Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. It is believed to arise from skeletal muscle progenitors, preserving the expression of genes critical for embryonic myogenic development such as MYOD1 and myogenin. RMS is classified as embryonal, which is more common in younger children, or alveolar, which is more prevalent in elder children and adults. Despite aggressive management including surgery, radiation, and chemotherapy, the outcome for children with metastatic RMS is dismal, and the prognosis has remained unchanged for decades. Apoptosis is a highly regulated process critical for embryonic development and tissue and organ homeostasis. Like other types of cancers, RMS develops by evading intrinsic apoptosis via mutations in the p53 tumor suppressor gene. However, the ability to induce apoptosis via the death receptor-dependent extrinsic pathway remains largely intact in tumors with p53 mutations. This paper focuses on activating extrinsic apoptosis as a therapeutic strategy for RMS by targeting the death receptor DR5 with a recombinant TRAIL ligand or agonistic antibodies directed against DR5. 1. Introduction Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue tumor. Despite extensive research and aggressive clinical management, the overall outcome for children with metastatic disease is dismal with a prognosis largely unchanged in decades [1, 2]. RMS tumors are histologically classified into two major subtypes, embryonic (ERMS) and alveolar (ARMS), which are associated with unique genetic changes. The majority of ARMSs are characterized by the presence of PAX3/7:FOXO1 translocation [3, 4]. ERMSs, on the other hand, are more frequently associated with activated RAS signaling via mutations in RAS genes or deletions in NF1, a tumor suppressor that encodes an RAS inhibitor [5–7]. The two subtypes of RMS also have distinct prognoses. ERMSs are often found in younger patients who generally do better, whereas ARMSs are more frequently diagnosed in adolescents and young adults who have a worse prognosis with a five-year survival rate of less than 50% [8–11]. Additional mutations in tumor suppressors are important for the development of RMS. In particular, RMS is the most common pediatric cancer in families with Li-Fraumeni syndrome [12]. Mutations in p53 are important for pathogenesis and commonly found in RMS [13, 14]. Despite advances in radiation and chemotherapy, there has been little change in the 5-year survival rate for pediatric RMS [10]. The cure rate for advanced RMS is not expected to improve
References
[1]
R. Dagher and L. Helman, “Rhabdomyosarcoma: an overview,” Oncologist, vol. 4, no. 1, pp. 34–44, 1999.
[2]
A. C. Paulino and M. F. Okcu, “Rhabdomyosarcoma,” Current Problems in Cancer, vol. 32, no. 1, pp. 7–34, 2008.
[3]
N. Galili, R. J. Davis, W. J. Fredericks et al., “Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma,” Nature Genetics, vol. 5, no. 3, pp. 230–235, 1993.
[4]
R. J. Davis, C. M. D'Cruz, M. A. Lovell, J. A. Biegel, and F. G. Barr, “Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar rhabdomyosarcoma,” Cancer Research, vol. 54, no. 11, pp. 2869–2872, 1994.
[5]
V. Paulson, G. Chandler, D. Rakheja et al., “High-resolution array CGH identifies common mechanisms that drive embryonal rhabdomyosarcoma pathogenesis,” Genes Chromosomes and Cancer, vol. 50, no. 6, pp. 397–408, 2011.
[6]
D. Olmos, A. S. Martins, R. L. Jones, S. Alam, M. Scurr, and I. R. Judson, “Targeting the insulin-like growth factor 1 receptor in Ewing's sarcoma: reality and expectations,” Sarcoma, vol. 2011, Article ID 402508, 13 pages, 2011.
[7]
A. S. Martins, D. Olmos, E. Missiaglia, and J. Shipley, “Targeting the insulin-like growth factor pathway in rhabdomyosarcomas: rationale and future perspectives,” Sarcoma, vol. 2011, Article ID 209736, 11 pages, 2011.
[8]
J. L. Meza, J. Anderson, A. S. Pappo, and W. H. Meyer, “Analysis of prognostic factors in patients with nonmetastatic rhabdomyosarcoma treated on intergroup rhabdomyosarcoma studies III and IV: the children's oncology group,” Journal of Clinical Oncology, vol. 24, no. 24, pp. 3844–3851, 2006.
