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

Ciuleanu, Tudor-Eliade; Bazin, I.; Lungulescu, Dan; Miron, Lucian; Bondarenko, Igor; Deptała, Andrzej; Rodrı́guez-Torres, Maribel; Giantonio, Bruce J.; Fox, Norma Lynn; Wissel, Paul; Egger, Jacki; Ding, Meichun; Kalyani, Rubana N.; Humphreys, Robin; Gribbin, Matthew; Sun, Weijing

doi:10.1093/annonc/mdw004

Cited by 37 publications

(20 citation statements)

References 40 publications

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“…Recently, multiple studies have documented the efficacy of mapatumumab, a human agonistic monoclonal antibody against DR4 [ 45 – 47 ]; however, the use of mapatumumab has not shown clinical benefits in clinical trials [ 48 , 49 ]. In these studies, mapatumumab was adjunctively used with other anti-cancer or molecular targeted agents.…”

Section: Discussionmentioning

confidence: 99%

Suppression of SOCS3 enhances TRAIL-induced cell growth inhibition through the upregulation of DR4 expression in renal cell carcinoma cells

et al. 2018

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BackgroundTumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a tumor-selective apoptosis inducer that is expressed in natural killer cells, whose cytotoxicity is activated by interferon (IFN). We investigated the effect of suppressor of cytokine signaling (SOCS) 3 on the expression of TRAIL receptors (DR4) and on TRAIL sensitivity in renal cell carcinoma (RCC) cells.MethodsVector expression, RNA interference and IL-6 receptor antibody tocilizumab were used to investigate the functional role of SOCS3 in DR4 expression. Immunoprecipitation was employed to detect the biochemical interaction between SOCS3 and DR4. The expression of DR4 induced by combination with IFN-α and tocilizumab was also examined by immunohistochemical staining using mice xenograft model.ResultsDR4 expression was up-regulated by IFN stimulation in RCC cells. 786-O cells were resistant to TRAIL and showed higher SOCS3 expression. ACHN cells showed higher DR4 expression and lower SOCS3 expression. Suppression of SOCS3 up-regulated DR4 expression and enhanced the TRAIL sensitivity in 786-O cells. In ACHN cells, DR4 expression was down-regulated by transfection with pCI-SOCS3, and the cells became resistant to TRAIL. Immunoprecipitation revealed the biochemical interaction between SOCS3 and DR4. A marked increase in IFN-induced DR4 protein expression after tocilizumab treatment was observed by immunohistochemical staining in the tumor from the mice xenograft model.ConclusionsOur results indicate that IFN and SOCS3 regulate DR4 expression in RCC cells. Combination therapy with IFN-α, tocilizumab and an anti-DR4 agonistic ligand appears to effectively inhibit advanced RCC cell growth.

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Section: Discussionmentioning

confidence: 99%

Suppression of SOCS3 enhances TRAIL-induced cell growth inhibition through the upregulation of DR4 expression in renal cell carcinoma cells

et al. 2018

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“…Dulanermin (rhTRAIL) [62,71,72,73,74,75] did not show clear clinical responses, possibly due to its short half-life (<60 min). DR4-specific agonist mapatumumab [63,76,77,78,79,80,81,82,83], DR5-specific agonists drozitumab [64,65,84], conatumumab [66,67,85], lexatumumab [68,86,87,88,89], HGS-TR2J [90,91], tigatuzumab [69,92,93,94,95,96], and LBY135 [70] were all discontinued after phase 1 or 2 trials without impactful benefits despite their safety (Supplementary Table S1). The reasons why compelling pre-clinical findings with these agonist antibodies did not translate into more robust clinical efficacy remain poorly characterized.…”

Section: Extrinsic Pathway Targetingmentioning

confidence: 99%

Novel Apoptosis-Inducing Agents for the Treatment of Cancer, a New Arsenal in the Toolbox

Greer

Lipkowitz

Takebe

2019

Cancers

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: Evasion from apoptosis is an important hallmark of cancer cells. Alterations of apoptosis pathways are especially critical as they confer resistance to conventional anti-cancer therapeutics, e.g., chemotherapy, radiotherapy, and targeted therapeutics. Thus, successful induction of apoptosis using novel therapeutics may be a key strategy for preventing recurrence and metastasis. Inhibitors of anti-apoptotic molecules and enhancers of pro-apoptotic molecules are being actively developed for hematologic malignancies and solid tumors in particular over the last decade. However, due to the complicated apoptosis process caused by a multifaceted connection with cross-talk pathways, protein–protein interaction, and diverse resistance mechanisms, drug development within the category has been extremely challenging. Careful design and development of clinical trials incorporating predictive biomarkers along with novel apoptosis-inducing agents based on rational combination strategies are needed to ensure the successful development of these molecules. Here, we review the landscape of currently available direct apoptosis-targeting agents in clinical development for cancer treatment and update the related biomarker advancement to detect and validate the efficacy of apoptosis-targeted therapies, along with strategies to combine them with other agents.

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“…Developed by the Human Genome Science (HGS) in 2005, this fully human DR4-agonistic demonstrated selective and high binding to DR4, as well as cytotoxicity efficiency [98]. Mapatumumab has been evaluated in several phase I and II clinical trials [99,100,101,102,103,104,105,106,107,108], but none of the assays met the initial objectives, prompting discontinuation of its clinical development. Other mouse moAbs targeting DR4 and displaying pro-apoptotic potential have been described in preclinical studies, including m921/922 [109], 4H6/4G7 [110], AY4 [111], and TR1-mAbs [112], but as far as we are aware of, none are being evaluated in the clinic.…”

Section: First Antibodies In Clinical Trialsmentioning

confidence: 99%

Antibodies and Derivatives Targeting DR4 and DR5 for Cancer Therapy

Dubuisson

Micheau

2017

Antibodies

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Developing therapeutics that induce apoptosis in cancer cells has become an increasingly attractive approach for the past 30 years. The discovery of tumor necrosis factor (TNF) superfamily members and more specifically TNF-related apoptosis-inducing ligand (TRAIL), the only cytokine of the family capable of eradicating selectively cancer cells, led to the development of numerous TRAIL derivatives targeting death receptor 4 (DR4) and death receptor 5 (DR5) for cancer therapy. With a few exceptions, preliminary attempts to use recombinant TRAIL, agonistic antibodies, or derivatives to target TRAIL agonist receptors in the clinic have been fairly disappointing. Nonetheless, a tremendous effort, worldwide, is being put into the development of novel strategic options to target TRAIL receptors. Antibodies and derivatives allow for the design of novel and efficient agonists. We summarize and discuss here the advantages and drawbacks of the soar of TRAIL therapeutics, from the first developments to the next generation of agonistic products, with a particular insight on new concepts.

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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

Cited by 37 publications

References 40 publications

Suppression of SOCS3 enhances TRAIL-induced cell growth inhibition through the upregulation of DR4 expression in renal cell carcinoma cells

Suppression of SOCS3 enhances TRAIL-induced cell growth inhibition through the upregulation of DR4 expression in renal cell carcinoma cells

Novel Apoptosis-Inducing Agents for the Treatment of Cancer, a New Arsenal in the Toolbox

Antibodies and Derivatives Targeting DR4 and DR5 for Cancer Therapy

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