Biology:Hedgehog pathway inhibitors

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Hedgehog pathway inhibitors are small molecules that inhibit the activity of a component of the Hedgehog signaling pathway. Due to the role of aberrant Hedgehog signaling in tumor progression[1][2][3][4][5][6] and cancer stem cell maintenance[7][8][9] across cancer types, inhibition of the Hedgehog signaling pathway can be a useful strategy for restricting tumor growth and for preventing the recurrence of the disease post-surgery, post-radiotherapy, or post-chemotherapy. Thus, Hedgehog pathway inhibitors are an important class of anti-cancer drugs.[10][11][12] At least three Hedgehog pathway inhibitors have been approved by the Food and Drug Administration (FDA) for cancer treatment.[12] These include Vismodegib[13] and Erismodegib,[14] both inhibitors of Smoothened (SMO), which are being used for the treatment of basal cell carcinoma. Arsenic Trioxide, an inhibitor of GLI transcription factors, is being used for the treatment of acute promyelocytic leukemia.[15] In addition, multiple other Hedgehog pathway inhibitors are in different phases of clinical trials.[12]

Overview of the Hedgehog Signaling Pathway

The classical Hedgehog signaling pathway involves glycoproteins that are secreted by cells into the intercellular space. Multiple such glycoproteins have been characterized: Sonic Hedgehog (Shh), Indian Hedgehog (Ihh), and Desert Hedgehog (Dhh).[16] Among these, Shh is the most potent. It binds and inactivates the transmembrane protein Patched1 (PTCH1). In the absence of Shh, PTCH1 inhibits the activity of Smoothened (SMO), another transmembrane protein. Upon the inactivation of PTCH1 by Shh, glioma-associated (GLI) transcription factors enter the nucleus and activate the expression of multiple genes including Myc, Bcl-2, NANOG, and SOX2. Targets of GLIs include genes involved in cell proliferation, apoptosis, angiogenesis, epithelial-mesenchymal transition, and self-renewal of stem cells.[17][18][19]

In addition to the canonical pathway described above, some alternate pathways related to Shh signaling have also been reported. One example is the activation of SMO without the subsequent entry of GLI transcription factors into the nucleus. Another, better characterized pathway is the activation of GLIs independent of Shh or PTCH1 / SMO. This alternate mode of triggering the activity of GLIs is common in cancer cells. Oncogenes such as KRAS can activate the GLIs in the absence of Shh signaling.[20] Transcriptional activity of GLIs is also upregulated upon the knockdown of p53, a tumor-suppressor gene often lost during cancer progression.[21]

Role of Hedgehog Signaling in Cancer

As mentioned above, targets of the Hedgehog signaling pathway include genes involved in cell proliferation, apoptosis, angiogenesis, epithelial-mesenchymal transition, and self-renewal of stem cells. Dysregulation of all these cellular processes has been reported across cancer types. Abnormal control of these processes in cancer cells is often a consequence of dysregulated Shh signaling.

The first major breakthrough in understanding the role of Shh signaling in cancer progression was the discovery that mutations in the PTCH1 gene, which codes for the PTCH1 protein, were responsible for Gorlin syndrome.[22][23] Gorlin syndrome is an autosomal dominant disorder characterized by developmental abnormalities and increased risk of developing basal cell carcinoma or medulloblastoma.[24][25] Mutations in the PTCH1 gene can lead to the abnormal activation of GLI transcriptional activity which in turn promotes tumor development and progression. Overexpression of Shh ligand has been reported in multiple cancer types including pancreatic, colorectal,[26] prostate,[27] and gliomas.[28] This can lead to the activation of GLI transcriptional activity in the cell over-secreting Shh (autocrine signaling) or in neighboring cells (paracrine signaling). Further, Shh ligands can stimulate the production of growth factors by stromal cells present in the tumor microenvironment. These growth factors, in turn, promote the growth, survival, and proliferation of cancer cells.[29]

Aberrant Shh signaling has also been implicated in the maintenance of cancer stem cells (CSCs). In chronic myeloid leukemia and breast cancer, inhibition of Shh signaling has been shown to reduce stem cell propagation and renewal.[8][9] In pancreatic and colorectal cancer, Shh signaling in CSCs drives epithelial-mesenchymal transition and, ultimately, cancer metastasis.[30][31] CSCs exhibit increased potential for self-renewal, differentiation, and for starting secondary tumors at distant organ sites. CSCs also exhibit mechanisms that drive resistance to chemotherapies and radiotherapy. As a result, while chemotherapy and radiotherapy are often successful in eliminating the bulk of the tumor (which consists of non-CSCs), CSCs that are left behind can lead to tumor recurrence.[32][33] Thus, via its role in CSC maintenance, Shh signaling contributes towards the failure of anti-cancer therapies.

