doi.org/10.1007/s40265-013-0045-z