Lexatumumab: Results of a phase I trial in pediatric patients with advanced solid tumors.

Merchant, Mythili; Chou, Alexander J.; Price, Anita P.; Geller, James I.; Tsokos, Maria; Graham, Charles H.; Meyers, Paul A.; Mackall, Crystal L.

doi:10.1200/jco.2010.28.15_suppl.9500

Cited by 4 publications

(3 citation statements)

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“…Thus, only agonistic antibodies against DR5 are likely to be effective. Multiple phase I single agent studies with advanced tumors were completed with lexatumumab [ 42 – 44 ], drozitumab [ 45 ], conatumumab [ 46 , 47 ], and TRA-8/CS-1008 [ 48 ] ( Table 1 ). These agonistic antibodies were generally well tolerated at the doses tested, and most did not reach the maximum tolerated dose.…”

Section: Clinical Development Of Therapeutics Targeting Death Recementioning

confidence: 99%

Activating Death Receptor DR5 as a Therapeutic Strategy for Rhabdomyosarcoma

2012

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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. It is believed to arise from skeletal muscle progenitors, preserving the expression of genes critical for embryonic myogenic development such asMYOD1andmyogenin. RMS is classified as embryonal, which is more common in younger children, or alveolar, which is more prevalent in elder children and adults. Despite aggressive management including surgery, radiation, and chemotherapy, the outcome for children with metastatic RMS is dismal, and the prognosis has remained unchanged for decades. Apoptosis is a highly regulated process critical for embryonic development and tissue and organ homeostasis. Like other types of cancers, RMS develops by evading intrinsic apoptosis via mutations in thep53tumor suppressor gene. However, the ability to induce apoptosis via the death receptor-dependent extrinsic pathway remains largely intact in tumors withp53mutations. This paper focuses on activating extrinsic apoptosis as a therapeutic strategy for RMS by targeting the death receptor DR5 with a recombinant TRAIL ligand or agonistic antibodies directed against DR5.

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Section: Clinical Development Of Therapeutics Targeting Death Recementioning

confidence: 99%

Activating Death Receptor DR5 as a Therapeutic Strategy for Rhabdomyosarcoma

2012

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“…GTGTCTCATGCTGGATCCCCACT GGATACGGCCAGGCATTGAAGT p53 exons [5][6] TGCAGGAGGTGCTTACGCATGT CCTTAACCCCTCCTCCCAGAGAC p53 exons 7-9 ACAGGTCTCCCCAAGGCGCACT TTGAGGCATCACTGCCCCCTGAT p53 exon 10 GTCAGCTGTATAGGTACTTGAAGTGCAG TGGCAGCTGAGCTAGACCTCG p53 exon 11 CCTTAGGCCCTTCAAAGCATTGGTCA GTGCTTCTGACGCACACCTATTGCAAG Explant system. The ex vivo sarcoma tissue explant system was adapted from methods previously described (32).…”

Section: Rna Interferencementioning

confidence: 99%

“…Based on their selective ability to induce apoptosis in a variety of human cancer cell lines and xenografts while sparing normal cells (1), several agents are currently undergoing phase I and II clinical testing both as single agents and in combination with traditional chemotherapies. These include monoclonal agonistic antibodies which specifically target either DR5, drozitumab (Genetech) (2), lexatumumab (Human Genome Sciences) (3)(4)(5)(6), conatumumab (Amgen) (7)(8)(9)(10), tigatuzumab (humanized IgG1 antibody; Daiichi-Sankyo) and LBY135 [chimeric (mouse/human) IgG1 antibody; Novartis] (11) or DR4, mapatumumab (Human Genome Sciences) (12)(13)(14)(15)(16)(17) or both cognate receptors as well as three decoy receptors of recombinant human TRAIL (rhApo2L/TRAIL) (dulanermin, Amgen/Genentech) (18).…”

Section: Introductionmentioning

confidence: 99%

Pre-activation of the p53 pathway through Nutlin-3a sensitises sarcomas to drozitumab therapy

et al. 2013

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16th April 2015 ONCOLOGY REPORTS 30: 471-477, 2013 Abstract. The present study evaluated the efficacy of drozitumab, a human monoclonal agonistic antibody directed against death receptor 5 (DR5), as a new therapeutic avenue for the targeted treatment of bone and soft-tissue sarcomas. The antitumour activity of drozitumab as a monotherapy or in combination with Nutlin-3a was evaluated in a panel of sarcoma cell lines in vitro and human sarcoma patient samples ex vivo. Knockdown experiments were used to investigate the central role of p53 as a regulator of drozitumab cytotoxicity. Pre-activation of the p53 pathway through Nutlin-3a upregulated DR5, subsequently sensitising sarcoma cell lines and human sarcoma specimens to the pro-apoptotic effects of drozitumab. Silencing of p53 strongly decreased DR5 mRNA expression resulting in abrogation of drozitumab-induced apoptosis. Our study provides the first pre-clinical evaluation of combination therapy using p53-activating agents with drozitumab to further sensitise sarcomas to the cytotoxic effects of DR5 antibody therapy.

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Tumor-Necrosis-Factor-Related Apoptosis-Inducing Ligand (TRAIL)

Fulda

2014

Advances in Experimental Medicine and Biology

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The concept to exploit death receptors for cancer therapy is very attractive, since these cell surface receptors have a direct connection to the intracellular cell death machinery. Among the death receptor superfamily, the tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) receptor/ligand system is of special interest. TRAIL receptor agonists have recently entered the stage of clinical evaluation for the treatment of human cancers. Further insights into the regulatory mechanisms of TRAIL signaling will help to better understand the determinants of TRAIL sensitivity versus resistance of human cancers.

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Lexatumumab: Results of a phase I trial in pediatric patients with advanced solid tumors.

Cited by 4 publications

References 0 publications

Activating Death Receptor DR5 as a Therapeutic Strategy for Rhabdomyosarcoma

Activating Death Receptor DR5 as a Therapeutic Strategy for Rhabdomyosarcoma

Pre-activation of the p53 pathway through Nutlin-3a sensitises sarcomas to drozitumab therapy

Tumor-Necrosis-Factor-Related Apoptosis-Inducing Ligand (TRAIL)

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