Mechanism of Action of Hedgehog Pathway Inhibitors

Given the role of Shh signaling in promoting tumor progression and in the failure of anti-cancer therapies, the Hedgehog signaling pathway is an important therapeutic target for restricting tumor progression and to prevent disease recurrence post-treatment. Different parts of the Hedgehog signaling pathway may be targeted to abrogate the activation of pathways that promote tumor progression.

SMO Inhibitors

Inhibition of the transmembrane protein Smoothened (SMO) prevents the induction of GLI transcriptional activity upon exposure of cancer cells to Shh ligands. Loss of induction of GLIs upon activation of Shh signaling inhibits the ability of Shh signaling to promote tumor progression and cancer stem cell maintenance. Therefore, SMO has been a primary target in the development of Hedgehog pathway inhibitors. Two such inhibitors, Sonidegib and Vismodegib have been approved by the Food and Drug Administration (FDA) for treating basal cell carcinoma. Multiple other SMO inhibitors are in active clinical trials.

GDC-0449 (Vismodegib / Erivedge)

Vismodegib was created by Roche / Genentech / Curis. It directly binds to SMO, preventing GLI activation.[13] In January 2012, it became the first Hedgehog pathway inhibitor to be approved by the FDA for the treatment of any cancer. Vismodegib is currently used for the treatment of metastatic basal cell carcinoma (BCC) in adults. It is also used for treating patients with locally advanced BCC who are not candidates for surgery or radiation therapy.[34] However, it has been shown that cancer cells in BCC patients can develop resistance to Vismodegib via mutations in the SMO protein which prevents the binding of the drug to SMO.[35][36][37] Effectiveness of Vismodegib as a monotherapy and in combination with other chemotherapies is currently being tested in multiple clinical trials across cancer types, including medulloblastoma, small cell lung cancer, pancreatic cancer, intracranial meningioma, recurrent glioblastoma, and acute myeloid leukemia.[12]

LDE-225 (Erismodegib / Sonidegib / Odomzo)

Erismodegib was created by Novartis. It is a SMO antagonist that can induce arrest of cell division and promote apoptosis in cancer cells.[14] Erismodegib has been effective in limiting the invasive potential of multiple cancer types including glioblastoma,[38] prostate cancer,[39] and renal cell carcinoma.[40] It received FDA approval in July 2015 and is being used for the treatment of BCC that has recurred post-surgery or post-radiation therapy. Erismodegib can also be used in BCC patients who are not candidates for surgery or radiation therapy. Effectiveness of this drug in other cancer types including hematological malignancies is currently being tested in multiple clinical trials.[12]

Other SMO inhibitors currently under clinical trial include IPI-926 (Saridegib),[41] BMS-833923 / XL139 (developed by Bristol-Myers Squibb / Exelexis),[42] PF-04449913 (Glasdegib; developed by Pfizer),[43] and LY2940680 (Taladegib; developed by Eli Lilly and Company).[44][12]

GLI Inhibitors

GLI transcription factors are the terminal effectors of the Hedgehog signaling pathway. Thus, inhibition of GLIs abrogates the ability of Hedgehog signaling to trigger processes that contribute towards tumor progression and recurrence. Since the transcriptional activity of GLIs can be activated via alternate pathways, independent of SMO, GLIs are an important therapeutic target in the development of Hedgehog pathway inhibitors for cancer treatment.

GANTs

GANTs, or GLI inhibitors, were discovered at the National Cancer Institute.[45] GANT-58 and GANT-61 have both been shown to inhibit the GLI-mediated activation of genes. GANT-61 effectively reduced the DNA-binding affinity of GLI1 and GLI2 in multiple cancer cell lines, including rhabdomyosarcoma,[46] osteosarcoma,[47] neuroblastoma,[48] and ovarian cancer.[49]

Arsenic Trioxide (ATO)

