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3. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial

Author

Akce, Mehmet, Ales Diaz, Inmaculada, Alves, Gustavo, Anand, Sumitra, Arslan, Cagatay, Asselah, Jamil, Assenat, Eric, Aubin, Francine, Bai, Li-Yuan, Bai, Yuxian, Barajas, Olga, Bates, Susan, Begbie, Stephen, Ben-Aharon, Irit, Beri, Nina, Berres, Marie-Luise, Blanc, Jean-Frederic, Borbath, Ivan, Bordonaro, Robert, Bouattour, Mohamed, Brandi, Giovanni, Burgoyne, Adam, Butthongkomvong, Kritiya, Camandaroba, Marcos, Cao, Ke, Carballido, Marcela, Chan, Stephan Lam, Chen, Jen-Shi, Chen, Ming-Huang, Chen, Xiaoming, Cheng, Ashley, Chiu, Tai-Jan, Choi, Hye Jin, Chon, Hong Jae, Collignon, Joelle, Cubillo Gracian, Antonio, Davis, Sarah, de Carvalho, Ricardo Saraiva, de Groot, D.J.A., Demols, Anne, De Vos, Judith, Diab, Maria, Easaw, Jacob, Eatock, Martin, Edeline, Julien, Elias, Rawad, Eskens, Fredericus, Falcone, Alfredo, Fernandez, Plinio, Finn, Richard, Franke, Fabio, Furukawa, Masayuki, Furuse, Junji, Gbolahan, Olumide, Geboes, Karen, Geneser, Keri-Lee, Geng, Zhimin, Geva, Ravit, Gillmore, Roopinder, Goetze, Thorsten, Gou, Hongfeng, Grasselli, Julieta, Gu, Shanzhi, Gumus, Mahmut, Haj Mohammad, Nadia, Hao, Chunyi, Harputluoglu, Hakan, Hatoum, Hassan, Heinemann, Volker, Ho, Wang Kwong, Hsu, Chiun, Hubert, Ayala, Hwang, Juneul, Inanc, Mevlude, Iseas, Soledad, Jeyasingam, Vaishnavi, Jimenez Fonseca, Paula, Joubert, Warren, Juengsamarn, Jitlada, Kaen, Diego, Kanai, Masashi, Kasper-Virchow, Stefan, Kazemi, Ghazaleh, Kelleher, Fergal, Kelley, Robin, Kim, Jin Won, Kim, Jong Gwang, Kinupe Abrahao, Ana Beatriz, Klumpen, Heinz, Kochenderfer, Mark, Kose, Fatih, Lam, Ho Ching, Lee, Choong-kun, Lee, Hyun Woo, Lee, Margaret, Lee, Myung Ah, Lee, Wai Man Sarah, Le Sourd, Samuel, Li, Dongliang, Li, Wei, Liang, Houjie, Liang, Tingbo, Lim, Chun Sen, Lingerfelt, Brian, Lopez, Charles, Low, John, Macarulla Mercade, Teresa, Malka, David, Mao, Yimin, Masi, Gianluca, McCune, Steven, McDermott, Ray, McWhirter, Elaine, Mendez, Guillermo, Milella, Michele, Mizuno, Nobumasa, Mizutani, Tomonori, Moniz, Camila, Morales, Luisa, Munoz Martin, Andres Jesús, Nervi, Bruno, Ngamphaiboon, Nuttapong, Oh, Sang Cheul, Oksuzoglu, Berna, Outlaw, Darryl, Ozaka, Masato, Ozguroglu, Mustafa, Ozyilkan, Ozgur, Painemal, Claudio, Pan, Yueyin, Park, Joon Oh, Pelzer, Uwe, Peng, Chuang, Petorin, Caroline, Pezet, Denis, Power, Derek, Qin, Shukui, Ren, Zhenggang, Roohullah, Aflah, Ryu, Hyewon, Salman, Pamela, Sasaki, Mitsuhito, Sasidharan, Rita, Satoh, Taroh, Schulze, Kornelius, Scott-Brown, Martin, Segovia, Ruben, Seufferlein, Thomas, Siena, Salvatore, Sinapi, Isabelle, Smolenschi, Cristina, Song, Tianqiang, Sookprasert, Aumkhae, Soparattanapaisarn, Nopadol, Starling, Naureen, Stein, Stacey, Stemmer, Salomon, Su, Haichuan, Sugimoto, Rie, Suksombooncharoen, Thatthan, Tam, Vincent, Tan, Ai Lian, Tan, Chih Kiang, Tanasanvimon, Suebpong, Tonini, Giuseppe, Tortora, Giampaolo, Tsuji, Akihito, Ueno, Makoto, Uribe, Rodrigo, Venerito, Marino, Verdaguer Mata, Helena, Verslype, Chris, Victorino, Ana Paula, Vogel, Arndt, Wade, James, Waldschmidt, Dirk Thomas, Wang, Lu, Wan Isahk, Wan Zamaniah, Wasan, Harpeet, Weschenfelder, Rui, Wong, Chun Yin, Wong, Yoke Fui, Yalcin, Suayib, Yanez Weber, Patricio, Yang, Xuezhong, Yasui, Hisateru, Yau, Thomas, Yazici, Ozan, Yen, Chia-Jui, Ying, Jieer, Yoo, Changhoon, Yu, Wenchang, Zhao, Haitao, Kelley, Robin Kate, Finn, Richard S, Klümpen, Heinz-Josef, Chan, Stephen L, Valle, Juan W, Yu, Li, Malhotra, Usha, and Siegel, Abby B

