THE HEDGEHOG PATHWAY IN MALIGNANT MESOTHELIOMA

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1 THE HEDGEHOG PATHWAY IN MALIGNANT MESOTHELIOMA Chuan Bian Lim B.Sc. This thesis is presented for the degree of Doctor of Philosophy from the University of Western Australia School of Medicine and Pharmacology March 2015

2 ABSTRACT Malignant mesothelioma is an invasive, locally aggressive tumor, predominantly of the pleura and peritoneum, which is associated with asbestos exposure. Its incidence is increasing worldwide and it has an extremely poor prognosis, due to resistance to conventional treatment modalities, with a median survival of less than one year after diagnosis. Clearly, novel therapeutic strategies are required to improve survival of mesothelioma patients. Mounting evidence supports the aberrant hyperactivation of the Hedgehog (Hh) signaling pathway as crucial to the pathogenesis of certain cancers, including mesothelioma. The Hh pathway is critical for embryonic development and adult homeostasis but hyperactivation of the pathway, through mutations in the Hh pathway genes or overexpression of ligand or receptors, have been shown to drive tumorigenesis. This thesis examines the general hypothesis that targeting the Hh pathway can be a therapeutic strategy against mesothelioma. More specifically, this thesis aims to: 1. Identify mutations in Hh pathway genes in mesothelioma 2. Functionally characterize the mutations identified through in silico and in vitro analysis 3. Determine the preclinical efficacy of Hh pathway inhibitors, in particular the Gli inhibitor GANT61, on mesothelioma cells in vitro 4. Characterize the biological effects of GANT61 using the mesothelioma cell line LO68. Real-time PCR analysis of Hh pathway genes PTCH1, GLI1 and GLI2 were performed on seven human mesothelioma cell lines. Exon sequencing of 13 Hh pathway genes was also performed in cell lines and human mesothelioma tumors. In silico programs were used to predict the likelihood that an amino-acid substitution would have a functional effect. 2

3 GLI1, GLI2 and PTCH1 were highly expressed in mesothelioma cells, indicative of active Hh signaling. PTCH1, SMO and SUFU mutations were found in 2 of 11 mesothelioma cell lines examined. A non-synonymous missense SUFU mutation (p.t411m) was identified in LO68 cells. In silico characterization of the SUFU mutant suggested that the p.t411m mutation might alter protein function, however, no functional effect of this mutation on Gli activity was demonstrated. Deletion of exons of the PTCH1 gene and a 3- bp insertion (69_70insCTG) in SMO was also identified in JU77 cells and predicted to alter protein function. Although Hh pathway mutations are relatively rare in mesothelioma, these data suggest a possible role for a dysfunctional Hh pathway in the pathogenesis of a subgroup of mesothelioma patients and help rationalize the exploration of Hh pathway inhibitors for mesothelioma therapy. Recent studies link aberrant Hh signaling with mesothelioma growth and survival. Gli transcription factors, one of the critical and terminal elements of the Hh pathway, control cell growth and survival via the upregulation of genes related to proliferation and apoptosis. Overexpression of GLI1 has been reported to be significantly associated with worse overall survival in human mesothelioma. The Gli inhibitor GANT61 has been shown to inhibit the Hh signaling pathway by interfering with Gli transcription factors binding to DNA. In human mesothelioma LO68 cells displaying hyperactivated Hh signaling, GANT61 reduced the intracellular levels of GLI1 and GLI2. The reduction attenuated the expression of Gli target genes such as PTCH1 and Bcl-2. GANT61 was also found to suppress cell proliferation and clonogenic survival in LO68 cells. GANT61 treatment also led to induction of autophagy, as evidenced by the accumulation of autophagosomes observed by staining cells with acridine orange and CytoID Green autophagy detection reagent. Pharmacologic inhibition of GANT61-induced autophagy by bafilomycin A1, 3-methyladenine or chloroquine enhanced GANT61-induced 3

