2 Safety and early evidence of activity of a first-in-human phase I study of the novel cancer stem cell (CSC) targeting antibody OMP-52M51 (anti-Notch1) administered intravenously to patients with certain advanced solid tumors

Patnaik, Amita; LoRusso, Patricia; Münster, Pamela N.; Tolcher, A. W.; Davis, S. Lindsey; Heymach, John V.; Ferraroto, Renata; Xu, Liangpeng; Kapoun, Ann M.; Faoro, Leonardo; Lewicki, John; Dupont, Jakob; Eckhardt, S. Gail

doi:10.1016/s0959-8049(14)70128-5

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“…However, severe gastrointestinal toxicity due to goblet cell metaplasia, or reduced GSI exposure due to CYP3A4-mediated deactivation, has forced suboptimal dosing and schedule alterations, limiting their therapeutic utility (30)(31)(32)(33). Inhibitory antibodies targeting Notch1 have been developed in an effort to limit toxicity, but gastrointestinal and other toxicities have still been reported in preclinical and clinical settings (27,34,35). Nevertheless, signs of clinical response have been seen in patients treated with Notch1 antibody (35), indicating that Notch1 inhibition can be efficacious.…”

Section: Introductionmentioning

confidence: 99%

“…Inhibitory antibodies targeting Notch1 have been developed in an effort to limit toxicity, but gastrointestinal and other toxicities have still been reported in preclinical and clinical settings (27,34,35). Nevertheless, signs of clinical response have been seen in patients treated with Notch1 antibody (35), indicating that Notch1 inhibition can be efficacious. Recent preclinical studies demonstrate that a soluble decoy encompassing a subset of the Notch1 EGF-like repeats can block Notch1 signaling without inducing gut toxicity, suggesting that inhibition and toxicity can be uncoupled (36).…”

Section: Introductionmentioning

confidence: 99%

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23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity

Proia

Jiang

Bell

et al. 2015

Molecular Cancer Therapeutics

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Dysregulation of Notch signaling has been implicated in the development of many different types of cancer. Notch inhibitors are being tested in the clinic, but in most cases gastrointestinal and other toxicities have limited the dosage and, therefore, the effectiveness of these therapies. Herein, we describe the generation of a monoclonal antibody against the ligand-binding domain of the Notch1 receptor that specifically blocks ligand-induced activation. This antibody, 23814, recognizes both human and murine Notch1 with similar affinity, enabling examination of the effects on both tumor and host tissue in preclinical models. 23814 blocked Notch1 function in vivo, inhibited functional angiogenesis, and inhibited tumor growth without causing gastrointestinal toxicity. The lack of toxicity allowed for combination of 23814 and the VEGFR inhibitor tivozanib, resulting in significant growth inhibition of several VEGFR inhibitor-resistant tumor models. Analysis of the gene expression profiles of an extensive collection of murine breast tumors enabled the successful prediction of which tumors were most likely to respond to the combination of 23814 and tivozanib. Therefore, the use of a specific Notch1 antibody that does not induce significant toxicity may allow combination treatment with angiogenesis inhibitors or other targeted agents to achieve enhanced therapeutic benefit. Mol Cancer Ther; 14(8); 1858–67. ©2015 AACR.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity

Proia

Jiang

Bell

et al. 2015

Molecular Cancer Therapeutics

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Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors

Krishnamurthy

Kurzrock

2018

Cancer Treatment Reviews

798

645

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The Wnt/beta-catenin pathway is a family of proteins that is implicated in many vital cellular functions such as stem cell regeneration and organogenesis. Several intra-cellular signal transduction pathways are induced by Wnt, notably the Wnt/beta-catenin dependent pathway or canonical pathway and the non-canonical or beta-catenin-independent pathway; the latter includes the Wnt/Ca2+ and Planar Cell Polarity pathway (PCP). Wnt activation occurs at the intestinal crypt floor, and is critical to optimal maintenance of stem cells. Colorectal cancers show evidence of Wnt signaling pathway activation and this is associated with loss of function of the tumor regulator APC. Wnt activation has been observed in breast, lung, and hematopoietic malignancies and contributes to tumor recurrence. The Wnt pathway cross talks with the Notch and Sonic Hedgehog pathways, which has implications for therapeutic interventions in cancers. There are significant challenges in targeting the Wnt pathway, including finding agents that are efficacious without damaging the system of normal somatic stem cell function in cellular repair and tissue homeostasis. Here, we comprehensively review the Wnt pathway and its interactions with the Notch and Sonic Hedgehog pathways. We present the state of the field in effectors and inhibitors of Wnt signaling, including updates on clinical trials in various cancers with inhibitors of Wnt, Notch, and Sonic Hedgehog.

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2 Safety and early evidence of activity of a first-in-human phase I study of the novel cancer stem cell (CSC) targeting antibody OMP-52M51 (anti-Notch1) administered intravenously to patients with certain advanced solid tumors

Cited by 2 publications

References 0 publications

23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity

23814, an Inhibitory Antibody of Ligand-Mediated Notch1 Activation, Modulates Angiogenesis and Inhibits Tumor Growth without Gastrointestinal Toxicity

Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors

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