DOCSLIB.ORG

Vismodegib Resistance in Basal Cell Carcinoma: Not a Smooth Fit

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Vismodegib Resistance in Basal Cell Carcinoma: Not a Smooth Fit View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Cancer Cell Previews Vismodegib Resistance in Basal Cell Carcinoma: Not a Smooth Fit Todd W. Ridky1 and George Cotsarelis1,* 1Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, BRB 1053, 421 Curie Boulevard, Philadelphia, PA 19104, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccell.2015.02.009 In this issue of Cancer Cell, two complementary papers by Atwood and colleagues and Sharpe and colleagues show that basal cell carcinomas resistant to the Smoothened (SMO) inhibitor vismodegib frequently harbor SMO mutations that limit drug binding, with mutations at some sites also increasing basal SMO activity. Basal cell carcinoma (BCC) of the skin is target, Smoothened (SMO), was subse- to mutations downstream of SMO at the the most common human cancer in lightly quently identified in 2000 (Cooper et al., level of Gli2 or SUFU (a Gli regulator). pigmented individuals. Mutations acti- 1998; Incardona et al., 1998; Taipale By aligning the mutations with a vating the Hedgehog (HH) signaling et al., 2000). That initial work defining recently solved crystal structure of the pathway drive BCC. Secreted HH exerts the SMO-cyclopamine interaction also SMO transmembrane domain, the au- its effects through binding to Patched included the observation that some thors were able to separate the resis- (PTCH), a 12-pass membrane bound re- SMO point mutants driving BCCs not tance-associated mutations into two ceptor, which relieves PTCH inhibitory only increase basal SMO activity, but groups: (1) mutations within or immedi- activity on the downstream heptahelical simultaneously confer cyclopamine resis- ately adjacent to the ligand/drug binding transmembrane protein Smoothened tance. The elegant and comprehensive pocket and (2) mutations at more distant (SMO). How PTCH actually inhibits SMO work presented by Atwood et al. (2015) sites. Using HH pathway reporter con- is not clear, but SMO activation leads to and Sharpe et al. (2015) in this issue of structs in cell lines engineered to express downstream activation of Gli transcription Cancer Cell uses cutting edge technol- mutant SMO proteins, both groups factors that ultimately drive HH target ogy and a large collection of tumor demonstrate that the resistance-associ- gene expression. Several human malig- samples to pinpoint exact mutations in ated mutations confer vismodegib resis- nancies including medulloblastoma (MB) SMO that confer resistance to vismode- tance. Interestingly, the mutations outside and BCC are driven by mutations in gib, the cyclopamine analog used to treat of the ligand binding pocket also increase one or more HH pathway genes, most HH driven tumors. the basal activity of SMO, even in the commonly PTCH1. Germline mutations Because most BCCs are driven by absence of the inhibitor. These mutations in PTCH1 cause Gorlin’s syndrome, which PTCH mutations, most tumors initially include the W535L mutation, a bona fide is associated with developmental abnor- respond to vismodegib. However, at least oncodriver highlighted in the seminal malities and tumor susceptibility that in- 20% develop resistance. The two papers work that established SMO as the cyclop- cludes BCC and MB. HH signaling is by Atwood et al. (2015) and Sharpe et al. amine target. Tumors harboring this mu- critical during embryologic development (2015) show that BCC resistance to the tation at the outset should not respond but has only limited roles in adult tissues, SMO inhibitor is frequently the result of to vismodegib. In contrast, the binding making it an excellent target for cancer mutations in SMO, similar to resistance pocket mutations have little effect on therapeutics. mechanisms for MB (Yauch et al., 2009). basal SMO activity and are likely not suffi- The development of drugs targeting Both groups sequenced DNA from cient oncodrivers on their own, because the HH pathway began in 1957 when BCCs arising in three settings: (1) sponta- most are still inhibited by PTCH1. Idaho farmers noted that many of their neously in the general population, (2) In addition to cell-based functional newborn sheep were born with severe Gorlin’s syndrome patients, and (3) recur- studies demonstrating vismodegib resis- developmental defects, including a single rent/resistant tumors in patients treated tance and