4 apoptotic cell death. Furthermore, exposure of LO68 cells to GANT61 led to G1 phase arrest and apoptotic cell death with increased annexin V staining. Notably, GANT61- induced apoptosis did not depend on its purported target - GLI1 or GLI2, but does involve reactive oxygen species (ROS). GANT61 triggered the generation of ROS and quenching of ROS by N-acetyl-cysteine, a ROS scavenger, which protected from GANT61-induced apoptosis in mesothelioma cells. Furthermore, it was demonstrated that mitochondria are important in GANT61-induced ROS production and apoptosis: (1) ROS production and apoptosis was significantly blocked by the mitochondrial complex I inhibitor rotenone; (2) GANT61 promoted superoxide formation in mitochondria and depolarization of mitochondrial membrane potential; and (3) mitochondrial DNA-deficient LO68 cells failed to induce superoxide compared to wild-type cells, and were more resistant than wild-type cells to apoptosis induced by GANT61. Taken together, the data demonstrate for the first time that GANT61 induces apoptosis in LO68 cells by promoting mitochondrial superoxide generation, independent of Gli inhibition. In conclusion, the data presented in this thesis suggest that mutations in the coding regions of Hh pathway genes are unlikely to be responsible for the hyperactivation of the pathway in mesothelioma. The driving mechanism of aberrant Hh signaling in mesothelioma is likely to be related to Hh-dependent activation of Gli transcription factors. This thesis also presented the first evidence that mitochondrial superoxide may be responsible for the anticancer effects of GANT61 and the concomitant inhibition of cytoprotective autophagy potentiates the anticancer effects of GANT61 in mesothelioma. Overall, this thesis provides a strong rationale for developing GANT61 as a novel treatment for mesothelioma. 4

5 DECLARATION The work presented in this thesis was performed solely by the candidate except where otherwise acknowledged and has been accomplished during enrolment. This thesis has not been previously accepted for any other degree in this or another institution. Chuan Bian Lim 5

6 ACKNOWLEDGEMENTS To everyone who has helped and encouraged me in this journey, my heartfelt thanks. First, I would like to thank my primary supervisor, Professor Steven Mutsaers for his unwavering support and confidence in my work and giving me the freedom to pursue my scientific interests. I would also like to acknowledge my co-supervisors, Associate Professor Cecilia Prêle, Professor Philip Thompson and Dr. Svetlana Baltic for their inputs and encouragement. My thanks are also to my labmates Faang Cheah, Huimin Cheah and Kimberly Birnie for their encouragement, support and importantly, friendship. I would like to thank Winthrop Professor Bruce Robinson, Professor Jenette Creaney and Professor Steven Albelda for mesothelioma cells; Associate Professor Brian McCaughan for patient samples; Professor Rune Toftgård for the Gli luciferase construct. I would also like to thank Associate Professor Paul Rigby, Associate Professor Matthew Linden, Ms Tracey Lee-Pullen and Ms Alysia Buckley (Centre for Microscopy, Characterisation and Analysis, University of Western Australia) for support with flow cytometry and confocal microscopy; Dr David Chandler, Dr Shane Herbert and Mr Matthew Davis (Australian Genome Research Facility) for support with sequencing. Last but not least, I like to thank Mom, Dad and Fatty for their patience, listening ears and love. 6

7 LIST OF PUBLICATIONS 1. Lim CB, Prêle CM, Cheah HM, Cheng YY, Klebe S, Reid G, Watkins DN, Baltic S, Thompson PJ & Mutsaers SE. Mutational analysis of Hedgehog signaling pathway genes in human malignant mesothelioma, PLoS ONE 8(6): e66685, Lim CB, Prêle CM, Arthur PG, Creaney J, Watkins DN, Baltic S, Thompson PJ & Mutsaers SE. Mitochondria-derived reactive oxygen species drives GANT61- induced malignant mesothelioma cell apoptosis. Oncotarget, 6(3): ,

8 LIST OF PUBLISHED ABSTRACTS 1. Lim CB, Cheah HM, Baltic S, Thompson PJ, Prêle CM & Mutsaers SE. Mutations in Hedgehog pathway genes PTCH1 and SMO are rare in malignant mesothelioma cells. Respirology, 17 (Supplement S1), TP-123, Lim CB, Thompson PJ, Baltic S, Lee YCG, Watkins DN, Prêle CM & Mutsaers SE. Targeting of Hedgehog pathway via pharmacologic inhibition of Gli induces apoptosis in human malignant mesothelioma cells. Respirology, 18 (Supplement 2), O103, Lim CB, Prêle CM, Arthur PG, Creaney J, Watkins DN, Baltic S, Thompson PJ & Mutsaers SE. Induction of mesothelioma cell apoptosis by GANT61, a small molecule inhibitor of Gli transcription factors: Evidence for redox-driven cytotoxicity. Respirology, 20 (Supplement 2), TP-227B,