[9]
J. C. Breneman, E. Lyden, A. S. Pappo et al., “Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma—a report from the Intergroup Rhabdomyosarcoma Study IV,” Journal of Clinical Oncology, vol. 21, no. 1, pp. 78–84, 2003.
[10]
S. Ognjanovic, A. M. Linabery, B. Charbonneau, and J. A. Ross, “Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975–2005,” Cancer, vol. 115, no. 18, pp. 4218–4226, 2009.
[11]
D. M. Parham and D. A. Ellison, “Rhabdomyosarcomas in adults and children: an update,” Archives of Pathology and Laboratory Medicine, vol. 130, no. 10, pp. 1454–1465, 2006.
[12]
D. Malkin, F. P. Li, L. C. Strong et al., “Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms,” Science, vol. 250, no. 4985, pp. 1233–1238, 1990.
[13]
C. A. Felix, C. C. Kappel, T. Mitsudomi et al., “Frequency and diversity of p53 mutations in childhood rhabdomyosarcoma,” Cancer Research, vol. 52, no. 8, pp. 2243–2247, 1992.
[14]
L. Diller, E. Sexsmith, A. Gottlieb, F. P. Li, and D. Malkin, “Germline p53 mutations are frequently detected in young children with rhabdomyosarcoma,” Journal of Clinical Investigation, vol. 95, no. 4, pp. 1606–1611, 1995.
[15]
L. E. S. Crose and C. M. Linardic, “Receptor tyrosine kinases as therapeutic targets in rhabdomyosarcoma,” Sarcoma, vol. 2011, Article ID 756982, 11 pages, 2011.
[16]
J. M. Lee and A. Bernstein, “Apoptosis, cancer and the p53 tumour suppressor gene,” Cancer and Metastasis Reviews, vol. 14, no. 2, pp. 149–161, 1995.
[17]
A. Ashkenazi, “Directing cancer cells to self-destruct with pro-apoptotic receptor agonists,” Nature Reviews Drug Discovery, vol. 7, no. 12, pp. 1001–1012, 2008.
[18]
R. M. Locksley, N. Killeen, and M. J. Lenardo, “The TNF and TNF receptor superfamilies: integrating mammalian biology,” Cell, vol. 104, no. 4, pp. 487–501, 2001.
[19]
F. C. Kischkel, D. A. Lawrence, A. Chuntharapai, P. Schow, K. J. Kim, and A. Ashkenazi, “Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5,” Immunity, vol. 12, no. 6, pp. 611–620, 2000.
[20]
F. C. Kischkel, D. A. Lawrence, A. Tinel et al., “Death receptor recruitment of endogenous caspase-10 and apoptosis initiation in the absence of caspase-8,” Journal of Biological Chemistry, vol. 276, no. 49, pp. 46639–46646, 2001.
[21]
A. Ashkenazi and R. S. Herbst, “To kill a tumor cell: the potential of proapoptotic receptor agonists,” Journal of Clinical Investigation, vol. 118, no. 6, pp. 1979–1990, 2008.
[22]
I. M. Ghobrial, T. E. Witzig, and A. A. Adjei, “Targeting apoptosis pathways in cancer therapy,” Ca-A Cancer Journal for Clinicians, vol. 55, no. 3, pp. 178–194, 2005.
[23]
D. Hanahan and R. A. Weinberg, “Hallmarks of cancer: the next generation,” Cell, vol. 144, no. 5, pp. 646–674, 2011.
[24]
D. Hanahan and R. A. Weinberg, “The hallmarks of cancer,” Cell, vol. 100, no. 1, pp. 57–70, 2000.
[25]
S. Fulda and K. M. Debatin, “Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy,” Oncogene, vol. 25, no. 34, pp. 4798–4811, 2006.
[26]
A. Letai, “Pharmacological manipulation of Bcl-2 family members to control cell death,” Journal of Clinical Investigation, vol. 115, no. 10, pp. 2648–2655, 2005.