computer modeling predicting cyclopic eye. Curiously, the pregnant with vismodegib. Findings from the two altered binding affinity, Sharpe et al. mothers had no obvious symptoms. An studies are quite similar, showing that (2015) used physical biochemisty ap- 11-year Food and Drug Administration 15%–33% of untreated BCCs harbor proaches with 3H-labeled vismodegib to investigation eventually identified the SMO mutations. This increases to 69%– demonstrate that SMO mutations inside veratrum alkaloid cyclopamine, which 77% in resistant tumors. Resistant tumors and outside the ligand binding pocket was present in the California corn lily without SMO mutations still maintain HH both compromise drug binding. They plant growing in the fields grazed by pathway activation, as evidenced by a also demonstrate that vismodegib resis- sheep, as the causative agent. Thirty high level HH target gene (Gli) expression tant mutations confer cross-resistance years later, a pair of papers using avian and relatively unchanged tumor histology. to other small molecule SMO inhibitors, systems determined that cyclopamine In many of these resistant cases without suggesting that combinations of SMO in- inhibits HH signaling, and the molecular SMO mutations, resistance is likely due hibitors from the vismodegib class will Cancer Cell 27, March 9, 2015 ª2015 Elsevier Inc. 315 Cancer Cell Previews likely not provide additional trioxide, which promotes Gli therapeutic benefit. HH protein degradation and also vismodegib As predicted by Peter inhibits HH activity driven by Nowell’s classic evolutionary an inhibitor-resistant SMO model of tumor development mutation. Because BCC (Nowell, 1976), the hetero- itraconazole tumors have demonstrated geneity of mutations within SMO several mechanisms of different cells within a tumor PTCH bypassing SMO inhibitors SUFU protects against the demise ι/λ that maintain HH signaling, PSI aPKC of the tumor by specifically Gli perhaps the optimal thera- targeted therapies. The inevi- Arsenic trioxide peutic approach will be to table conclusion from this treat patients with multiple work, as also seen with the inhibitors from the outset, Gli remarkable new therapies rather than sequentially as for melanoma, is that, while resistant clones emerge. targeted agents can produce spectacular initial responses, REFERENCES resistance develops as minor clones expand in the pres- Atwood, S.X., Li, M., Lee, A., Tang, ence of drug. Both groups J.Y., and Oro, A.E. (2013). Nature Figure 1. HH Signaling Pathway 494, 484–488. conclude that, unlike many BCC is driven by activation of the HH pathway. Normally, Patched signaling in- other human malignancies, hibits Smoothened, which prevents Smoothened from activating Gli transcrip- Atwood, S.X., Sarin, K.Y., Whitson, tion factors that transcribe HH target genes. Gli is also inhibited by Supressor of which are capable of R.J., Li, J.R., Kim, G., Rezaee, M., fused (SUFU) and activated by aPKC-i/l. During development, and in a few Ally, M.S., Kim, J., Yao, C., Chang, engaging other mitogenic adult tissues, HH binds to Patched, releasing its inhibitory activity on SMO A.L.S., et al. (2015). Cancer Cell pathways to circumvent tar- and thereby activating the pathway. BCC is driven most commonly by inactivat- 27, this issue, 342–353. PTCH geting inhibitors, BCC ap- ing mutations in , although activating mutations in SMO or Gli can also serve as oncodrivers. Tumor resistance to vismodegib usually results from Cooper, M.K., Porter, J.A., Young, pears dependent on the SMO mutations that prevent drug binding. Targeting the pathway downstream K.E., and Beachy, P.A. (1998). Sci- HH pathway. Therefore, over- may therefore be a useful therapeutic strategy. Red, elements that normally ence 280, 1603–1607. coming vismodegib resis- suppress HH signaling; green, elements that activate the pathway; yellow, phar- macologic agents that may be useful for primary or vismodegib resistant BCC. Incardona, J.P., Gaffield, W., Kapur, tance will require combina- R.P., and Roelink, H. (1998). Devel- tion therapy with agents that opment 125, 3553–3562. inhibit SMO through different mecha- downstream of SMO would be predicted Kim, J., Aftab, B.T., Tang, J.Y., Kim, D., Lee, nisms or that target the HH pathway at to lead to resistance to any SMO-targeted A.H., Rezaee, M., Kim, J., Chen, B., King, points downstream of SMO. Potential inhibitor, so an ideal therapeutic approach E.M., Borodovsky, A., et al. (2013). Cancer Cell 23 SMO-targeting agents with efficacy may include a drug combination that also , 23–34. against SMO resistant mutants include targets Gli. In that regard, Atwood et al. Nowell, P.C. (1976). Science 194, 23–28. substituted bis-amides (which have struc- (2015) present data using an atypical pro- tural similarity to vismodegib) and the tein kinase C i/l (aPKC-i/l) inhibitor that Sharpe, H.J., Pau, G., Dijkgraaf, G.J., Basset- FDA-approved antifungal agent itracona- inhibits Gli activation and retains efficacy Seguin, N., Modrusan, Z., Januario, T., Tsui, V., Durham, A.B., Dlugosz, A.A., Haverty, M.P., zole, which targets SMO at a site