Arsenic Trioxide (ATO) directly binds to GLI1 and GLI2 and inhibits the expression of target genes of the Hedgehog signaling pathway, thereby promoting cancer cell apoptosis and reducing cancer cell growth.[15][50] ATO has been approved by the FDA for the treatment of acute promyelocytic leukemia. Further, it has been shown to be effective in restricting the growth of malignant pleural mesothelioma,[51] malignant rhabdosarcoma,[52] prostate cancer,[53] and colon cancer[54] cell lines. ATO has also been shown to inhibit cancer stem cell maintenance in pancreatic cancer.[55] Several clinical trials, ranging from Phase I to Phase IV, are currently underway to test the effectiveness of ATO in both solid tumors and hematological malignancies.[12]

Shh Inhibitors

Sonic Hedgehog (Shh) is the most potent of the three Hedgehog ligands. Inhibition of Shh expression and activity can thus be an effective way of restricting Hedgehog signaling-mediated tumor progression. RU-SKI 43 inhibits the activity of SHHat, an enzyme that catalyzes the palmitoylation of Shh.[56] Since palmitoylation is essential for the activity of Shh,[57] inhibition of SHHat by RU-SKI 43 inhibits Shh signaling in cancer cells.[58][59] 5E1, a monoclonal antibody against Shh, has been shown to inhibit medulloblastoma growth in mouse models.[60] 5E1 also restricts the proliferation of pancreatic cancer cells in mice.[61] While shown to be effective in the lab, both these Shh inhibitors are yet to make their way to human trials.

