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Antileukemic Treatment Targeted at Apoptosis Regulators
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Simone Fulda, Klaus-Michael Debatin
Currently, recombinant soluble TRAIL and fully human mAb directed at TRAIL-R1 or TRAIL-R2 are evaluated in early clinical trials (Table 2). Results from ongoing trials in patients with advanced solid tumors showed no major dose-limiting toxicities for recombinant TRAIL or fully human mAb to TRAIL-R1 and defined the maximal tolerated dose for mAb to TRAIL-R2 (143–145). In a phase II trial with HGS-ETR1, a fully human mAb against TRAIL-R1 (mapatumumab; Humane Genome Sciences, Rockville, Maryland, U.S.), in patients with NHL, tumor responses were seen in 3 out of 40 patients (8%) (146). Also, the antibody was well tolerated, with little toxicity observed (146). On the basis of preclinical studies showing cooperation of TRAIL receptor agonists with chemotherapeutics, clinical trials using HGS-ETR1 in combination with anti-cancer agents such as carboplatin or paclitaxel or gemcitabine and cisplatin, were also launched (147,148).
Apoptosis and Cell Death
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
Agonistic antibodies that engage death receptors are in trials for various cancers in which the signalling pathway is intact – for example, the TRAIL-R1 antibody Mapatumumab and the TRAIL-R2 antibody Lexatumumab. As single agents these were initially disappointing, in part because TRAIL receptors must trimerize in order to signal effectively, and an antibody can only cross-link two death receptors.34 However, their combination with other agents is looking more promising, at least in vitro. Agents inducing synergistic apoptosis include chemotherapeutic drugs, histone deacetylation inhibitors, proteosome inhibitors, NF-κB inhibitors and BH3 mimetics. Moreover, new TRAIL receptor antibodies that will form higher order complexes are being developed.35 Other recent strategies use more stable versions of the TRAIL trimer, targeted delivery of TRAIL in nanoparticles, and tumour-targeting of TRAIL constructs.36
Other Novel Targeted Therapies in Lung Cancer
Published in Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo, Lung Cancer, 2016
Kyriakos P. Papadopoulos, Anthony W. Tolcher
As noted previously, recombinant soluble TRAIL has only recently completed phase-I testing. More advanced in development is the promising strategy focusing on developing antibody agonists specific to the functional TRAIL receptors. Mapatumumab [HGS-ETR1 (TRM-1), Human Genome Sciences, Rockville, Maryland, U.S.A.] and lexatumumab (HGS-ETR2) are fully humanized monoclonal antibody agonists to TRAIL-R1 and TRAIL-R2, respectively. Preclinical in vitro and human tumor xenograft data demonstrate single-agent induction of apoptosis, growth inhibition, and cytotoxicity by these antibodies in NSCLC (91). Enhanced cytotoxicity and tumor growth inhibition of lung cancer tumors have also been shown when mapatumumab and lexatumumab are combined with cisplatin chemotherapy (91,92). These data collectively support further study of these antibodies in NSCLC patients. Interestingly, receptor expression is not a reliable indicator of sensitivity to the TRAIL receptor antibodies (91). Both mapatumumab and lexatumumab have undergone phase-I evaluation, with doses of 10 mg/kg for both drugs showing good tolerance and stable disease as best response (93,94). A subsequent multicenter phase-II trial evaluating the efficacy and safety of mapatumumab in 32 heavily pretreated patients with relapsed or recurrent NSCLC has been completed (95). Mapatumumab at 10 mg/kg every three weeks for up to four cycles was administered and patients with stable or responding disease could continue on treatment. With the exception of lymphopenia, no grade-3 toxicity exceeded 7% and no treatment-related severe adverse events occurred. Median PFS was 1.2 months and 29% of patients had stable disease (SD) of 2.3 months median duration. Plans to evaluate mapatumumab in combination with chemotherapy in patients with NSCLC are ongoing. To date, mapatumumab at doses of 10 or 20 mg/kg has been safely combined with paclitaxel (200 mg/m2) and carboplatin [area under the curve (AUC) 6] every 21 days in a phase-I trial involving 28 patients (96). There were no unexpected toxicities, no evidence of drug–drug interactions, and evidence of PR in three patients with NSCLC.