9 TABLE OF CONTENTS Abstract 2 Declaration 5 Acknowledgements 6 List of publications 7 List of published abstracts 8 Table of contents 9 Abbreviations 15 Chapter 1 General introduction Overview Mesothelioma Genetics and mesothelioma Management of mesothelioma Molecularly targeted therapy in mesothelioma The Hedgehog signaling pathway Hedgehog signaling in a nutshell Hedgehog ligand Hedgehog ligand reception at cell membrane surface SMO as signal transducer Gli as transcription factors Regulation of Gli by SUFU Primary cilium and Hedgehog signaling Hedgehog signaling and cancer Ligand-independent mutational activation of Hedgehog signaling Autocrine, ligand-dependent Hedgehog 9

10 signaling Paracrine, ligand-dependent Hedgehog signaling Hedgehog signaling and the cell cycle Hedgehog signaling and apoptosis Hedgehog signaling and autophagy Drugging the Hedgehog pathway Reactive oxygen species and cancer therapy Summary and scope of thesis Thesis layout 55 Chapter 2 Materials and methods Cell lines and culture conditions Ethics statement Patients and tumors DNA isolation PCR amplification DNA sequence analysis PCR assay for detection of PTCH1 exon deletions In silico characterization of polymorphisms in exons Drugs Cell proliferation assay Colony formation assay Cell cycle analysis by DNA content Detection of apoptosis WST (Water-Soluble Tetrazolium)-1 assay ROS detection 66 10

11 2.16 Mitochondrial membrane potential (ΔΨm) detection OxyDNA assay Detection of autophagy Immunofluorescence analysis RNA interference Gli luciferase reporter assay Western blot analysis Antibodies Generation of mitochondrial DNA-depleted LO68 cells RNA isolation cdna synthesis Quantitative real-time PCR (qrt-pcr) analysis of gene expression Drug combination analysis Statistical analysis 73 Chapter 3 Mutational analysis of Hedgehog pathway genes in mesothelioma Introduction Materials and methods RNA isolation, cdna synthesis and quantitative real-time PCR (qrt-pcr) analysis of gene expression Gli luciferase reporter assay Results The canonical Hedgehog signaling pathway is active in human mesothelioma cell lines PTCH1, SMO and SUFU mutations in mesothelioma cell lines Hedgehog pathway gene variants in 11

12 mesothelioma cell lines PTCH1, SMO and SUFU mutations in FFPE mesothelioma tumors Functional characterisation of SUFU mutant Discussion 92 Chapter 4 Targeting of Hedgehog pathway using Gli inhibitor GANT Introduction Results Gli inhibitor GANT61 is a more potent Hedgehog pathway inhibitor than Smo inhibitors (cyclopamine and GDC-0449) GANT61 induced higher levels of apoptosis than Smo inhibitors (cyclopamine and GDC-0449) GANT61 targets Gli transcription factors GANT61 sensitivity correlates with GLI2 and GLI2 mrna expression Depletion of GLI1, GLI2 and SMO reduces cell growth GANT61-induced apoptosis and cell cycle are independent of Gli inhibition GANT61 triggers induction of autophagy Autophagy inhibition enhances GANT61-induced apoptosis GANT61 sensitizes LO68 cells to standard mesothelioma chemotherapy-induced apoptosis GANT61 mediates antagonistic to synergistic sensitization effects on standard chemotherapyinduced apoptosis GANT61 triggers the production of reactive oxygen species Discussion 135 Chapter 5 Mitochondria-derived ROS are critical in GANT61-12

13 induced apoptosis Introduction Results ROS production does not appear to be a class phenomenon for Gli inhibitors GANT61 kills LO68 cells through ROS -mediated DNA damage GANT61 kils LO68 cells through ROS -mediated impairment of DNA repair GANT61 downregulates GLI1, GLI2 and PTCH1 through ROS GANT61-induced ROS is independent of Gli Inhibition GANT61-induced apoptosis and ROS production are dependent on NADPH oxidase GANT61-induced apoptosis and ROS production are dependent on mitochondria Dissipation of mitochondrial membrane potential mediates GANT61-induced apoptosis Mitochondrial superoxide is essential for GANT61 -induced apoptosis Discussion 176 Chapter 6 General discussion Future perspective Conclusions 194 References 195 Appendices 228 Appendix A Intronic primer sequences for amplification of exons of Hedgehog pathway genes 229 Appendix B PCR protocols for amplification of exons of Hedgehog pathway genes 236 Appendix C Exonic primer sequences for PCR assay for detection 13