Load more

Recommended publications
  • Cyclopamine Inhibition of Sonic Hedgehog Signal Transduction Is
    Developmental Biology 224, 440–452 (2000) doi:10.1006/dbio.2000.9775, available online at http://www.idealibrary.com on View metadata, citation and similar papers at core.ac.uk brought to you by CORE Cyclopamine Inhibition of Sonic Hedgehog Signalprovided by Elsevier - Publisher Connector Transduction Is Not Mediated through Effects on Cholesterol Transport John P. Incardona,* William Gaffield,† Yvonne Lange,‡ Adele Cooney,§ Peter G. Pentchev,§ Sharon Liu,¶ John A. Watson,¶ Raj P. Kapur,ሻ and Henk Roelink*,1 *Department of Biological Structure and Center for Developmental Biology and ࿣Department of Pathology, University of Washington, Seattle, Washington 98195; †Western Regional Research Center, ARS, United States Department of Agriculture, Albany, California 94710; ‡Department of Pathology, Rush–Presbyterian–St. Luke’s Medical Center, Chicago, Illinois 60612; §Developmental and Metabolic Neurobiology Branch, NINDS, National Institutes of Health, Bethesda, Maryland 20892; and ¶Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, California 94143 Cyclopamine is a teratogenic steroidal alkaloid that causes cyclopia by blocking Sonic hedgehog (Shh) signal transduction. We have tested whether this activity of cyclopamine is related to disruption of cellular cholesterol transport and putative secondary effects on the Shh receptor, Patched (Ptc). First, we report that the potent antagonism of Shh signaling by cyclopamine is not a general property of steroidal alkaloids with similar structure. The structural features of steroidal alkaloids previously associated with the induction of holoprosencephaly in whole animals are also associated with inhibition of Shh signaling in vitro. Second, by comparing the effects of cyclopamine on Shh signaling with those of compounds known to block cholesterol transport, we show that the action of cyclopamine cannot be explained by inhibition of intracellular cholesterol transport.
    [Show full text]
  • Sonidegib for the Treatment of Advanced Basal Cell Carcinoma
    Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2016 Sonidegib for the treatment of advanced basal cell carcinoma Ramelyte, Egle ; Amann, Valerie C ; Dummer, Reinhard DOI: https://doi.org/10.1080/14656566.2016.1225725 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-125862 Journal Article Accepted Version Originally published at: Ramelyte, Egle; Amann, Valerie C; Dummer, Reinhard (2016). Sonidegib for the treatment of advanced basal cell carcinoma. Expert Opinion on Pharmacotherapy, 17(14):1963-1968. DOI: https://doi.org/10.1080/14656566.2016.1225725 Sonidegib for the treatment of advanced basal cell carcinoma Egle Ramelyte1,2,MD, Valerie C. Amann1, MD, Reinhard Dummer 1, MD, 1 - Department of Dermatology, University Hospital Zurich, Zurich, Switzerland 2 - Vilnius University, Centre of Dermatovenereology, Vilnius, Lithuania Corresponding author: Reinhard Dummer, MD University Hospital of Zurich Department of Dermatology Gloriastrasse 31 CH-8091, Zürich, Switzerland Phone: 41-44-255-2507 Fax: 41-44-255-8988 E-mail: [email protected] 1 Abstract Introduction. Advanced and metastatic basal cell carcinomas (BCCs) are rare but still present a severe medical problem. These tumors are often disfiguring and impact the quality of life by pain or bleeding. Based on discovery of the hedgehog (Hh) signaling pathway and it’s role in pathogenesis of BCCs, Smoothened (SMO) inhibitors have been developed with Sonidegib being the 2nd in class. It is the only Hh pathway inhibitor investigated in a randomized trial accompanied by pharmacodynamic investigations. Also, the disease assessment criteria applied were more stringent than those used in trials of 1st developed SMO inhibitor – vismodegib, and required annotated photographs, MRI as well as multiple biopsies in case of regression.