References

  1. ↑ Berman DM, Karhadkar SS, Hallahan AR, Pritchard JI, Eberhart CG, Watkins DN, Chen JK, Cooper MK, Taipale J, Olson JM, Beachy PA. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science. 2002 Aug 30;297(5586):1559-61.
  2. ↑ Sanchez P, Hernández AM, Stecca B, Kahler AJ, DeGueme AM, Barrett A, Beyna M, Datta MW, Datta S, i Altaba AR. Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling. Proceedings of the National Academy of Sciences. 2004 Aug 24;101(34):12561-6.
  3. ↑ Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, Qi YP, Gysin S, Fernández-del Castillo C, Yajnik V, Antoniu B. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature. 2003 Oct;425(6960):851.
  4. ↑ Tojo M, Kiyosawa H, Iwatsuki K, Kaneko F. Expression of a sonic hedgehog signal transducer, hedgehog‐interacting protein, by human basal cell carcinoma. British Journal of Dermatology. 2002 Jan;146(1):69-73.
  5. ↑ 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 Mar;422(6929):313.
  6. ↑ Yuan Z, Goetz JA, Singh S, Ogden SK, Petty WJ, Black CC, Memoli VA, Dmitrovsky E, Robbins DJ. Frequent requirement of hedgehog signaling in non-small cell lung carcinoma. Oncogene. 2007 Feb;26(7):1046.
  7. ↑ Dierks C, Beigi R, Guo GR, Zirlik K, Stegert MR, Manley P, Trussell C, Schmitt-Graeff A, Landwerlin K, Veelken H, Warmuth M. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer cell. 2008 Sep 9;14(3):238-49.
  8. ↑ 8.0 8.1 Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, Suri P, Wicha MS. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer research. 2006 Jun 15;66(12):6063-71.
  9. ↑ 9.0 9.1 Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J, Kwon HY, Kim J, Chute JP, Rizzieri D, Munchhof M. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature. 2009 Apr;458(7239):776.
  10. ↑ Rubin LL, de Sauvage FJ. Targeting the Hedgehog pathway in cancer. Nature reviews Drug discovery. 2006 Dec;5(12):1026.
  11. ↑ Peukert S, Miller‐Moslin K. Small‐molecule inhibitors of the hedgehog signaling pathway as cancer therapeutics. ChemMedChem: Chemistry Enabling Drug Discovery. 2010 Apr 6;5(4):500-12.
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 Rimkus T, Carpenter R, Qasem S, Chan M, Lo HW. Targeting the sonic hedgehog signaling pathway: review of smoothened and GLI inhibitors. Cancers. 2016 Feb;8(2):22.
  13. ↑ 13.0 13.1 Robarge KD, Brunton SA, Castanedo GM, Cui Y, Dina MS, Goldsmith R, Gould SE, Guichert O, Gunzner JL, Halladay J, Jia W. GDC-0449—a potent inhibitor of the hedgehog pathway. Bioorganic & medicinal chemistry letters. 2009 Oct 1;19(19):5576-81.
  14. ↑ 14.0 14.1 Pan S, Wu X, Jiang J, Gao W, Wan Y, Cheng D, Han D, Liu J, Englund NP, Wang Y, Peukert S. Discovery of NVP-LDE225, a potent and selective smoothened antagonist. ACS medicinal chemistry letters. 2010 Mar 16;1(3):130-4.
  15. ↑ 15.0 15.1 List A, Beran M, DiPersio J, Slack J, Vey N, Rosenfeld CS, Greenberg P. Opportunities for Trisenox®(arsenic trioxide) in the treatment of myelodysplastic syndromes. Leukemia. 2003 Aug;17(8):1499.
  16. ↑ Varjosalo M, Taipale J. Hedgehog: functions and mechanisms. Genes & development. 2008 Sep 15;22(18):2454-72.
  17. ↑ Hui CC, Angers S. Gli proteins in development and disease. Annual review of cell and developmental biology. 2011 Nov 10;27:513-37.
  18. ↑ Scales SJ, de Sauvage FJ. Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends in pharmacological sciences. 2009 Jun 1;30(6):303-12.
  19. ↑ Stecca B, Ruiz i Altaba A. Context-dependent regulation of the GLI code in cancer by HEDGEHOG and non-HEDGEHOG signals. Journal of molecular cell biology. 2010 Apr 1;2(2):84-95.
  20. ↑ Rajurkar M, De Jesus-Monge WE, Driscoll DR, Appleman VA, Huang H, Cotton JL, Klimstra DS, Zhu LJ, Simin K, Xu L, McMahon AP. The activity of Gli transcription factors is essential for Kras-induced pancreatic tumorigenesis. Proceedings of the National Academy of Sciences. 2012 Apr 24;109(17):E1038-47.
  21. ↑ Stecca B, i Altaba AR. A GLI1‐p53 inhibitory loop controls neural stem cell and tumour cell numbers. The EMBO Journal. 2009 Mar 18;28(6):663-76.
  22. ↑ Aszterbaum M, Rothman A, Fisher M, Xie J, Bonifas JM, Zhang X, Epstein Jr EH, Johnson RL, Scott MP. Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. Journal of investigative dermatology. 1998 Jun 1;110(6):885-8.
  23. ↑ Hahn H, Wicking C, Zaphiropoulos PG, Gailani MR, Shanley S, Chidambaram A, Vorechovsky I, Holmberg E, Unden AB, Gillies S, Negus K. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996 Jun 14;85(6):841-51.