14 of PTCH1 exon deletions 240 Appendix D Buffers and solutions

15 ABBREVIATIONS 3-MA ABC ABL BafA1 BCC 3-methyladenine Adenosine triphosphate-binding cassette Abelson oncogene Bafilomycin A1 Basal cell carcinoma BCL2 B-cell CLL/lymphoma 2 Β-TrCP BCR BOC BSO β-transducin-repeat containing protein Breakpoint cluster region Brother of CDO Buthionine sulfoximine CDK1 Cyclin-dependent kinase 1 CDO Cell adhesion molecule-related/down-regulated by oncogenes CK1 Casein kinase 1 CML CI DHH DMSO ddh 2 O DPI FBS FOXM1 Chronic myelogenous leukemia Combination index Desert hedgehog Dimethyl sulfoxide double distilled H 2 O Diphenylene iodonium Fetal bovine serum Foxhead box M1 GAS1 Growth arrest specific 1 GPCR GSK3β H 2 O 2 G-protein-coupled receptor Glycogen synthase kinase 3β Hydrogen peroxide 15

16 Hh HHIP HPI-1 IHH GLI MDR mtor NOX PBS PI3K PKA PTCH Hedgehog Hedgehog interacting protein Hedgehog pathway inhibitor-1 Indian hedgehog GLI-Kruppel family member Multidrug resistance Mammalian target of rapamycin NADPH oxidase Phosphate buffered saline Phosphoinositide 3-kinase Protein kinase A Patched RFC1 Reduced folate carrier protein 1 SEM SHH sirna SMO SUFU Standard error of the mean Sonic hedgehog Small interfering RNA Smoothened Suppressor of fused SV40 Simian virus 40 TBS TGFβ Tris buffered saline Transforming growth factor β TGFBR1 Transforming growth factor β receptor 1 TGFBR2 Transforming growth factor β receptor 2 WST-1 Water-soluble tetrazolium-1 16

17 CHAPTER 1 GENERAL INTRODUCTION 17

18 1.1 OVERVIEW Malignant mesothelioma poses a significant public health threat worldwide, with one of the lowest survival rates of fewer than 10% of patients surviving more than five years (Yan et al, 2011b). This cancer is associated with asbestos exposure (Robinson & Chahinian, 2002) and originates predominantly from the pleura (73.1%), while other sites include peritoneum (23.7%) and pericardium (0.3%) (Suzuki, 2001). Despite advances in treatment modalities, survival rates remain disappointingly low (Yan et al, 2011b). Clearly new targets and novel therapeutic approaches need to be identified. Recent evidence has shown that the Hedgehog (Hh) signaling pathway is hyperactivated in mesothelioma, and thus therapeutic blockade of this pathway might be beneficial to a subset of mesothelioma patients in whom a deregulated Hh pathway seems to be driving the cancer (Shi et al, 2012). The thesis will test the hypothesis that targeting the Hh pathway can be a therapeutic strategy against mesothelioma. The thesis will identify mutations in Hh pathway genes in mesothelioma and characterize the mutations identified, in a bid to understand how genetic alteration might influence the pathogenesis of mesothelioma. This thesis will also examine the feasibility of targeting the Hh pathway in mesothelioma using small molecule inhibitors, and elucidate the mechanisms driving inhibitor responses. 1.2 MALIGNANT MESOTHELIOMA Malignant mesothelioma is an aggressive cancer that arises from mesothelial cells that line the serosal cavities of the pleura, peritoneum, pericardium and tunica vaginalis testis, of which pleural mesothelioma accounts for 70% of the cases (Suzuki, 2001). Mesothelioma can be classified into four main histologic types: epithelioid, sarcomatoid, desmoplastic and biphasic (Figure 1.1), according to the 2004 World Health Organisation 18