    [Show full text]
  • Assessment Report
    25 June 2015 EMA/472165/2015 Committee for Medicinal Products for Human Use (CHMP) Assessment report Odomzo International non-proprietary name: sonidegib Procedure No. EMEA/H/C/002839/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2015. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure ............................................ 7 1.1. Submission of the dossier ...................................................................................... 7 1.2. Manufacturers ...................................................................................................... 8 1.3. Steps taken for the assessment of the product ......................................................... 8 2. Scientific discussion .............................................................................. 9 2.1. Introduction......................................................................................................... 9 2.2. Quality aspects .................................................................................................. 11 2.2.1. Introduction .................................................................................................... 11
    [Show full text]
  • Australian Public Assessment Report for Odomzo
    Australian Public Assessment Report for Odomzo Proprietary Product Name: Sonidegib Sponsor: Novartis Pharmaceuticals Australia Pty Ltd November 2019 Therapeutic Goods Administration About the Therapeutic Goods Administration (TGA) • The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health and is responsible for regulating medicines and medical devices. • The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance) when necessary. • The work of the TGA is based on applying scientific and clinical expertise to decision- making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. • The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action. • To report a problem with a medicine or medical device, please see the information on the TGA website <https://www.tga.gov.au>. About AusPARs • An Australian Public Assessment Report (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission. • AusPARs are prepared and published by the TGA. • An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations and extensions of indications. • An AusPAR is a static document; it provides information that relates to a submission at a particular point in time. • A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA.
    [Show full text]
  • Hedgehog Targeting by Cyclopamine Suppresses Head and Neck Squamous Cell Carcinoma and Enhances Chemotherapeutic Effects
    ANTICANCER RESEARCH 33: 2415-2424 (2013) Hedgehog Targeting by Cyclopamine Suppresses Head and Neck Squamous Cell Carcinoma and Enhances Chemotherapeutic Effects CHRISTIAN MOZET*, MATTHAEUS STOEHR*, KAMELIA DIMITROVA, ANDREAS DIETZ and GUNNAR WICHMANN Department of Otolaryngology, Head and Neck Surgery, University of Leipzig, Leipzig, Germany Abstract. Background: The hedgehog signaling pathway prognosis is worse for those with metastatic disease (2). (HH) is involved in tumorigenesis in a variety of human Besides known risk factors (e.g. alcohol and smoking) and malignancies. In head and neck squamous cell carcinomas occupational exposure to other poorly understood factors, the (HNSCC), Hh overexpression was associated with poor entirety of the relevant tumor biology is still unclear. prognosis. Therefore, we analyzed the effect of Hh signaling Mortality rates of HNSCC have remained almost unchanged blockade with cyclopamine on colony formation of cells from for decades, even though the detection of tumor-specific HNSCC samples. Patients and Methods: HNSCC biopsies pathways has developed rapidly and offers a number of new were cultured alone for reference or with serial dilutions of targets in tumor therapy regimes (e.g. the epidermal growth cyclopamine (5-5,000 nM), docetaxel (137.5-550 nM), or factor-receptor, EGFR, and its tyrosine kinases). Proven cisplatin (1,667-6,667 nM) and their binary combinations. standardized concepts of tumor therapy in first- or second- Cytokeratin-positive colonies were counted after fluorescent line protocols are combinations of well-established cytostatic staining. Results: Cyclopamine concentration-dependently drugs such as platinum-derivates like cisplatin, taxanes like inhibited HNSCC ex vivo [(IC50) at about 500 nM]. In binary docetaxel or others (e.g.
