A first-in-human phase I study of the oral Notch inhibitor, LY900009, in patients with advanced cancer

Pant, Shubham; Jones, Suzanne F.; Kurkjian, Carla; Infante, Jeffrey R.; Moore, Kathleen N.; Burris, Howard A.; McMeekin, D. Scott; Benhadji, Karim A.; Patel, Bharvin K.R.; Frenzel, Martin; Kursar, Jonathan D.; Zamek‐Gliszczynski, Maciej J.; Yuen, Eunice; Chan, Edward M.; Bendell, Johanna C.

doi:10.1016/j.ejca.2015.11.021

Cited by 76 publications

(44 citation statements)

References 43 publications

(32 reference statements)

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“…molecular regulators of EMT/CSCs such as Notch4 , Twist4 , YAP1 , and CD44/c‐Met . For some of these targets, investigational drugs are available . For example, a novel compound that has Nodal and Notch4 as major targets and that blocks VM in vitro is under clinical development .…”

Section: Discussionmentioning

confidence: 99%

Targeting PDGF‐mediated recruitment of pericytes blocks vascular mimicry and tumor growth

Thijssen

Paulis

Nowak-Śliwińska

et al. 2018

The Journal of Pathology

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Aggressive tumor cells can adopt an endothelial cell‐like phenotype and contribute to the formation of a tumor vasculature, independent of tumor angiogenesis. This adoptive mechanism is referred to as vascular mimicry and it is associated with poor survival in cancer patients. To what extent tumor cells capable of vascular mimicry phenocopy the angiogenic cascade is still poorly explored. Here, we identify pericytes as important players in vascular mimicry. We found that pericytes are recruited by vascular mimicry‐positive tumor cells in order to facilitate sprouting and to provide structural support of the vascular‐like networks. The pericyte recruitment is mediated through platelet‐derived growth factor (PDGF)‐B. Consequently, preventing PDGF‐B signaling by blocking the PDGF receptors with either the small tyrosine kinase inhibitor imatinib or blocking antibodies inhibits vascular mimicry and tumor growth. Collectively, the current study identifies an important role for pericytes in the formation of vascular‐like structures by tumor cells. Moreover, the mechanism that controls the pericyte recruitment provides therapeutic opportunities for patients with aggressive vascular mimicry‐positive cancer types. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Discussionmentioning

confidence: 99%

Targeting PDGF‐mediated recruitment of pericytes blocks vascular mimicry and tumor growth

Thijssen

Paulis

Nowak-Śliwińska

et al. 2018

The Journal of Pathology

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“…DAPT, a γ-secretase inhibitor, which reduces gamma-secretase in Notch1 signaling pathway was reported as a highly promising novel therapeutic drug candidate for ovarian cancer patient [21]. LY900009, a first-in-human phase I study of the oral Notch inhibitor was also reported in patients with advanced cancer including ovarian cancer [22]. MK-0752 is another novel γ-secretase inhibitor, which is evaluated in clinical trial for treatment of several types of cancer including ovarian cancer [23].…”

Section: Introductionmentioning

confidence: 99%

Prognostic roles of Notch receptor mRNA expression in human ovarian cancer

et al. 2017

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Aberrant activation of Notch signaling pathway has been correlated with high grade ovarian carcinoma and carcinogenesis. However, the predictive and prognostic values of Notch signaling pathway in ovarian cancer patients remains unclear. We utilize “The Kaplan-Meier plotter” (KM plotter) background database to access the prognostic values including overall survival (OS), progression-free survival (PFS), as well as post-progression survival (PPS) of four Notch receptor mRNA expression in ovarian cancer patients. Notch1 mRNA high expression was not correlated with OS, PFS and PPS for all ovarian cancer patients, but significantly correlated with poor PFS in TP53 wild type and favorite PFS in TP53 mutation type ovarian cancer patients. Notch2 mRNA high expression was significantly correlated with poor PFS for all ovarian cancer patients, especially in grade II patients. Notch3 mRNA high expression was significantly correlated with favorite PFS for all ovarian cancer patients. Notch4 mRNA high expression was significantly correlated with favorite OS, but not PFS and PPS for all ovarian cancer patients. The results strongly support that there are distinct prognostic values of four Notch receptor mRNA expression in ovarian cancer patients.

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“…Inhibition of the Notch pathway via γ ‐secretase inhibitors prevents notch receptor cleavage at the cell surface, and blocks activation of self‐renewal target genes. Currently, γ ‐secretase inhibitors RO4929097, LY900009 and PF‐003084014 are being used in independent clinical studies against breast cancer, ovarian cancer and T cell acute lymphoblastic leukaemia and alzheimer's respectivelyHowever, it is evidently reported in rodents that these inhibitors caused abnormalities in the gastrointestinal tract, thymus and spleen. These toxic effects were due to prolonged use of these inhibitors causing malfunctioning in cell fate decisions .…”

Section: Notch Signalling and Recent Developments In Therapeutic Apprmentioning

confidence: 99%

Dichotomy of Notch signalling in regulating tumour immune surveillance

2019

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Notch signalling is an evolutionarily conserved multifaceted pathway that controls diverse cellular processes. Its role in regulating development and tissue homeostasis is well established. Aberrant activation of the Notch pathway has been implicated in the initiation and progression of many types of cancers. However, although in some cancers Notch signalling acts as a tumour-promoter, in others it is reported to suppress tumour growth and progression. Accumulating evidence suggests the involvement of both the innate and adaptive immune system in the development of various tumours. Currently, extensive studies on investigating the effects of Notch signalling in tumour immune surveillance are being carried out.Interestingly, recent literature shows how the changing expression of Notch genes in different T cell subsets like CD4 and CD8 helps in controlling anti-tumour immune responses. In this review, we discuss in depth the roles of Notch signalling molecules and different immune cells in the context of the tumour microenvironment. We also outline how current knowledge can be exploited to develop novel therapies in order to control the propagation of cancer stem cells.

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A first-in-human phase I study of the oral Notch inhibitor, LY900009, in patients with advanced cancer

Abstract: The recommended MTD schedule for future studies was 30 mg thrice weekly, which exceeds the target inhibition level observed in preclinical models to promote tumour regression in humans.

Cited by 76 publications

References 43 publications

Targeting PDGF‐mediated recruitment of pericytes blocks vascular mimicry and tumor growth

Targeting PDGF‐mediated recruitment of pericytes blocks vascular mimicry and tumor growth

Prognostic roles of Notch receptor mRNA expression in human ovarian cancer

Dichotomy of Notch signalling in regulating tumour immune surveillance

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