19 classification scheme for pleural tumors (Travis et al, 2004). Of the four histologic types, the epithelioid type is the most common (61%), followed by biphasic (22%), sarcomatous (16%) and desmoplastic (1-2%) cell type (Inai, ; Suzuki, 2001). However, the percentage of biphasic mesothelioma could increase to 63% when larger tumor specimens are taken via thoracoscopy, thoracotomy and autopsy for histologic diagnosis (van Gelder et al, 1991). Correct histologic classification has significant prognostic and therapeutic implications. A number of studies have demonstrated that epithelioid mesothelioma has a better prognosis than biphasic and sarcomatoid mesotheliomas (Haber & Haber, 2011; Neumann et al, 2004; Nojiri et al, 2011; Sugarbaker et al, 1993). However, despite the best clinical care, mesothelioma remains an invariably fatal cancer with a median survival of months from the time of diagnosis (Curran et al, 1998; Edwards et al, 2000). Poorer prognostic factors include males, older age, weight loss, chest pain, poor performance status, low haemoglobin, leukocytosis, thrombocytosis and non-epithelioid histology (Edwards et al, 2000). Occupational asbestos exposure is the main risk factor for mesothelioma, accounting for 80% of the cases in men and 40% of the cases in women (Robinson & Chahinian, 2002). Intriguingly, 20-60% of people with mesothelioma in different studies do not have an obvious history of exposure to asbestos (Robinson & Chahinian, 2002). This clearly suggests that exposure to carcinogens other than asbestos could cause mesothelioma or that minimal environmental exposure to asbestos is sufficient in some people to trigger the disease. Exposure to erionite, an asbestos-like fibrous mineral with potent carcinogenic properties, has also been shown to cause mesothelioma in humans and rats (Baris et al, 1987; Baris et al, 1981; Wagner et al, 1985). In addition, ionizing radiation as well as Simian virus 40 (SV40) infection has been implicated in the genesis of mesothelioma (Baris et al, 1987; Carbone et al, 1994; Cicala et al, 1993; De Bruin et al, 19

20 2009; Wagner et al, 1985). 20

21 Figure 1.1 Mesothelioma. A) Epithelioid B) Biphasic C) Sarcomatoid D) Demosplastic. Source: Travis et al,

22 1.2.1 Genetics and mesothelioma Although occupational exposure to asbestos accounts for approximately 80% of mesothelioma cases, less than 5% of heavily exposed asbestos workers develop mesothelioma (Below et al, 2011). This finding suggests that, in addition to asbestos exposure, inter-individual genetic differences might influence mesothelioma risk. The strongest evidence comes from studies of a mesothelioma epidemic in three villages (Karain, Sarihidir and Tuzkoy) in the Cappadocian region of Turkey (Dogan et al, 2006). Exposure to environmental erionite was found to be responsible for the high incidence of mesothelioma observed in these villages. Erionite is a naturally occurring zeolite fibre with morphology that resembles amplibolic asbestos (IARC, 2012). Despite the similarity in appearance, erionite has been shown to be more carcinogenic than asbestos (Carthew et al, 1992; Wagner et al, 1985). Mesothelioma appears to be clustered in certain Turkish families, whereby more than 50% of all deaths were attributed to mesothelioma (Roushdy-Hammady et al, 2001). An extended pedigree analysis on six of these families consisting of 526 individuals suggests that mesothelioma was consistent with autosomal dominant transmission with incomplete penetrance (Roushdy-Hammady et al, 2001). Recently, Testa and co-workers were able to demonstrate through the use of arraycomparative genomic hybridisation and linkage analysis, that germline mutations in BAP1 (BRCA1 associated protein-1) gene predispose individuals to mesothelioma (Testa et al, 2011). In addition to mesothelioma, BAP1 germline mutations are also associated with breast cancer, lung adenocarcinoma, melanocytic tumors, meningioma, renal cancer, skin cancer and uveal melanoma (Abdel-Rahman et al, 2011; Njauw et al, 2012; Popova et al, 2013; Testa et al, 2011; Wiesner et al, 2011). The association of BAP1 germline mutations with the increased risk of developing a myriad of human cancers point to the important tumor suppressor role played by BAP1 in different tissues (Goldstein, 2011). 22