    [Show full text]
  • Comprehensive Investigation of Bioactive Steroidal Alkaloids in Veratrum Californicum
    COMPREHENSIVE INVESTIGATION OF BIOACTIVE STEROIDAL ALKALOIDS IN VERATRUM CALIFORNICUM by Matthew West Turner A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomolecular Sciences Boise State University December 2019 © 2019 Matthew West Turner ALL RIGHTS RESERVED BOISE STATE UNIVERSITY GRADUATE COLLEGE DEFENSE COMMITTEE AND FINAL READING APPROVALS of the dissertation submitted by Matthew West Turner Dissertation Title: Comprehensive Investigation of Bioactive Steroidal Alkaloids in Veratrum californicum Date of Final Oral Examination: 01 October 2019 The following individuals read and discussed the dissertation submitted by student Matthew West Turner, and they evaluated the student’s presentation and response to questions during the final oral examination. They found that the student passed the final oral examination. Owen M. McDougal, Ph.D. Chair, Supervisory Committee Julia T. Oxford, Ph.D. Member, Supervisory Committee Daniel Fologea, Ph.D. Member, Supervisory Committee Xinzhu Pu, Ph.D. Member, Supervisory Committee The final reading approval of the dissertation was granted by Owen M. McDougal, Ph.D., Chair of the Supervisory Committee. The dissertation was approved by the Graduate College. DEDICATION This dissertation is dedicated to my beloved wife Lindsey, and to my daughter Matilda. Lindsey, thank you for your support, love, and encouragement. Matilda, you are my heart’s darling. iv ACKNOWLEDGMENTS This work was made possible by the monumental effort put forth by those that came before me and those that worked with me to make the progress described in this dissertation. I wish to acknowledge the literature review, initial extraction methods, meticulously detailed record keeping, and plant harvest contribution made by Chris Chandler.
    [Show full text]
  • The Effects of Inhibiting Hedgehog Signaling Pathways by Using Specific Antagonist Cyclopamine on the Chondrogenic Differentiation of Mesenchymal Stem Cells
    Int. J. Mol. Sci. 2013, 14, 5966-5977; doi:10.3390/ijms14035966 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Article The Effects of Inhibiting Hedgehog Signaling Pathways by Using Specific Antagonist Cyclopamine on the Chondrogenic Differentiation of Mesenchymal Stem Cells Xing Wu 1,*, Zheng-Dong Cai 1, Lei-Ming Lou 1 and Zheng-Rong Chen 2 1 Department of Orthopaedics, Shanghai tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China; E-Mails: [email protected] (Z.-D.C.); [email protected] (L.-M.L.) 2 Department of Orthopaedics, Shanghai Zhongshan Hospital, Fudan University School of Medicine, Shanghai 200032, China; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +86-21-6630-0588; Fax: +86-21-6630-1051. Received: 18 January 2013; in revised form: 5 March 2013 / Accepted: 7 March 2013 / Published: 14 March 2013 Abstract: This study aimed to investigate the effects of cyclopamine, a specific inhibitor of Hedgehog signaling pathways, on the chondrogenic differentiation of mesenchymal stem cells (MSCs). During culture, the experimental groups were treated with cyclopamine and their cell proliferation status was assessed using the MTT test. The extra-bone cellular matrix (ECM) and Collagen II (Col II) was detected by toluidine blue staining and immunohistochemistry of cells. The concentrations of Col II and aggrecan in the culture solution and cytosol were detected using ELISA on the 7th, 14th, and 21st days of cyclopamine induction. Gene and protein expression of Col II and aggrecan were analyzed on the 14th day of cyclopamine induction using real-time PCR and western blot analyses.