[27]
J. K. Brunelle and A. Letai, “Control of mitochondrial apoptosis by the Bcl-2 family,” Journal of Cell Science, vol. 122, no. 4, pp. 437–441, 2009.
[28]
A. M. Chinnaiyan, “The apoptosome: heart and soul of the cell death machine,” Neoplasia, vol. 1, no. 1, pp. 5–15, 1999.
[29]
J. Henry-Mowatt, C. Dive, J. C. Martinou, and D. James, “Role of mitochondrial membrane permeabilization in apoptosis and cancer,” Oncogene, vol. 23, no. 16, pp. 2850–2860, 2004.
[30]
K. H. Vousden and X. Lu, “Live or let die: the cell's response to p53,” Nature Reviews Cancer, vol. 2, no. 8, pp. 594–604, 2002.
[31]
J. S. Fridman and S. W. Lowe, “Control of apoptosis by p53,” Oncogene, vol. 22, no. 56, pp. 9030–9040, 2003.
[32]
B. Vogelstein, D. Lane, and A. J. Levine, “Surfing the p53 network,” Nature, vol. 408, no. 6810, pp. 307–310, 2000.
[33]
S. W. Lowe, E. Cepero, and G. Evan, “Intrinsic tumour suppression,” Nature, vol. 432, no. 7015, pp. 307–315, 2004.
[34]
S. Ognjanovic, M. Oliver, T. L. Bergemann, and P. Hainaut, “Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 database,” Cancer, vol. 118, no. 5, pp. 1387–1396, 2012.
[35]
L. M. Mulligan, G. J. Matlashewski, H. J. Scrable, and W. K. Cavenee, “Mechanisms of p53 loss in human sarcomas,” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 15, pp. 5863–5867, 1990.
[36]
S. W. Lowe, H. E. Ruley, T. Jacks, and D. E. Housman, “p53-Dependent apoptosis modulates the cytotoxicity of anticancer agents,” Cell, vol. 74, no. 6, pp. 957–967, 1993.
[37]
S. W. Lowe, E. M. Schmitt, S. W. Smith, B. A. Osborne, and T. Jacks, “p53 is required for radiation-induced apoptosis in mouse thymocytes,” Nature, vol. 362, no. 6423, pp. 847–849, 1993.
[38]
A. A. Gibson, F. G. Harwood, D. M. Tillman, and J. A. Houghton, “Selective sensitization to DNA-damaging agents in a human rhabdomyosarcoma cell line with inducible wild-type p53 overexpression,” Clinical Cancer Research, vol. 4, no. 1, pp. 145–152, 1998.
[39]
D. W. Chang, Z. Xing, Y. Pan et al., “C-FLIPL is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis,” EMBO Journal, vol. 21, no. 14, pp. 3704–3714, 2002.
[40]
Z. Jin, Y. Li, R. Pitti et al., “Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling,” Cell, vol. 137, no. 4, pp. 721–735, 2009.
[41]
R. S. Herbst, S. G. Eckhardt, R. Kurzrock et al., “Phase I dose-escalation study of recombinant human Apo2L/TRAIL, a dual proapoptotic receptor agonist, in patients with advanced cancer,” Journal of Clinical Oncology, vol. 28, no. 17, pp. 2839–2846, 2010.
[42]
R. Plummer, G. Attard, S. Pacey et al., “Phase 1 and pharmacokinetic study of lexatumumab in patients with advanced cancers,” Clinical Cancer Research, vol. 13, no. 20, pp. 6187–6194, 2007.
[43]
H. A. Wakelee, A. Patnaik, B. I. Sikic et al., “Phase I and pharmacokinetic study of lexatumumab (HGS-ETR2) given every 2 weeks in patients with advanced solid tumors,” Annals of Oncology, vol. 21, no. 2, pp. 376–381, 2009.
[44]
M. S. Merchant, A. J. Chou, A. P. Price, et al., “Lexatumumab: results of a phase I trial in pediatric patients with advanced solid tumors,” Journal of Clinical Oncology, vol. 28, no. 15s, 9500, ASCO Annual Meeting, 2010.
