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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.
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.
Development of molecular intervention strategies for B-cell lymphoma
Published in Expert Review of Hematology, 2021
It was reported that the mouse double minute 2 (MDM2) can degrade p53 through a negative feedback system and maintain a low expression level of p53. In addition, abnormal amplification and protein expression of MDM2 inhibited TP53-mediated transcriptional activation [4,5] (Figure 1). TP53 mutations in hematological malignancies are associated with the progression of the disease and lower survival rates. Christian Brueghel, in a study using a continuous single-center cohort of 290 newly diagnosed CLL patients [6], found that the prognosis of patients with TP53 mutation without del (17p) was not significantly different whether TP53 mutation was a high burden (variant allele frequency >10%) or low burden (variant allele frequency ≤10%), while the prognosis of patients with TP53 mutation with del (17p) was poor. Therefore, it is recommended to evaluate TP53 abnormalities (TP53ab: del (17p) or TP53 mutation) before any treatment [6]. Several drugs targeting the downstream elements of the p53 pathway, such as chlorambucil, doxorubicin, and lexatumumab, are routinely used in the clinic to treat B-cell lymphoma. Table 1 summarizes the B-cell lymphoma interventions targeting the TP53 pathway.
TRAIL pathway targeting therapeutics
Published in Expert Review of Precision Medicine and Drug Development, 2018
Marie D. Ralff, Wafik S. El-Deiry
Death receptor agonistic antibodies that have been tested clinically include one DR4 agonistic antibody (mapatumumab) and five DR5 agonistic antibodies (drozitumumab, conatumumab, lexatumumab, tigatuzumab, LBY-135). A recent study compared the efficacy of anti-DR5 antibody tigatuzumab plus nanoparticle albumin-bound paclitaxel or nanoparticle albumin-bound paclitaxel alone in patients with triple negative breast cancer. Prolonged survival of several patients treated with the combination support further study of these agents [38]. While TRA antibodies including tigatuzumab have been generally well tolerated, they have not yet advanced into phase III.