    [Show full text]
  • VIEW Open Access Targeting Hedgehog Signaling in Myelofibrosis and Other Hematologic Malignancies Raoul Tibes* and Ruben a Mesa
    Tibes and Mesa Journal of Hematology & Oncology 2014, 7:18 http://www.jhoonline.org/content/7/1/18 JOURNAL OF HEMATOLOGY & ONCOLOGY REVIEW Open Access Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies Raoul Tibes* and Ruben A Mesa Abstract Treatment of myelofibrosis (MF), a BCR-ABL–negative myeloproliferative neoplasm, is challenging. The only current potentially curative option, allogeneic hematopoietic stem cell transplant, is recommended for few patients. The remaining patients are treated with palliative therapies to manage MF-related anemia and splenomegaly. Identification of a mutation in the Janus kinase 2 (JAK2)gene(JAK2 V617F) in more than half of all patients with MF has prompted the discovery and clinical development of inhibitors that target JAK2. Although treatment with JAK2 inhibitors has been shown to improve symptom response and quality of life in patients with MF, these drugs do not alter the underlying disease; therefore, novel therapies are needed. The hedgehog (Hh) signaling pathway has been shown to play a role in normal hematopoiesis and in the tumorigenesis of hematologic malignancies. Moreover, inhibitors of the Hh pathway have been shown to inhibit growth and self-renewal capacity in preclinical models of MF. In a mouse model of MF, combined inhibition of the Hh and JAK pathways reduced JAK2 mutant allele burden, reduced bone marrow fibrosis, and reduced white blood cell and platelet counts. Preliminary clinical data also suggest that inhibition of the Hh pathway, alone or in combination with JAK2 inhibition, may enable disease modification in patients with MF. Future studies, including one combining the Hh pathway inhibitor sonidegib and the JAK2 inhibitor ruxolitinib, are underway in patients with MF and will inform whether this combination approach can lead to true disease modification.
    [Show full text]
  • The Evolution of Sensory and Neurosecretory Cell Types in Bilaterian Brains
    The evolution of sensory and neurosecretory cell types in bilaterian brains DISSERTATION zur Erlangung des Doktorgrades der Naturwissenschaften Doctor rerum naturalium (Dr. rer. nat.) dem Fachbereich Biologie der Philipps-Universität Marburg vorgelegt von Dipl.-Biol. K. G. Kristin Teßmar–Raible aus Görlitz Marburg/ Lahn 2004 Vom Fachbereich Biologie der Philipps-Universität Marburg als Dissertation am angenommen. Erstgutachterin: Prof. Dr. Monika Hassel Zweitgutachterin : Prof. Dr. Renate Renkawitz-Pohl Tag der mündlichen Prüfung: The evolution of sensory and neurosecretory cell types in bilaterian brains To my parents and my husband for their encouragement and patience Acknowledgements I am very thankful to the following persons in Marburg and Heidelberg that made this study possible: Dr. Monika Hassel at Marburg University for the supervision of my PhD thesis and correction of the text; Dr. Detlev Arendt at the EMBL in Heidelberg for giving me the opportunity to spend time in his lab as a guest and for scientific advice; Dr. Monika Hassel, Dr. Renate Renkawitz-Pohl and the other members of my defense committee for reviewing this thesis. I want to acknowledge all members and guests of the Arendt lab, in particular Sebastian Klaus, Heidi Snyman, and Patrick Steinmetz, for for their help, their useful critical comments, and the interesting scientific discussions; in addition, I want to thank Heidi Snyman for very reliable practical help, especially with degenerated PCRs, minipreps, and restriction digests; and Dr. Detlev Arendt for minipreps of the Pdu-barH1 cloning. Moreover, I thank Dr. Florian Raible and Dr. Detlev Arendt for extensive critical feedback on previous versions of this text.
    [Show full text]
  • The Hedgehog Signaling Pathway in Cancer
    Published OnlineFirst June 19, 2012; DOI: 10.1158/1078-0432.CCR-11-2509 Clinical Cancer Molecular Pathways Research Molecular Pathways: The Hedgehog Signaling Pathway in Cancer Ross McMillan and William Matsui Abstract The Hedgehog (Hh) signaling pathway regulates embryonic development and may be aberrantly activated in a wide variety of human cancers. Efforts to target pathogenic Hh signaling have steadily progressed from the laboratory to the clinic, and the recent approval of the Hh pathway inhibitor vismodegib for patients with advanced basal cell carcinoma represents an important milestone. On the other hand, Hh pathway antagonists have failed to show significant clinical activity in other solid tumors. The reasons for these negative results are not precisely understood, but it is possible that the impact of Hh pathway inhibition has not been adequately measured by the clinical endpoints used thus far or that aberrancies in Hh signal transduction limits the activity of currently available pathway antagonists. Further basic and correlative studies to better understand Hh signaling in human tumors and validate putative antitumor mechanisms in the clinical setting may ultimately improve the success of Hh pathway inhibition to other tumor types. Clin Cancer Res; 18(18); 4883–8. Ó2012 AACR. Background and GLI3 represses Hh target genes that include GLI1, PTCH1 Cyclin D1 c-Myc Bcl-2 The Hedgehog (Hh) signaling pathway is highly con- , , , and , whereas GLI2 can act served from flies to humans and is essential for develop- in either a positive or negative manner depending on ment of the normal embryo (1, 2). In mammals, Hh posttranscriptional and posttranslational processing events signaling regulates both patterning and polarity events (4).
