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Archivum Immunologiae Et Therapiae... Dec 2014Ovarian cancer has emerged as a multifaceted and genomically complex disease. Genetic/epigenetic mutations, suppression of tumor suppressors, overexpression of... (Review)
Review
Ovarian cancer has emerged as a multifaceted and genomically complex disease. Genetic/epigenetic mutations, suppression of tumor suppressors, overexpression of oncogenes, rewiring of intracellular signaling cascades and loss of apoptosis are some of the deeply studied mechanisms. In vitro and in vivo studies have highlighted different molecular mechanisms that regulate tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apoptosis in ovarian cancer. In this review, we bring to limelight, expansion in understanding systematical characterization of ovarian cancer cells has led to the rapid development of new drugs and treatments to target negative regulators of TRAIL mediated signaling pathway. Wide ranging synthetic and natural agents have been shown to stimulate mRNA and protein expression of death receptors. This review is compartmentalized into programmed cell death protein 4, platelet-derived growth factor signaling and miRNA control of TRAIL mediated signaling to ovarian cancer. Mapatumumab and PRO95780 have been tested for efficacy against ovarian cancer. Use of high-throughput screening assays will aid in dissecting the heterogeneity of this disease and increasing a long-term survival which might be achieved by translating rapidly accumulating information obtained from molecular and cellular studies to clinic researches.
Topics: Apoptosis; Apoptosis Regulatory Proteins; CASP8 and FADD-Like Apoptosis Regulating Protein; Female; Humans; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; MicroRNAs; NF-kappa B; Ovarian Neoplasms; RNA-Binding Proteins; Receptors, Platelet-Derived Growth Factor; Receptors, TNF-Related Apoptosis-Inducing Ligand; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; alpha-Crystallin B Chain
PubMed: 25030086
DOI: 10.1007/s00005-014-0307-9 -
Annals of Oncology : Official Journal... Apr 2016This randomized, double-blind, placebo-controlled, phase II study evaluated the efficacy and safety of mapatumumab (a human agonistic monoclonal antibody against tumor... (Randomized Controlled Trial)
Randomized Controlled Trial
A randomized, double-blind, placebo-controlled phase II study to assess the efficacy and safety of mapatumumab with sorafenib in patients with advanced hepatocellular carcinoma.
BACKGROUND
This randomized, double-blind, placebo-controlled, phase II study evaluated the efficacy and safety of mapatumumab (a human agonistic monoclonal antibody against tumor necrosis factor-related apoptosis-inducing ligand receptor 1) in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC).
PATIENTS AND METHODS
Patients with advanced HCC (stratified by Barcelona Clinic Liver Cancer stage and Eastern Cooperative Oncology Group performance status) were randomized 1:1 to receive sorafenib (400 mg, twice daily per 21-day cycle) and either placebo (placebo-sorafenib arm) or mapatumumab (30 mg/kg on day 1 per 21-day cycle; mapatumumab-sorafenib arm). The primary end point was time to (radiologic) progression (TTP), assessed by blinded independent central review. Key secondary end points included progression-free survival, overall survival, and objective response.
RESULTS
In total, 101 patients were randomized (placebo-sorafenib arm: N = 51; mapatumumab-sorafenib arm: N = 50). There was no significant difference in median TTP between both arms [5.6 versus 4.1 months, respectively; adjusted hazard ratio (one-sided 90% confidence interval) 1.192 (0-1.737)]. No mapatumumab-related benefit was identified when TTP was evaluated in the stratified subgroups. The addition of mapatumumab to sorafenib did not demonstrate improvement in the secondary efficacy end points. The reported frequency of adverse events (AEs) and serious AEs was comparable in both treatment arms.
CONCLUSIONS
The addition of mapatumumab to sorafenib did not improve TTP or other efficacy end points, nor did it substantially change the toxicity profile of sorafenib in patients with advanced HCC. Based on these results, further development of the combination of mapatumumab and sorafenib in HCC is not planned.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Disease-Free Survival; Double-Blind Method; Female; Humans; Kaplan-Meier Estimate; Liver Neoplasms; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Sorafenib; Treatment Outcome
PubMed: 26802147
DOI: 10.1093/annonc/mdw004 -
Molecular Cancer Oct 2007The incidence of malignant pleural mesothelioma (MPM) is associated with exposure to asbestos, and projections suggest that the yearly number of deaths in Western Europe...
BACKGROUND
The incidence of malignant pleural mesothelioma (MPM) is associated with exposure to asbestos, and projections suggest that the yearly number of deaths in Western Europe due to MPM will increase until 2020. Despite progress in chemo- and in multimodality therapy, MPM remains a disease with a poor prognosis. Inducing apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or agonistic monoclonal antibodies which target TRAIL-receptor 1 (TRAIL-R1) or TRAIL-R2 has been thought to be a promising cancer therapy.
RESULTS
We have compared the sensitivity of 13 MPM cell lines or primary cultures to TRAIL and two fully human agonistic monoclonal antibodies directed to TRAIL-R1 (Mapatumumab) and TRAIL-R2 (Lexatumumab) and examined sensitization of the MPM cell lines to cisplatin-induced by the TRAIL-receptor antibodies. We found that sensitivity of MPM cells to TRAIL, Mapatumumab and Lexatumumab varies largely and is independent of TRAIL-receptor expression. TRAIL-R2 contributes more than TRAIL-R1 to death-receptor mediated apoptosis in MPM cells that express both receptors. The combination of cisplatin with Mapatumumab or Lexatumumab synergistically inhibited the cell growth and enhanced apoptotic death. Furthermore, pre-treatment with cisplatin followed by Mapatumumab or Lexatumumab resulted in significant higher cytotoxic effects as compared to the reverse sequence. Combination-induced cell growth inhibition was significantly abrogated by pre-treatment of the cells with the antioxidant N-acetylcysteine.