Published
2023
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4. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial

Author

Kumar, Shaji K, Jacobus, Susanna J, Cohen, Adam D, Weiss, Matthias, Callander, Natalie, Singh, Avina K, Parker, Terri L, Menter, Alexander, Yang, Xuezhong, Parsons, Benjamin, Kumar, Pankaj, Kapoor, Prashant, Rosenberg, Aaron, Zonder, Jeffrey A, Faber, Edward, Jr, Lonial, Sagar, Anderson, Kenneth C, Richardson, Paul G, Orlowski, Robert Z, Wagner, Lynne I, and Rajkumar, S Vincent

Published
2020
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5. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial

Author

Kelley, Robin Kate, primary, Ueno, Makoto, additional, Yoo, Changhoon, additional, Finn, Richard S, additional, Furuse, Junji, additional, Ren, Zhenggang, additional, Yau, Thomas, additional, Klümpen, Heinz-Josef, additional, Chan, Stephen L, additional, Ozaka, Masato, additional, Verslype, Chris, additional, Bouattour, Mohamed, additional, Park, Joon Oh, additional, Barajas, Olga, additional, Pelzer, Uwe, additional, Valle, Juan W, additional, Yu, Li, additional, Malhotra, Usha, additional, Siegel, Abby B, additional, Edeline, Julien, additional, Vogel, Arndt, additional, Akce, Mehmet, additional, Ales Diaz, Immaculada, additional, Alves, Gustavo, additional, Anand, Sumitra, additional, Arslan, Cagatay, additional, Asselah, Jamil, additional, Assenat, Eric, additional, Aubin, Francine, additional, Bai, Li-Yuan, additional, Bai, Yuxian, additional, Bates, Susan, additional, Begbie, Stephen, additional, Ben-Aharon, Irit, additional, Beri, Nina, additional, Berres, Marie-Luise, additional, Blanc, Jean-Frederic, additional, Borbath, Ivan, additional, Bordonaro, Robert, additional, Brandi, Giovanni, additional, Burgoyne, Adam, additional, Butthongkomvong, Kritiya, additional, Cao, Ke, additional, Carballido, Marcela, additional, Camandaroba, Marcos, additional, Chang, Stephan Lam, additional, Chen, Jen-Shi, additional, Chen, Ming-Huang, additional, Chen, Xiaoming, additional, Cheng, Ashley, additional, Chiu, Tai-Jan, additional, Choi, Hye Jin, additional, Chon, Hong Jae, additional, Collignon, Joelle, additional, Cubillo Gracian, Antonio, additional, Davis, Sarah, additional, de Carvalho, Ricardo Saraiva, additional, de Groot, D.J.A., additional, Demols, Anne, additional, De Vos, Judith, additional, Diab, Maria, additional, Easaw, Jacob, additional, Eatock, Martin, additional, Elias, Rawad, additional, Eskens, Fredericus, additional, Falcone, Alfredo, additional, Fernandez, Plinio, additional, Finn, Richard, additional, Franke, Fabio, additional, Furukawa, Masayuki, additional, Gbolahan, Olumide, additional, Geboes, Karen, additional, Geneser, Keri-Lee, additional, Geng, Zhimin, additional, Geva, Ravit, additional, Gillmore, Roopinder, additional, Goetze, Thorsten, additional, Gou, Hongfeng, additional, Grasselli, Julieta, additional, Gu, Shanzhi, additional, Gumus, Mahmut, additional, Haj Mohammad, Nadia, additional, Hao, Chunyi, additional, Harputluoglu, Hakan, additional, Hatoum, Hassan, additional, Heinemann, Volker, additional, Ho, Wang