[45]
D. R. Camidge, R. S. Herbst, M. S. Gordon et al., “A phase I safety and pharmacokinetic study of the death receptor 5 agonistic antibody PRO95780 in patients with advanced malignancies,” Clinical Cancer Research, vol. 16, no. 4, pp. 1256–1263, 2010.
[46]
R. S. Herbst, R. Kurzrock, D. S. Hong et al., “A first-in-human study of conatumumab in adult patients with advanced solid tumors,” Clinical Cancer Research, vol. 16, no. 23, pp. 5883–5891, 2010.
[47]
T. Doi, H. Murakami, A. Ohtsu et al., “Phase 1 study of conatumumab, a pro-apoptotic death receptor 5 agonist antibody, in Japanese patients with advanced solid tumors,” Cancer Chemotherapy and Pharmacology, vol. 68, no. 3, pp. 733–741, 2011.
[48]
A. Forero-Torres, J. Shah, T. Wood et al., “Phase I trial of weekly tigatuzumab, an agonistic humanized monoclonal antibody targeting death receptor 5 (DR5),” Cancer Biotherapy and Radiopharmaceuticals, vol. 25, no. 1, pp. 13–19, 2010.
[49]
J. C. Soria, E. Smit, D. Khayat et al., “Phase 1b study of dulanermin (recombinant human Apo2L/TRAIL) in combination with paclitaxel, carboplatin, and bevacizumab in patients with advanced non-squamous non-small-cell lung cancer,” Journal of Clinical Oncology, vol. 28, no. 9, pp. 1527–1533, 2010.
[50]
C. Scaffidi, S. Fulda, A. Srinivasan et al., “Two CD95 (APO-1/Fas) signaling pathways,” EMBO Journal, vol. 17, no. 6, pp. 1675–1687, 1998.
[51]
N. ？z？ren and W. S. El-Deiry, “Defining characteristics of types I and II apoptotic cells in response to TRAIL,” Neoplasia, vol. 4, no. 6, pp. 551–557, 2002.
[52]
D. Williamson, Y. J. Lu, T. Gordon et al., “Relationship between MYCN copy number and expression in rhabdomyosarcomas and correlation with adverse prognosis in the alveolar subtype,” Journal of Clinical Oncology, vol. 23, no. 4, pp. 880–888, 2005.
[53]
D. M. Langenau, M. D. Keefe, N. Y. Storer et al., “Effects of RAS on the genesis of embryonal rhabdomyosarcoma,” Genes and Development, vol. 21, no. 11, pp. 1382–1395, 2007.
[54]
A. I. Nieminen, J. I. Partanen, A. Hau, and J. Klefstrom, “c-Myc primed mitochondria determine cellular sensitivity to TRAIL-induced apoptosis,” EMBO Journal, vol. 26, no. 4, pp. 1055–1067, 2007.
[55]
Y. Wang, K. C. Quon, D. A. Knee, A. Nesterov, and A. S. Kraft, “RAS, MYC, and sensitivity to tumor necrosis factor-α-related apoptosis-inducing ligand-induced apoptosis,” Cancer Research, vol. 65, no. 4, pp. 1615–1617, 2005.
[56]
Y. Wang, I. H. Engels, D. A. Knee, M. Nasoff, Q. L. Deveraux, and K. C. Quon, “Synthetic lethal targeting of MYC by activation of the DR5 death receptor pathway,” Cancer Cell, vol. 5, no. 5, pp. 501–512, 2004.
[57]
E. M. Hersh, B. S. Metch, F. M. Muggia et al., “Phase II studies of recombinant human tumor necrosis factor alpha in patients with malignant disease: a summary of the Southwest Oncology Group experience,” Journal of Immunotherapy, vol. 10, no. 6, pp. 426–431, 1991.
[58]
J. Ogasawara, R. Watanabe-Fukunaga, M. Adachi et al., “Lethal effect of the anti-Fas antibody in mice,” Nature, vol. 364, no. 6440, pp. 806–809, 1993.
[59]
H. Walczak, R. E. Miller, K. Ariail et al., “Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo,” Nature Medicine, vol. 5, no. 2, pp. 157–163, 1999.