CONCLUSION
Our results suggest that the sequential administration of cisplatin followed by Mapatumumab or Lexatumumab deserves investigation in the treatment of patients with MPM.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; Cisplatin; Drug Synergism; Flow Cytometry; Humans; Immunoblotting; Jurkat Cells; Mesothelioma; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor
PubMed: 17953743
DOI: 10.1186/1476-4598-6-66 -
Frontiers in Molecular Biosciences 2021TRAIL (tumor-necrosis factor related apoptosis-inducing ligand, CD253) and its death receptors TRAIL-R1 and TRAIL-R2 selectively trigger the apoptotic cell death in... (Review)
Review
TRAIL (tumor-necrosis factor related apoptosis-inducing ligand, CD253) and its death receptors TRAIL-R1 and TRAIL-R2 selectively trigger the apoptotic cell death in tumor cells. For that reason, TRAIL has been extensively studied as a target of cancer therapy. In spite of the promising preclinical observations, the TRAIL-based therapies in humans have certain limitations. The two main therapeutic approaches are based on either an administration of TRAIL-receptor (TRAIL-R) agonists or a recombinant TRAIL. These approaches, however, seem to elicit a limited therapeutic efficacy, and only a few drugs have entered the phase II clinical trials. To deliver TRAIL-based therapies with higher anti-tumor potential several novel TRAIL-derivates and modifications have been designed. These novel drugs are, however, mostly preclinical, and many problems continue to be unraveled. We have reviewed the current status of all TRAIL-based monotherapies and combination therapies that have reached phase II and phase III clinical trials in humans. We have also aimed to introduce all novel approaches of TRAIL utilization in cancer treatment and discussed the most promising drugs which are likely to enter clinical trials in humans. To date, different strategies were introduced in order to activate anti-tumor immune responses with the aim of achieving the highest efficacy and minimal toxicity.In this review, we discuss the most promising TRAIL-based clinical trials and their therapeutic strategies.
PubMed: 33791337
DOI: 10.3389/fmolb.2021.628332 -
PloS One 2012Mapatumumab and lexatumumab (targeting death receptor 4 (DR4) and 5 (DR5), respectively) are agonistic TRAIL receptor antibodies that induce apoptosis in a wide range of...
Mapatumumab and lexatumumab (targeting death receptor 4 (DR4) and 5 (DR5), respectively) are agonistic TRAIL receptor antibodies that induce apoptosis in a wide range of cancer cells. The potency of mapatumumab and lexatumumab was assessed in mono therapy protocols, and the ability to sensitize for dacarbazine (DTIC) treatment was explored in ten different melanoma cell lines. Our data indicated that melanoma cell lines tend to be resistant to mapatumumab, most likely due to low expression of DR4, while a dose dependent response to lexatumumab was observed. Combining DTIC and lexatumumab induced an additive or synergistic effect on cell death in the various melanoma cell lines. The synergistic effect observed in the FEMX-1 cell line was related to enhanced cleavage of Bid in parallel with elevated expression of the pro-apoptotic proteins Bim, Bax and Bak. Furthermore, the anti-apoptotic proteins Bcl-XL, cIAP-1, XIAP and livin were down regulated. Cleavage of Bid and down regulation of cIAP-2 and livin were observed in vivo. Altogether, these data suggest a change in the balance between pro- and anti-apoptotic proteins favoring induction of apoptosis. In the more therapy resistant cell line, HHMS, no changes in the pro- and anti-apoptotic proteins were observed. FEMX-1 xenografts treated with DTIC and lexatumumab showed reduced growth and increased level of apoptosis compared to the control groups, providing arguments for further evaluation of this combination in melanoma patients.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; Caspases; Cell Death; Cell Line, Tumor; Cell Survival; Dacarbazine; Drug Synergism; Female; Humans; Inhibitor of Apoptosis Proteins; Melanoma; Mice; Proto-Oncogene Proteins c-bcl-2; Receptors, TNF-Related Apoptosis-Inducing Ligand; Tumor Stem Cell Assay; Xenograft Model Antitumor Assays
PubMed: 23029050
DOI: 10.1371/journal.pone.0045492 -
American Journal of Cancer Research 2022TRAIL-based therapies are of significant clinical interest because of its unique ability to induce apoptosis in cancer cells while sparing normal and untransformed...
TRAIL-based therapies are of significant clinical interest because of its unique ability to induce apoptosis in cancer cells while sparing normal and untransformed cells. This selective antitumor potential of the TRAIL pathway has been harnessed by development of therapeutics including recombinant (rh)TRAIL and TRAIL-receptor agonist antibodies such as mapatumumab and lexatumumab. While these TRAIL-based therapies have proven successful in preclinical studies and safe in early phase clinical trials, the limited serum half-life has been a hurdle for further clinical development. Here we characterize miR-3132, a novel and first-in class TRAIL-inducing miRNA with potent anti-proliferative and pro-apoptotic effects in cancer cell lines. Initial mechanistic studies indicate that miR-3132 engages the interferon signaling pathway to induce TRAIL and subsequent TRAIL-dependent apoptosis in cancer cell lines. Our data further suggests that the binding of miR-3132 to toll-like receptors could be the upstream pathway for the interferon response. The current study the first report to demonstrate miR-3132's efficacy and preliminary mechanism of action in cancer cell lines.
PubMed: 35141020
DOI: No ID Found