Kwong, additional, Hsu, Chiun, additional, Hubert, Ayala, additional, Hwang, Juneul, additional, Inanc, Mevlude, additional, Iseas, Soledad, additional, Jeyasingam, Vaishnavi, additional, Jimenez Fonseca, Paula, additional, Joubert, Warren, additional, Juengsamarn, Jitlada, additional, Kaen, Diego, additional, Kanai, Masahi, additional, Kasper-Virchow, Stefan, additional, Kazemi, Ghazaleh, additional, Kelleher, Fergal, additional, Kelley, Robin, additional, Kim, Jin Won, additional, Kim, Jong Gwang, additional, Kinupe Abrahao, Ana Beatriz, additional, Klumpen, Heinz, additional, Kochenderfer, Mark, additional, Kose, Fatih, additional, Lam, Ho Ching, additional, Lee, Choong-kun, additional, Lee, Hyun Woo, additional, Lee, Margaret, additional, Lee, Myung Ah, additional, Lee, Wai Man Sarah, additional, Le Sourd, Samuel, additional, Li, Dongliang, additional, Li, Wei, additional, Liang, Houjie, additional, Liang, Tingbo, additional, Lim, Chun Sen, additional, Lingerfelt, Brian, additional, Lopez, Charles, additional, Low, John, additional, Macarulla Mercade, Teresa, additional, Malka, David, additional, Mao, Yimin, additional, Masi, Gianluca, additional, McCune, Steven, additional, McDermott, Ray, additional, McWhirter, Elaine, additional, Mendez, Guillermo, additional, Milella, Michele, additional, Mizutani, Tomonori, additional, Moniz, Camila, additional, Morales, Luisa, additional, Munoz Martin, Andres Jesús, additional, Nervi, Bruno, additional, Ngamphaiboon, Nuttapong, additional, Oh, Sang Cheul, additional, Oksuzoglu, Berna, additional, Outlaw, Darryl, additional, Ozguroglu, Mustafa, additional, Ozyilkan, Ozgur, additional, Painemeal, Claudio, additional, Pan, Yueyin, additional, Peng, Chuang, additional, Petorin, Caroline, additional, Pezet, Denis, additional, Power, Derek, additional, Qin, Shukui, additional, Roohullah, Aflah, additional, Ryu, Hyewon, additional, Salman, Pamela, additional, Sasidharan, Rita, additional, Satho, Taroh, additional, Schulze, Kornelius, additional, Scott-Brown, Martin, additional, Segovia, Ruben, additional, Seufferlin, Thomas, additional, Siena, Salvatore, additional, Sinapi, Isabelle, additional, Smolenschi, Cristina, additional, Song, Tianqiang, additional, Sookprasert, Aumkhae, additional, Soparattanapaisarn, Nopadol, additional, Starling, Naureen, additional, Stein, Stacey, additional, Stemmer, Salomon, additional, Su, Haichuan, additional, Sugimoto, Rie, additional, Suksombooncharoen, Thatthan, additional, Tam, Vincent, additional, Tan, Ai Lian, additional, Tan, Chih Kiang, additional, Tanasanvimon, Suebpong, additional, Tonini, Giuseppe, additional, Tortora, Giampaolo, additional, Tsuji, Akihito, additional, Uribe, Rodrigo, additional, Venerito, Marino, additional, Verdaguer Mata, Helena, additional, Victorino, Ana Paula, additional, Wade, James, additional, Waldschmidt, Dirk Thomas, additional, Wang, Lu, additional, Wan Isahk, Wan Zamaniah, additional, Wasan, Harpeet, additional, Weschenfelder, Rui, additional, Wong, Chun Yin, additional, Wong, Yoke Fui, additional, Yalcin, Suayib, additional, Yanez Weber, Patricio, additional, Yang, Xuezhong, additional, Yasui, Hisateru, additional, Yazici, Ozan, additional, Yen, Chia-Jui, additional, Ying, Jieer, additional, Yu, Wenchang, additional, and Zhao, Haitao, additional