[60]
A. W. Tolcher, M. Mita, N. J. Meropol et al., “Phase I pharmacokinetic and biologic correlative study of mapatumumab, a fully human monoclonal antibody with agonist activity to tumor necrosis factor-related apoptosis-inducing ligand receptor-1,” Journal of Clinical Oncology, vol. 25, no. 11, pp. 1390–1395, 2007.
[61]
F. Gonzalvez and A. Ashkenazi, “New insights into apoptosis signaling by Apo2L/TRAIL,” Oncogene, vol. 29, no. 34, pp. 4752–4765, 2010.
[62]
K. W. Wagner, E. A. Punnoose, T. Januario et al., “Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL,” Nature Medicine, vol. 13, no. 9, pp. 1070–1077, 2007.
[63]
Y. Zhang and B. Zhang, “TRAIL resistance of breast cancer cells is associated with constitutive endocytosis of death receptors 4 and 5,” Molecular Cancer Research, vol. 6, no. 12, pp. 1861–1871, 2008.
[64]
A. Eramo, R. Pallini, F. Lotti et al., “Inhibition of DNA methylation sensitizes glioblastoma for tumor necrosis factor-related apoptosis-inducing ligand-mediated destruction,” Cancer Research, vol. 65, no. 24, pp. 11469–11477, 2005.
[65]
S. Hopkins-Donaldson, J. L. Bodmer, K. B. Bourloud, C. B. Brognara, J. Tschopp, and N. Gross, “Loss of caspase-8 expression in highly malignant human neuroblastoma cells correlates with resistance to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis,” Cancer Research, vol. 60, no. 16, pp. 4315–4319, 2000.
[66]
A. R. Safa, T. W. Day, and C. H. Wu, “Cellular FLICE-like inhibitory protein (C-FLIP): a novel target for cancer therapy,” Current Cancer Drug Targets, vol. 8, no. 1, pp. 37–46, 2008.
[67]
J. M. Cummins, M. Kohli, C. Rago, K. W. Kinzler, B. Vogelstein, and F. Bunz, “X-linked inhibitor of apoptosis protein (XIAP) is a nonredundant modulator of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human cancer cells,” Cancer Research, vol. 64, no. 9, pp. 3006–3008, 2004.
[68]
M. S. Ricci, S. H. Kim, K. Ogi et al., “Reduction of TRAIL-induced Mcl-1 and cIAP2 by c-Myc or sorafenib sensitizes resistant human cancer cells to TRAIL-induced death,” Cancer Cell, vol. 12, no. 1, pp. 66–80, 2007.
[69]
M. H. Pespeni, M. Hodnett, K. S. Abayasiriwardana et al., “Sensitization of mesothelioma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by heat stress via the inhibition of the 3-phosphoinositide-dependent kinase 1/Akt pathway,” Cancer Research, vol. 67, no. 6, pp. 2865–2871, 2007.
[70]
I. Petak, L. Douglas, D. M. Tillman, R. Vernes, and J. A. Houghton, “Pediatric rhabdomyosarcoma cell lines are resistant to Fas-induced apoptosis and highly sensitive to TRAIL-induced apoptosis,” Clinical Cancer Research, vol. 6, no. 10, pp. 4119–4127, 2000.
[71]
G. Picarda, F. Lamoureux, L. Geffroy et al., “Preclinical evidence that use of TRAIL in Ewing's sarcoma and osteosarcoma therapy inhibits tumor growth, prevents osteolysis, and increases animal survival,” Clinical Cancer Research, vol. 16, no. 8, pp. 2363–2374, 2010.
[72]
H. U. Kontny, K. H？mmerle, R. Klein, P. Shayan, C. L. Mackall, and C. M. Niemeyer, “Sensitivity of Ewing's sarcoma to TRAIL-induced apoptosis,” Cell Death and Differentiation, vol. 8, no. 5, pp. 506–514, 2001.