23 BAP1 is an 81-kDa nuclear ubiquitin carboxy-terminal hydrolase that is 729 amino acids in length and is located on chromosome 3p21.3 (Jensen et al, 1998). Notably, many cancers including mesotheliomas frequently display chromosomal loss of 3p31.3 (Hesson et al, 2007). BAP1 was first identified as an interacting partner of BRCA1 by direct binding to the RING finger domain of BRCA1, and plays an important role in proliferation and cell death (Jensen et al, 1998; Misaghi et al, 2009; Ventii et al, ). Mounting evidence suggests that BAP1 acts as a bona fide tumor suppressor via its deubiquitinase activity (Ventii et al, ). Co-expression of BAP1 and BRCA1 significantly reduced the colony forming ability of MCF7 breast cancer cells, compared to expression of BRCA1 alone (Jensen et al, 1998). This enhancement of BRCA1 growth suppression activity is dependent on the ubiquitin hydrolase activity of BAP1 (Jensen et al, 1998). Knockout of BAP1 was embryonic lethal in mice, suggesting that BAP1 is essential for normal embryonic development (Dey et al, 2012). Dey and colleagues found that conditional BAP1 knockout mice developed myelodysplastic syndrome that has features of human chronic myelomonocytic leukemia (Dey et al, 2012). It was further demonstrated that BAP1 regulates gene transcription by deubiquitinating and stabilizing host cell factor-1 and O-linked N-acetylglucosamine transferase, two proteins that are involved in chromatin modification and remodeling (Dey et al, 2012). In the context of mesothelioma, knockdown of BAP1 using small interfering RNA (sirna) led to growth inhibition, deubiquitinating host cell factor-1 inactivation and reduction in E2F-responsive gene expression (Bott et al, 2011) Management of mesothelioma Despite years of research, mesothelioma remains an incurable cancer. At present, the therapeutic approaches to mesothelioma are classified either as life-prolonging or palliative (Favoni & Florio, 2011). Initial monotherapeutic approaches involving surgery, 23

24 radiation therapy or chemotherapy failed to provide clear survival benefit to the patients (Ceresoli et al, 2007; Kaufman & Flores, 2011; Steele & Klabatsa, 2005). Radiation therapy can only reduce the tumor burden and is therefore ineffective in extending the survival of mesothelioma patients (Baldini, 2009; McAleer et al, 2009). Due to the diffuse nature of the tumor, irradiation of the entire pleural surface is necessary which often results in fatal complications (Baldini, 2009; McAleer et al, 2009). In a study by Ball and Cruickshank (Ball & Cruickshank, 1990), out of 12 patients with pleural mesothelioma who were prescribed radical radiotherapy, two of them (17%) developed fatal hepatitis and myelopathy, respectively. Another study found a 46% rate of fatal pneumonitis after 13 patients were treated with intensity modulated radiation therapy after extrapleural pneumonectomy and adjuvant chemotherapy (Allen et al, 2006). These sequelae of radiation therapy led surgeons to propose radical surgical resection as an attempt to cure the disease. In a ground-breaking study conducted by Butchart and his co-workers in 1976, patients who are diagnosed with stage 1 epithelioid mesothelioma had a better prognosis after pleuropneumonectomy than those with biphasic and sarcomatoid mesothelioma that had progressed beyond stage 1 (Butchart et al, 1976). However, the rapid infiltration of the tumor throughout the hemithorax made it extremely difficult to achieve histologically negative margins and residual tumor left behind from the debulking procedure could seed tumor in the chest wall (Butchart, 1999; Favoni & Florio, 2011). For patients who are not suitable for radiotherapy and surgery, chemotherapy is the standard of care for treatment of mesothelioma (Metintas et al, 2001). To date, those chemotherapeutic regimens for mesothelioma only reduce tumor burden and offer 24

25 palliation of disease symptoms such as chest pain, breathlessness and chest wall masses (Sterman et al, 1999). Based on data from multicentre studies, two cisplatin-based combination regimens are recommended as first-line chemotherapy for mesothelioma. A multicentre phase III trial involving 448 patients reported a longer overall median survival of 12.1 months in patients treated with cisplatin/pemetrexed combination compared with 9 months in those treated with cisplatin alone (Vogelzang et al, 2003). The combination of cisplatin and gemcitabine has also been demonstrated in a multicentre phase II trial to produce an objective response rate of 47.6% with palliation of symptoms and improvement in quality of life (Nowak et al, 2002). However, no single approach is superior to supportive care alone in terms of overall survival in the treatment of mesothelioma (Jassem et al, ; Jenkins et al, 2011; Sharif et al, 2011; Zahid et al, 2011). Hence the nihilistic attitude toward mesothelioma harboured by many clinicians for many years are justified but a big change in the way mesothelioma is managed is to be expected with the advent of new therapies, which may bring hope to mesothelioma patients Molecularly targeted therapy in mesothelioma In the past few decades, drug discovery efforts have undergone a paradigm shift from predominantly cytotoxic agent-based treatment to therapy specifically directed at molecular gene targets. In 2001, the US Federal Drug Agency approved the small molecule inhibitor, Glivec (imatinib mesylate, Gleevec, Norvatis), for use in patients with chronic myelogenous leukemia (CML) and ushered in the era of molecularly targeted therapy in cancer. Glivec, a 2-phenylaminopyrimidine derivative, is a selective tyrosine kinase inhibitor of the chimeric BCR-ABL oncokinase (Stegmeier et al, 2010), which results from a chromosomal translocation involving a fusion of the Abelson oncogene 25