Published
2023
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8. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (E1A11): a multicenter, open label, phase 3, randomized, controlled trial

Author

Kumar, Shaji K., Jacobus, Susanna J., Cohen, Adam D., Weiss, Matthias, Callander, Natalie Scott, Singh, Avina K., Parker, Terri L., Menter, Alexander, Yang, Xuezhong, Parsons, Benjamin Marshall, Kumar, Pankaj, Kapoor, Prashant, Rosenberg, Aaron Seth, Zonder, Jeffrey A., Faber, Edward Anthony, Lonial, Sagar, Anderson, Kenneth C., Richardson, Paul G., Orlowski, Robert Z., Wagner, Lynne I., and Rajkumar, S. Vincent

Subjects
Article
Abstract

SUMMARY: BACKGROUND: Bortezomib, lenalidomide, and dexamethasone (VRd) is a standard therapy for newly diagnosed multiple myeloma (NDMM). Carfilzomib, a next-generation proteasome inhibitor, in combination with lenalidomide, and dexamethasone (KRd) has shown excellent efficacy in phase II trials and may improve outcomes compared with VRd. METHODS: In this randomized, open label, phase 3 trial, we recruited patients with NDMM, aged 18 years and older, who were not planned for immediate autologous stem-cell transplant (ASCT). Key inclusion was absence of the following high-risk features (del17p, t(14;16), t(14;20), plasma cell leukemia) and Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. Patients were randomized (1:1) to receive VRd or KRd for 36 weeks followed by a 2(nd) randomization (1:1) to indefinite versus 2 years of lenalidomide maintenance. Allocation was stratified by intent to ASCT at disease progression and was not masked to investigators and patients. VRd regimen included bortezomib 1·3 mg/m(2) on days 1, 4, 8, and 11 (d 1, 8 for cycles 9–12), lenalidomide 25 mg daily on days 1–14, and dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, 12 for twelve 3-week cycles. KRd regimen included carfilzomib 36 mg/m(2) on days 1, 2, 8, 9, 15, 16, lenalidomide 25 mg daily on days 1–21 and dexamethasone 40 mg on days 1, 8, 15, and 22 for nine 4-week cycles. The primary endpoint was progression-free survival, defined as the time from first randomization to disease progression or death, analyzed by intention to treat. Safety was assessed in patients who received at least one dose of their assigned treatment. Study recruitment is complete, all patients have completed induction therapy, and patients continue on maintenance as per second randomization and follow up is ongoing. The trial is registered at ClinicalTrials.gov:NCT01863550. FINDINGS: Between December 6, 2013 and February 6, 2019, we randomly assigned 1087 patients at 272 participating institutions (542 to VRd, 545 to KRd). At an estimated median (IQR) follow-up of 9 (5–23) months from randomization, median PFS was 34·4 (95% CI 30·1-NE) months for VRd compared with 34·6 (95% CI 28·8–37·8) months for KRd; the PFS treatment hazard ratio (HR=KRd/VRd) was 1·04 (95% CI 0·83–1·31); P=0·74. The most common grade 3–4 non-hematologic adverse events included fatigue (34 [6%] vs. 29 [6%]), hyperglycemia (23 [4%] vs. 34[7%]), peripheral neuropathy (44 [8%]vs. 4 [

Published
2020

10. Carfilzomib, lenalidomide, and dexamethasone (KRd) versus bortezomib, lenalidomide, and dexamethasone (VRd) for initial therapy of newly diagnosed multiple myeloma (NDMM): Results of ENDURANCE (E1A11) phase III trial.