[73]
F. Van Valen, S. Fulda, B. Truckenbrod et al., “Apoptotic responsiveness of the Ewing's sarcoma family of tumours to tumour necrosis factor—related apoptosis-inducing ligand (trail),” International Journal of Cancer, vol. 88, no. 2, pp. 252–259, 2000.
[74]
A. Kumar, A. Jasmin, M. T. Eby, and P. M. Chaudhary, “Cytotoxicity of tumor necrosis factor related apoptosis-inducing ligand towards Ewing's sarcoma cell lines,” Oncogene, vol. 20, no. 8, pp. 1010–1014, 2001.
[75]
N. Mitsiades, V. Poulaki, C. Mitsiades, and M. Tsokos, “Ewing's sarcoma family tumors are sensitive to tumor necrosis factor-related apoptosis-inducing ligand and express death receptor 4 and death receptor 5,” Cancer Research, vol. 61, no. 6, pp. 2704–2712, 2001.
[76]
Z. Kang, J.-J. Chen, Y. Yu et al., “Drozitumab, a human antibody to death receptor 5, has potent antitumor activity against rhabdomyosarcoma with the expression of caspase-8 predictive of response,” Clinical Cancer Research, vol. 17, no. 10, pp. 3181–3192, 2011.
[77]
H. S. Young, W. L. Jong, Y. K. Su et al., “CASPASE-8 gene is inactivated by somatic mutations in gastric carcinomas,” Cancer Research, vol. 65, no. 3, pp. 815–821, 2005.
[78]
Y. H. Soung, J. W. Lee, S. Y. Kim et al., “Caspase-8 gene is frequently inactivated by the frameshift somatic mutation 1225_1226delTG in hepatocellular carcinomas,” Oncogene, vol. 24, no. 1, pp. 141–147, 2005.
[79]
H. S. Kim, J. W. Lee, Y. H. Soung et al., “Inactivating mutations of caspase-8 gene in colorectal carcinomas,” Gastroenterology, vol. 125, no. 3, pp. 708–715, 2003.
[80]
S. Mandruzzato, F. Brasseur, G. Andry, T. Boon, and P. Van Der Bruggen, “A CASP-8 mutation recognized by cytolytic T lymphocytes on a human head and neck carcinoma,” Journal of Experimental Medicine, vol. 186, no. 5, pp. 785–793, 1997.
[81]
T. Teitz, T. Wei, M. B. Valentine et al., “Caspase 8 is deleted or silenced preferentially in childhood neuroblastomas with amplification of MYCN,” Nature Medicine, vol. 6, no. 5, pp. 529–535, 2000.
[82]
M. A. Grotzer, A. Eggert, T. J. Zuzak et al., “Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor cells correlates with a loss of caspase-8 expression,” Oncogene, vol. 19, no. 40, pp. 4604–4610, 2000.
[83]
S. Fulda, M. U. Küfer, E. Meyer, F. Van Valen, B. Dockhorn-Dworniczak, and K. M. Debatin, “Sensitization for death receptor- or drug-induced apoptosis by re-expression of caspase-8 through demethylation or gene transfer,” Oncogene, vol. 20, no. 41, pp. 5865–5877, 2001.
[84]
J. Takita, H. W. Yang, F. Bessho et al., “Absent or reduced expression of the caspase 8 gene occurs frequently in neuroblastoma, but not commonly in Ewing sarcoma or rhabdomyosarcoma,” Medical and Pediatric Oncology, vol. 35, no. 6, pp. 541–543, 2000.
[85]
S. Fulda and K. M. Debatin, “5-Aza- -deoxycytidine and IFN-γ cooperate to sensitize for TRAIL-induced apoptosis by upregulating caspase-8,” Oncogene, vol. 25, no. 37, pp. 5125–5133, 2006.
[86]
M. S. Merchant, X. Yang, F. Melchionda et al., “Interferon γ enhances the effectiveness of tumor necrosis factor-related apoptosis-inducing ligand receptor agonists in a xenograft model of Ewing's sarcoma,” Cancer Research, vol. 64, no. 22, pp. 8349–8356, 2004.