    [Show full text]
  • (IPI-926) Increases Lifespan in a Mouse Medulloblastoma Model
    Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model Michelle J. Leea,b,1, Beryl A. Hattona,1, Elisabeth H. Villavicencioa,c, Paritosh C. Khannad, Seth D. Friedmand, Sally Ditzlera, Barbara Pullara, Keith Robisone, Kerry F. Whitee, Chris Tunkeye, Michael LeBlancf, Julie Randolph-Habeckerg, Sue E. Knoblaughg, Stacey Hansena, Andrew Richardsa, Brandon J. Wainwrighth, Karen McGoverne, and James M. Olsona,b,c,2 aClinical Research Division, fPublic Health Sciences Division, gComparative Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; bNeurobiology and Behavior Program, Departments of dRadiology and cPediatrics, University of Washington and Seattle Children’s Hospital, Seattle, WA 98105; eInfinity Pharmaceuticals, Cambridge, MA 02139; and hDivision of Molecular Genetics and Development, Institute for Molecular Biosciences, University of Queensland, Brisbane QLD 4072, Australia Edited by Dennis A. Carson, University of California at San Diego, La Jolla, CA, and approved April 4, 2012 (received for review September 13, 2011) The Sonic Hedgehog (Shh) pathway drives a subset of medullo- drug resistance (4–6). It remains to be determined whether these blastomas, a malignant neuroectodermal brain cancer, and other drugs confer a survival benefit to medulloblastoma patients. The cancers. Small-molecule Shh pathway inhibitors have induced tu- identification of Smo inhibitors that remain active against cells mor regression in mice and patients with medulloblastoma; how- that develop resistance to other agents in this class could benefit ever, drug resistance rapidly emerges, in some cases via de novo patients, particularly if acquired resistance is limited or slower mutation of the drug target. Here we assess the response and to develop.
    [Show full text]
  • Efficacy and Safety of Sonic Hedgehog Pathway Inhibitors in Cancer
    HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Drug Saf Manuscript Author . Author manuscript; Manuscript Author available in PMC 2020 February 01. Published in final edited form as: Drug Saf. 2019 February ; 42(2): 263–279. doi:10.1007/s40264-018-0777-5. Efficacy and safety of sonic hedgehog pathway inhibitors in cancer Richard L Carpenter1,2,3,* and Haimanti Ray2 1Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 1001 E. 3rd St, Bloomington, IN 47405 2Medical Sciences, Indiana University School of Medicine, 1001 E. 3rd St, Bloomington, IN 47405 3Simon Cancer Center, Indiana University School of Medicine, 1001 E. 3rd St, Bloomington, IN 47405 Abstract The hedgehog pathway, for which sonic hedgehog (Shh) is the most prominent ligand, is highly conserved and is tightly associated with embryonic development in a number of species. This pathway is also tightly associated with development of several types of cancer, including basal cell carcinoma and acute promyelocytic leukemia (APL) among many others. Inactivating mutations in Patched 1 (PTCH1), leading to ligand-independent pathway activation, are frequent in several cancer types but most prominent in basal cell carcinoma. This has led to the development of several compounds targeting this pathway as a cancer therapeutic. These compounds target the inducers of this pathway in Smoothened (SMO) and the GLI transcription factors, although targeting SMO has had the most success. Despite the many attempts at targeting this pathway, there are only three FDA-approved drugs for cancers that affect the Shh pathway. Two of these compounds, vismodegib and sonidegib, target SMO to suppress signaling from either PTCH1 or SMO mutations that lead to upregulation of the pathway.
    [Show full text]