Author

Kumar, Shaji, primary, Jacobus, Susanna J., additional, Cohen, Adam D., additional, Weiss, Matthias, additional, Callander, Natalie Scott, additional, Singh, Avina A., additional, Parker, Terri L., additional, Menter, Alex R., additional, Yang, Xuezhong, additional, Parsons, Benjamin Marshall, additional, Kumar, Pankaj, additional, Kapoor, Prashant, additional, Rosenberg, Aaron Seth, additional, Zonder, Jeffrey A., additional, Faber, Edward Anthony, additional, Lonial, Sagar, additional, Richardson, Paul G., additional, Orlowski, Robert Z., additional, Wagner, Lynne I., additional, and Rajkumar, S. Vincent, additional

Published
2020
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14. Initial reporting of NRG-LU001 (NCT02186847), randomized phase II trial of concurrent chemoradiotherapy (CRT) +/- metformin in locally advanced Non-Small Cell Lung Cancer (NSCLC).

Author

Tsakiridis, Theodoros, primary, Hu, Chen, additional, Skinner, Heath Devin, additional, Santana-Davila, Rafael, additional, Lu, Bo, additional, Erasmus, Jeremy J., additional, Doemer, Anthony, additional, Videtic, Gregory M.M., additional, Coster, James, additional, Yang, Xuezhong, additional, Lee, Richard, additional, Werner-Wasik, Maria, additional, Schaner, Philip E., additional, McCormack, Steven Eric, additional, Esparaz, Benjamin, additional, McGarry, Ronald, additional, Bazan, Jose G., additional, Struve, Timothy, additional, and Bradley, Jeffrey D., additional

Published
2019
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16. P-0109 Survival Analysis of Maintenance Therapy with Capecitabine in Patients with Resected Pancreatic Adenocarcinoma after Adjuvant Therapy, a Retrospective Cohort Study

Author

Yang, Xuezhong, primary, Wu, Christina, additional, Hwang, Jimmy, additional, Akram, Madeeha, additional, Weinberg, Benjamin, additional, Pishvaian, Michael, additional, Luu, Dai, additional, Bekaii-Saab, Tanios, additional, He, Aiwu, additional, and Marshall, John, additional

Published
2012
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20. Maintenance therapy with capecitabine in patients with resected pancreatic adenocarcinoma after adjuvant therapy: a retrospective cohort study.

Author

Weinberg BA, Wang H, Yang X, Wu CS, Pishvaian MJ, He AR, Marshall JL, and Hwang JJ

Abstract

Background: The 5-year survival of pancreatic adenocarcinoma with surgery and adjuvant chemotherapy is below 25%. The original Gastrointestinal Tumor Study Group (GITSG) adjuvant study demonstrated a survival benefit attributed to weekly intravenous boluses of 5-fluorouracil (5-FU) for 2 years in addition to chemoradiation compared to surgery alone. In theory, the prolonged exposure to therapy could maintain pressure on dormant cancer cells that remain in G0 arrest and kill them as they infrequently enter the G1/S phase. We retrospectively evaluated outcomes in patients who were treated with adjuvant chemotherapy and maintenance capecitabine compared with those who received only adjuvant chemotherapy., Methods: Patients who had undergone surgical resection with curative intent and received adjuvant chemotherapy were analyzed. Those who subsequently received maintenance capecitabine therapy were compared to those who received adjuvant chemotherapy only. The primary end points were disease recurrence and all-cause mortality., Results: The median overall survival (OS) of patients receiving maintenance capecitabine was greater than 48.4 months (the exact estimate was not available, since the survival probability curve does not cross 0.5). It was 22.0 months (95% confidence interval [CI], 16.6-29.2) in patients who received adjuvant chemotherapy only (P < .001 by log-rank test). The median recurrence-free survival (RFS) was also longer in the maintenance capecitabine group: 54.3 (95% CI, 22.2-Inf) compared to 14.1 (95% CI, 11.6-16.7) months (P < .001, by log-rank test)., Conclusions: In this retrospective study, patients with resected pancreatic adenocarcinoma who received adjuvant chemotherapy had improved OS and RFS with additional maintenance therapy with capecitabine. These findings should be confirmed with a randomized, controlled trial.

Published
2014

21. Interferon gamma enhances the effectiveness of tumor necrosis factor-related apoptosis-inducing ligand receptor agonists in a xenograft model of Ewing's sarcoma.