26 (ABL) from chromosome 9q34 with breakpoint cluster region (BCR) on 22q11 (Heisterkamp et al, 1983). Early in vitro studies with Glivec showed that it is able to suppress proliferation and colony formation and induce apoptosis of BCR-ABL positive cells obtained from CML patients (Deininger et al, 1997; Druker et al, 1996; Gambacorti- Passerini et al, 1997). The prospective, randomized, multicentre, open-label phase III International Randomized Study of Interferon and STI571 (IRIS) clinical trial of Glivec for the treatment of CML in newly diagnosed patients have demonstrated that Glivec can induce complete hematologic response in 95.3% of patients and superior progression-free survival compared to the combination of interferon and cytarabine (O'Brien et al, 2003). These landmark studies provided the proof-of-concept that therapy could be directed against specific molecular targets in cancer cells while leaving normal cells unharmed, and has inspired many studies to identify new therapeutic targets in mesothelioma. Several selective agents targeting epidermal growth factor, platelet derived growth factor, vascular endothelial growth factor, src kinase, histone deacetylase and the proteasome have been evaluated in clinical trials (Kindler, ). Although these agents only demonstrated modest clinical efficacy in Phase I/II trials, these results further highlighted the pressing need to discover novel targets to control mesothelioma cell growth. More recently, approaches combining conventional chemotherapy with targeted agents are being trialled. Evidence from in vitro studies show that many drugs do not have singleagent activity but combining them with other chemotherapeutic agents often produce synergistic activity (Favoni & Florio, 2011). 1.3 THE HEDGEHOG SIGNALING PATHWAY The Hh gene was first discovered in a large-scale genetic screen for mutations that disrupt the Drosophila larval body plan (Nusslein-Volhard and Wieschaus, 1980). The Hh 26

27 pathway is a highly conserved signaling pathway responsible for the regulation of proliferation, differentiation and pattern specification during embryonic development (Ingham & McMahon, 2001). It is responsible for the formation of vertebrate structures, including bone and cartilage, cerebellum, eye, gut, gonads, heart, limbs, lung, muscle, neural crest, pancreas, prostate, tooth and tongue (Ingham & McMahon, 2001). The pathway is also involved in the regulation of adult tissue homeostasis and stem cell maintenance in the gastrointestinal tract, brain and blood (Crompton et al, 2007; Ingham & McMahon, 2001; Jiang & Hui, ; Palma et al, 2005; van den Brink, 2007; Varjosalo & Taipale, ). Overall, the key components of the Hh pathway are highly conserved from fruit flies to humans, although additional pathway components have added complexity to the pathway in vertebrates (Varjosalo et al, 2006). This introduction, however, will focus on Hh signaling in vertebrates due to the broad and diverse nature of this pathway across species Hedgehog signaling in a nutshell Signaling begins with the Hh ligand; Sonic (SHH), Desert (DHH) or Indian (IHH) Hh, being released from the producing cell. The Hh ligand binds to Patched (Ptch) receptors; PTCH1 and PTCH2 (Carpenter et al, 1998), on target cells (Stone et al, 1996). This leads to endosomal internalization and degradation of Ptch protein, thereby relieving the repression of a transmembrane protein Smoothened (SMO) (Denef et al, 2000; Incardona et al, 2002; Ingham et al, 2000; Murone et al, 1999). SMO then enters the primary cilia where it promotes the dissociation of a Suppressor of fused (SUFU)-GLI family zinc finger (Gli) complex (Tukachinsky et al, 2010). SUFU is the main repressor of the mammalian Hh signaling pathway by sequestering Gli transcription factors in the cytoplasm and nucleus (Kogerman et al, 1999). This repressor is negatively regulated by serine/threonine kinase 36 (STK36), which in turn promotes activation and nuclear 27

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