  24. ↑ Gorlin RJ, Goltz RW. Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib: a syndrome. New England Journal of Medicine. 1960 May 5;262(18):908-12.
  25. ↑ Kimonis VE, Goldstein AM, Pastakia B, Yang ML, Kase R, DiGiovanna JJ, Bale AE, Bale SJ. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. American journal of medical genetics. 1997 Mar 31;69(3):299-308.
  26. ↑ Varnat F, Duquet A, Malerba M, Zbinden M, Mas C, Gervaz P, i Altaba AR. 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 molecular medicine. 2009 Sep 28;1(6-7):338-51.
  27. ↑ Karhadkar SS, Bova GS, Abdallah N, Dhara S, Gardner D, Maitra A, Isaacs JT, Berman DM, Beachy PA. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature. 2004 Oct;431(7009):707.
  28. ↑ Carpenter RL, Paw I, Zhu H, Sirkisoon S, Xing F, Watabe K, Debinski W, Lo HW. The gain-of-function GLI1 transcription factor TGLI1 enhances expression of VEGF-C and TEM7 to promote glioblastoma angiogenesis. Oncotarget. 2015 Sep 8;6(26):22653.
  29. ↑ Yauch RL, Gould SE, Scales SJ, Tang T, Tian H, Ahn CP, Marshall D, Fu L, Januario T, Kallop D, Nannini-Pepe M. A paracrine requirement for hedgehog signalling in cancer. Nature. 2008 Sep;455(7211):406.
  30. ↑ Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, Mullendore M, Karikari C, Alvarez H, Iacobuzio-Donahue C, Jimeno A, Gabrielson KL. Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer research. 2007 Mar 1;67(5):2187-96.
  31. ↑ Rasheed ZA, Yang J, Wang Q, Kowalski J, Freed I, Murter C, Hong SM, Koorstra JB, Rajeshkumar NV, He X, Goggins M. Prognostic significance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma. Journal of the National Cancer Institute. 2010 Mar 3;102(5):340-51.
  32. ↑ Prieto-Vila M, Takahashi RU, Usuba W, Kohama I, Ochiya T. Drug resistance driven by cancer stem cells and their niche. International journal of molecular sciences. 2017 Dec 1;18(12):2574.
  33. ↑ Phi LT, Sari IN, Yang YG, Lee SH, Jun N, Kim KS, Lee YK, Kwon HY. Cancer stem cells (CSCs) in drug resistance and their therapeutic implications in cancer treatment. Stem cells international. 2018;2018.
  34. ↑ Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, Solomon JA, Yoo S, Arron ST, Friedlander PA, Marmur E. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. New England Journal of Medicine. 2012 Jun 7;366(23):2171-9.
  35. ↑ Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA, Fu L, Holcomb T, Stinson J, Gould SE, Coleman B, LoRusso PM. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. New England Journal of Medicine. 2009 Sep 17;361(12):1173-8.
  36. ↑ Yauch RL, Dijkgraaf GJ, Alicke B, Januario T, Ahn CP, Holcomb T, Pujara K, Stinson J, Callahan CA, Tang T, Bazan JF. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science. 2009 Oct 23;326(5952):572-4.
  37. ↑ Metcalfe C, de Sauvage FJ. Hedgehog fights back: mechanisms of acquired resistance against Smoothened antagonists. Cancer research. 2011 Aug 1;71(15):5057-61.
  38. ↑ Fu J, Rodova M, Nanta R, Meeker D, Van Veldhuizen PJ, Srivastava RK, Shankar S. NPV-LDE-225 (Erismodegib) inhibits epithelial mesenchymal transition and self-renewal of glioblastoma initiating cells by regulating miR-21, miR-128, and miR-200. Neuro-oncology. 2013 Mar 12;15(6):691-706.
  39. ↑ Nanta R, Kumar D, Meeker D, Rodova M, Van Veldhuizen PJ, Shankar S, Srivastava RK. NVP-LDE-225 (Erismodegib) inhibits epithelial–mesenchymal transition and human prostate cancer stem cell growth in NOD/SCID IL2Rγ null mice by regulating Bmi-1 and microRNA-128. Oncogenesis. 2013 Apr;2(4):e42.
  40. ↑ D’Amato C, Rosa R, Marciano R, D’Amato V, Formisano L, Nappi L, Raimondo L, Di Mauro C, Servetto A, Fulciniti F, Cipolletta A. Inhibition of Hedgehog signalling by NVP-LDE225 (Erismodegib) interferes with growth and invasion of human renal cell carcinoma cells. British journal of cancer. 2014 Sep;111(6):1168.
  41. ↑ Tremblay MR, Lescarbeau A, Grogan MJ, Tan E, Lin G, Austad BC, Yu LC, Behnke ML, Nair SJ, Hagel M, White K. Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926). Journal of medicinal chemistry. 2009 Jun 12;52(14):4400-18.
  42. ↑ Gendreau SB, Hawkins D, Ho CP, Lewin A, Lin T, Merchant A, Rowley RB, Wang Q, Matsui W, Fargnoli J. Abstract B192: Preclinical characterization of BMS‐833923 (XL139), a hedgehog (HH) pathway inhibitor in early clinical development.