Author

Merchant MS, Yang X, Melchionda F, Romero M, Klein R, Thiele CJ, Tsokos M, Kontny HU, and Mackall CL

Subjects
Animals, Cell Line, Tumor, Humans, Immunohistochemistry, Neoplasm Transplantation, Receptors, TNF-Related Apoptosis-Inducing Ligand, Interferon-gamma pharmacology, Receptors, Tumor Necrosis Factor agonists, Sarcoma, Ewing pathology
Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces selective apoptosis in a variety of tumors, including most cell lines derived from Ewing's sarcoma family of tumors, an aggressive sarcoma that afflicts children and young adults. To determine the in vivo efficacy of TRAIL receptor agonists in Ewing's sarcoma family of tumors, mice with orthotopic xenografts were treated with anti-TRAIL-R2 monoclonal antibody or TRAIL/Apo2L in a model that can identify effects on both primary tumors and metastases. Administration of either agonist slowed tumor growth in 60% of animals and induced durable remissions in 11 to 19% but did not alter the incidence of metastatic disease. Response rates were not improved by concurrent doxorubicin treatment. Cells recovered from both TRAIL receptor agonist-treated and nontreated tumors were found to be resistant to TRAIL-induced death in vitro unless pretreated with interferon (IFN) gamma. This resistance coincided with a selective down-regulation of TRAIL receptor expression on tumor cells. In vivo treatment with IFNgamma increased tumor expression of TRAIL receptors and caspase 8, but did not increase the antitumor effect of TRAIL receptor agonists on primary tumors. However, IFNgamma treatment alone or in combination with a TRAIL receptor agonist significantly decreased the incidence of metastatic disease and the combination of TRAIL receptor agonist therapy with IFNgamma-mediated impressive effects on both primary tumors and metastatic disease. These data demonstrate that in vivo growth favors TRAIL resistance but that TRAIL receptor agonists are active in Ewing's sarcoma family of tumors and that the combination of TRAIL receptor agonists with IFNgamma is a potent regimen in this disease capable of controlling both primary and metastatic tumors.

Published
2004
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22. Induction of caspase 8 by interferon gamma renders some neuroblastoma (NB) cells sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but reveals that a lack of membrane TR1/TR2 also contributes to TRAIL resistance in NB.

Author

Yang X, Merchant MS, Romero ME, Tsokos M, Wexler LH, Kontny U, Mackall CL, and Thiele CJ

Subjects
Antineoplastic Agents pharmacology, Apoptosis drug effects, Apoptosis Regulatory Proteins, Caspase 8, Caspase 9, Caspases genetics, Drug Resistance, Neoplasm, Enzyme Induction drug effects, Humans, Neuroblastoma drug therapy, Neuroblastoma genetics, Neuroblastoma pathology, RNA, Messenger genetics, RNA, Messenger metabolism, Receptors, TNF-Related Apoptosis-Inducing Ligand, Receptors, Tumor Necrosis Factor biosynthesis, Receptors, Tumor Necrosis Factor genetics, TNF-Related Apoptosis-Inducing Ligand, Transcription, Genetic drug effects, Transfection, Tumor Cells, Cultured, Caspases biosynthesis, Interferon-gamma pharmacology, Membrane Glycoproteins pharmacology, Neuroblastoma enzymology, Receptors, Tumor Necrosis Factor deficiency, Tumor Necrosis Factor-alpha pharmacology
Abstract

The resistance of neuroblastoma (NB) cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis has been attributed to a lack of caspase 8 expression. Here we demonstrate a clinically applicable molecular targeting strategy that not only increases caspase 8 expression ex vivo in NB cell lines but also in the tumor tissues of NB patients receiving IFN-gamma treatment. We identify the functional caspase 8 promoter, which is different from the methylated region reported previously, and show promoter activity is up-regulated by IFN-gamma through a IFN-gamma activation site-containing region. IFN-gamma also induces TRAIL expression in NB cell lines. However, the IFN-gamma restoration of caspase 8 in some NB cells revealed persistent TRAIL resistance in most NB cell lines examined. This additional lesion in the TRAIL path is because of a loss of cell membrane TRAIL receptors (TR1/TR2) not only in cell lines but in most of the NB tumor tissues evaluated. Restoration of TR2 expression by transfection enhances IFN-gamma-induced TRAIL sensitivity. Furthermore, we have found that we can improve TRAIL sensitivity in NB by reconstituting caspase 8 with IFN-gamma and TR2 with chemotherapeutic agents.

Published
2003

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