[87]
R. Komdeur, C. Meijer, M. Van Zweeden et al., “Doxorubicin potentiates TRAIL cytotoxicity and apoptosis and can overcome TRAIL-resistance in rhabdomyosarcoma cells,” International Journal of Oncology, vol. 25, no. 3, pp. 677–684, 2004.
[88]
K. Izeradjene, L. Douglas, A. B. Delaney, and J. A. Houghton, “Casein kinase I attenuates tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by regulating the recruitment of fas-associated death domain and procaspase-8 to the death-inducing signaling complex,” Cancer Research, vol. 64, no. 21, pp. 8036–8044, 2004.
[89]
K. Izeradjene, L. Douglas, A. Delaney, and J. A. Houghton, “Influence of casein kinase II in tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human rhabdomyosarcoma cells,” Clinical Cancer Research, vol. 10, no. 19, pp. 6650–6660, 2004.
[90]
L. Yee, H. A. Burris, M. Kozloff, et al., “Phase Ib study of recombinant human Apo2L/TRAIL plus irinotecan and cetuximab or FOLFIRI in metastatic colorectal cancer patients: preliminary results,” Journal of Clinical Oncology, vol. 27, no. 15S, 4129, ASCO Annual Meeting, 2009.
[91]
L. Yee, M. Fanale, K. Dimick, et al., “A phase IB safety and pharmacokinetic study of recombinant human Apo2L/TRAIL in combination with rituximab in patients with low-grade non-Hodgkin lymphoma,” Journal of Clinical Oncology, vol. 25, no. 18S, 8078, ASCO Annual Meeting Proceedings, 2007.
[92]
N. S. Wilson, B. Yang, A. Yang et al., “An Fcγ receptor-dependent mechanism drives antibody-mediated target-receptor signaling in cancer cells,” Cancer Cell, vol. 19, no. 1, pp. 101–113, 2011.
[93]
A. Ashkenazi, “Targeting death and decoy receptors of the tumour-necrosis factor superfamily,” Nature Reviews Cancer, vol. 2, no. 6, pp. 420–430, 2002.
[94]
H. M. Stern, M. Padilla, K. Wagner, L. Amler, and A. Ashkenazi, “Development of immunohistochemistry assays to assess GALNT14 and FUT3/6 in clinical trials of dulanermin and drozitumab,” Clinical Cancer Research, vol. 16, no. 5, pp. 1587–1596, 2010.
[95]
P. J. Kaplan-Lefko, J. D. Graves, S. J. Zoog et al., “Conatumumab, a fully human agonist antibody to death receptor 5, induces apoptosis via caspase activation in multiple tumor types,” Cancer Biology and Therapy, vol. 9, no. 8, pp. 618–631, 2010.
[96]
I. Zinonos, A. Labrinidis, M. Lee et al., “Apomab, a fully human agonistic antibody to DR5, exhibits potent antitumor activity against primary and metastatic breast cancer,” Molecular Cancer Therapeutics, vol. 8, no. 10, pp. 2969–2980, 2009.
[97]
C. Adams, K. Totpal, D. Lawrence et al., “Structural and functional analysis of the interaction between the agonistic monoclonal antibody Apomab and the proapoptotic receptor DR5,” Cell Death and Differentiation, vol. 15, no. 4, pp. 751–761, 2008.
[98]
A. Natoni, M. MacFarlane, S. Inoue et al., “TRAIL signals to apoptosis in chronic lymphocytic leukaemia cells primarily through TRAIL-R1 whereas cross-linked agonistic TRAIL-R2 antibodies facilitate signalling via TRAIL-R2,” British Journal of Haematology, vol. 139, no. 4, pp. 568–577, 2007.
[99]
R. W. Johnstone, A. J. Frew, and M. J. Smyth, “The TRAIL apoptotic pathway in cancer onset, progression and therapy,” Nature Reviews Cancer, vol. 8, no. 10, pp. 782–798, 2008.
[100]
A. Yang, N. S. Wilson, and A. Ashkenazi, “Proapoptotic DR4 and DR5 signaling in cancer cells: toward clinical translation,” Current Opinion in Cell Biology, vol. 22, no. 6, pp. 837–844, 2010.