Hyperthermia inhibits growth of nasopharyngeal carcinoma through degradation of c-Myc
Published in International Journal of Hyperthermia, 2022
Xiaole Li, Shichao Duan, Yingjuan Zheng, Yongqiang Yang, Lei Wang, Xinqiang Li, Qing Zhang, Rick F. Thorne, Wencai Li, Daoke Yang
One of the biophysical effects of hyperthermia is to cause protein aggregates within cells which in turn acts to promote protein turnover. Indeed, this mechanism was disclosed as the basis for the desensitizing cancer cells to death receptor signaling through TRAIL and Mapatumumab, the latter a monoclonal antibody that simulates the effects of TRAIL by activating death receptor 4 [49–51]. In these studies, hyperthermia increased the ubiquitination and proteasome-mediated destruction of c-FLIPL, relieving its inhibition of death receptor-mediated apoptosis. Likewise, DNA damage responses of cancer cells following hyperthermia were also compromised by rapid downregulation of BRCA2 via protein aggregation and proteasomal clearance [52]. We similarly found that hyperthermia treatment in NPC cells increased the ubiquitination of c-Myc and reduced its total cellular levels. Thus, in a similar manner, it would be envisaged that destabilizing c-Myc by hyperthermia could also be exploited in combinatorial approaches to sensitize cancer cells to a range of treatments. In this regard it has been shown that c-Myc plays an important role in both the chemoresistance and radioresistance of NPC [53,54]. For instance, c-Myc was shown to bind to the CHK1/2 promoter in nasopharyngeal carcinoma to regulate DNA damage checkpoint responses and radiation resistance [55]. Thus, the expression of c-Myc can be viewed as highly relevant to treatment responses in NPC. Nonetheless, hyperthermia can also be considered an effective treatment in its own right.
Experimental drug treatments for hepatocellular carcinoma: clinical trial failures 2015 to 2021
Published in Expert Opinion on Investigational Drugs, 2022
Zachary J. Brown, D. Brock Hewitt, Timothy M. Pawlik
Multiple novel therapies have been tried against sorafenib with no success. Pre-clinical studies have demonstrated that Vitamin K2 suppressed the growth of HCC cell lines through regulation of the hepatoma-derived growth factor (HDGF) gene [107,108]. In a phase II study combining Vitamin K2 with sorafenib versus sorafenib alone was associated with a significantly higher ORR and PFS in the Vitamin K2 group than that in the sorafenib only group. However, there was no difference in OS between the groups [109]. Tigatuzumab, a monoclonal antibody that targets member 10b of the tumor necrosis factor receptor superfamily (TNFRSF10B), in combination with sorafenib did not significantly improve TTP or OS versus sorafenib alone [110]. A phase II trial evaluated the efficacy and safety of AEG35156, a caspase inhibitor, in combination with sorafenib versus sorafenib alone. The median PFS and OS were 4.0 months and 6.5 months for the combination group, and 2.6 and 5.4 months for the sorafenib group [111]. The addition of mapatumumab, a monoclonal antibody that targets TRAIL-R1 on the tumor surface, to sorafenib did not improve median TTP versus sorafenib monotherapy [112]. In a phase II study of the combination of trebananib, a peptibody that selectively binds angiopoietin (Ang)-1 and Ang-2, with sorafenib in the first-line setting, there was a PFS rate at 4 months of approximately 57% and median OS of 17 months and no improvement compared with historic controls [113].
Targeting of keloid with TRAIL and TRAIL-R2/DR5
Published in Journal of Dermatological Treatment, 2021
Pengfei Sun, Zhensheng Hu, Bo Pan, Xiaosheng Lu
TRAIL-R agonistic antibodies activated antibodies selectively bind to TRAIL-R1/DR4 or to induce apoptosis, and do not bind to TRAIL-R3/DcR1,TRAIL-R4/DcR2 or TRAIL-R5/OPG, which improves the antitumor efficiency of drugs. Moreover, the half-life of these drugs in vivo is longer than that of recombinant human TRAIL, and the concentration of these drugs in cells is more stable. Due to different tumor cells have different responses to apoptosis induced by TRAIL receptor, such as colon cancer and breast cancer cells are sensitive to TRAIL-R2/DR5 mediated apoptosis signal, lymphoid cancer is sensitive to TRAIL-R1/DR4 mediated apoptosis signal, we can select different TRAIL-R agonistic antibodies activated antibodies and activate different TRAIL receptors to induce apoptosis in different parts of tumor cells, which improves the efficiency of targeted treatment of tumor cells (48). The agonistic antibodies present in the instrumental clinical trials are mainly Mapatumumab (TRAIL-R1/DR4 agonist), Conatumumab (TRAIL-R2/DR5 agonist), Drozitumab (DR5 agonist), Lexatumumab (TRAIL-R2/DR5 agonist), Tigatuzumab (TRAIL-R2/DR5 agonist), Ds-8273a (TRAIL-R2/DR5 agonist) (51–56). The first stage of the study showed that TRAIL-R agonistic antibodies drugs had good pharmacokinetics and low toxicity, but the effect of mediating apoptosis of tumor cells was not significant (57). Current studies focus on the combination of TRAIL-R agonistic antibodies drugs with other treatments (58), and I hope these studies will achieve significant results.