  43. ↑ Munchhof MJ, Li Q, Shavnya A, Borzillo GV, Boyden TL, Jones CS, LaGreca SD, Martinez-Alsina L, Patel N, Pelletier K, Reiter LA. Discovery of PF-04449913, a potent and orally bioavailable inhibitor of smoothened. ACS medicinal chemistry letters. 2011 Dec 21;3(2):106-11.
  44. ↑ Bender MH, Hipskind PA, Capen AR, Cockman M, Credille KM, Gao H, Bastian JA, Clay JM, Lobb KL, Sall DJ, Thompson ML. Identification and characterization of a novel smoothened antagonist for the treatment of cancer with deregulated hedgehog signaling.
  45. ↑ Lauth M, Bergström Å, Shimokawa T, Toftgård R. Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proceedings of the National Academy of Sciences. 2007 May 15;104(20):8455-60.
  46. ↑ Srivastava RK, Kaylani SZ, Edrees N, Li C, Talwelkar SS, Xu J, Palle K, Pressey JG, Athar M. GLI inhibitor GANT-61 diminishes embryonal and alveolar rhabdomyosarcoma growth by inhibiting Shh/AKT-mTOR axis. Oncotarget. 2014 Dec;5(23):12151.
  47. ↑ Shahi MH, Holt R, Rebhun RB. Blocking signaling at the level of GLI regulates downstream gene expression and inhibits proliferation of canine osteosarcoma cells. PLOS ONE. 2014 May 8;9(5):e96593.
  48. ↑ Wickström M, Dyberg C, Shimokawa T, Milosevic J, Baryawno N, Fuskevåg OM, Larsson R, Kogner P, Zaphiropoulos PG, Johnsen JI. Targeting the hedgehog signal transduction pathway at the level of GLI inhibits neuroblastoma cell growth in vitro and in vivo. International journal of cancer. 2013 Apr 1;132(7):1516-24.
  49. ↑ Chen Q, Xu R, Zeng C, Lu Q, Huang D, Shi C, Zhang W, Deng L, Yan R, Rao H, Gao G. Down-regulation of Gli transcription factor leads to the inhibition of migration and invasion of ovarian cancer cells via integrin β4-mediated FAK signaling. PLOS ONE. 2014 Feb 12;9(2):e88386.
  50. ↑ Beauchamp EM, Ringer L, Bulut G, Sajwan KP, Hall MD, Lee YC, Peaceman D, Özdemirli M, Rodriguez O, Macdonald TJ, Albanese C. Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. The Journal of clinical investigation. 2011 Jan 4;121(1):148-60.
  51. ↑ You M, Varona-Santos J, Singh S, Robbins DJ, Savaraj N, Nguyen DM. Targeting of the Hedgehog signal transduction pathway suppresses survival of malignant pleural mesothelioma cells in vitro. The Journal of thoracic and cardiovascular surgery. 2014 Jan 1;147(1):508-16.
  52. ↑ Kerl K, Moreno N, Holsten T, Ahlfeld J, Mertins J, Hotfilder M, Kool M, Bartelheim K, Schleicher S, Handgretinger R, Schüller U. Arsenic trioxide inhibits tumor cell growth in malignant rhabdoid tumors in vitro and in vivo by targeting overexpressed Gli1. International journal of cancer. 2014 Aug 15;135(4):989-95.
  53. ↑ Bansal N, Farley NJ, Wu L, Lewis J, Youssoufian H, Bertino JR. Darinaparsin inhibits prostate tumor–initiating cells and Du145 xenografts and is an inhibitor of Hedgehog signaling. Molecular cancer therapeutics. 2015 Jan 1;14(1):23-30.
  54. ↑ Cai X, Yu K, Zhang L, Li Y, Li Q, Yang Z, Shen T, Duan L, Xiong W, Wang W. Synergistic inhibition of colon carcinoma cell growth by Hedgehog-Gli1 inhibitor arsenic trioxide and phosphoinositide 3-kinase inhibitor LY294002. OncoTargets and therapy. 2015;8:877.
  55. ↑ Han JB, Sang F, Chang JJ, Hua YQ, Shi WD, Tang LH, Liu LM. Arsenic trioxide inhibits viability of pancreatic cancer stem cells in culture and in a xenograft model via binding to SHH-Gli. OncoTargets and therapy. 2013;6:1129.
  56. ↑ Petrova E, Rios-Esteves J, Ouerfelli O, Glickman JF, Resh MD. Inhibitors of Hedgehog acyltransferase block Sonic Hedgehog signaling. Nature chemical biology. 2013 Apr;9(4):247.
  57. ↑ Buglino JA, Resh MD. Hhat is a palmitoylacyltransferase with specificity for N-palmitoylation of Sonic Hedgehog. Journal of Biological Chemistry. 2008 Aug 8;283(32):22076-88.
  58. ↑ Matevossian A, Resh MD. Hedgehog Acyltransferase as a target in estrogen receptor positive, HER2 amplified, and tamoxifen resistant breast cancer cells. Molecular cancer. 2015 Dec;14(1):72.
  59. ↑ Petrova E, Matevossian A, Resh MD. Hedgehog acyltransferase as a target in pancreatic ductal adenocarcinoma. Oncogene. 2015 Jan;34(2):263.
  60. ↑ Coon V, Laukert T, Pedone CA, Laterra J, Kim KJ, Fults DW. Molecular therapy targeting Sonic hedgehog and hepatocyte growth factor signaling in a mouse model of medulloblastoma. Molecular cancer therapeutics. 2010 Sep 1;9(9):2627-36.
  61. ↑ Chang Q, Foltz WD, Chaudary N, Hill RP, Hedley DW. Tumor–stroma interaction in orthotopic primary pancreatic cancer xenografts during hedgehog pathway inhibition. International journal of cancer. 2013 Jul;133(1):225-34.




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