| Reference | 1. Cancer Discov. 2017 Feb;7(2):OF3. doi: 10.1158/2159-8290.CD-NB2016-159. Epub 2016
Dec 14.
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Notch Inhibitor Shows Modest Efficacy.
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Data from a phase I study indicate that LY3039478 is modestly effective against a
range of advanced or metastatic cancers. The investigational Notch-signaling
inhibitor induced partial responses and stable disease in patients with breast
cancer and rare malignancies such as adenoid cystic carcinoma and leiomyosarcoma.
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2. J Biol Chem. 2017 Jan 20;292(3):837-846. doi: 10.1074/jbc.M116.745208. Epub 2016
Dec 1.
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Notch Pathway Is Activated via Genetic and Epigenetic Alterations and Is a
Therapeutic Target in Clear Cell Renal Cancer.
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Bhagat TD(1), Zou Y(1), Huang S(2), Park J(2), Palmer MB(2), Hu C(1), Li W(1),
Shenoy N(1), Giricz O(1), Choudhary G(1), Yu Y(1), Ko YA(2), Izquierdo MC(2),
Park AS(2), Vallumsetla N(1), Laurence R(1), Lopez R(1), Suzuki M(1), Pullman
J(3), Kaner J(1), Gartrell B(1), Hakimi AA(4), Greally JM(1), Patel B(5),
Benhadji K(5), Pradhan K(1), Verma A(6), Susztak K(7).
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Author information: <br>
(1)From the Albert Einstein College of Medicine, Bronx, New York 10461.
(2)the Renal Electrolyte and Hypertension Division, Department of Medicine and
Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia,
Pennsylvania 19104.
(3)the Department of Pathology, Montefiore Medical Center, Bronx, New York 10467.
(4)the Sloan Kettering Cancer Center, New York, New York 10065, and.
(5)Eli Lilly, Indianapolis, Indiana 46221.
(6)From the Albert Einstein College of Medicine, Bronx, New York 10461,
[email protected].
(7)the Renal Electrolyte and Hypertension Division, Department of Medicine and
Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia,
Pennsylvania 19104, [email protected].
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Clear cell renal cell carcinoma (CCRCC) is an incurable malignancy in advanced
stages and needs newer therapeutic targets. Transcriptomic analysis of CCRCCs and
matched microdissected renal tubular controls revealed overexpression of NOTCH
ligands and receptors in tumor tissues. Examination of the TCGA RNA-seq data set
also revealed widespread activation of NOTCH pathway in a large cohort of CCRCC
samples. Samples with NOTCH pathway activation were also clinically distinct and
were associated with better overall survival. Parallel DNA methylation and copy
number analysis demonstrated that both genetic and epigenetic alterations led to
NOTCH pathway activation in CCRCC. NOTCH ligand JAGGED1 was overexpressed and
associated with loss of CpG methylation of H3K4me1-associated enhancer regions.
JAGGED2 was also overexpressed and associated with gene amplification in distinct
CCRCC samples. Transgenic expression of intracellular NOTCH1 in mice with
tubule-specific deletion of VHL led to dysplastic hyperproliferation of tubular
epithelial cells, confirming the procarcinogenic role of NOTCH in vivo Alteration
of cell cycle pathways was seen in murine renal tubular cells with NOTCH
overexpression, and molecular similarity to human tumors was observed,
demonstrating that human CCRCC recapitulates features and gene expression changes
observed in mice with transgenic overexpression of the Notch intracellular
domain. Treatment with the γ-secretase inhibitor LY3039478 led to inhibition of
CCRCC cells in vitro and in vivo In summary, these data reveal the mechanistic
basis of NOTCH pathway activation in CCRCC and demonstrate this pathway to a
potential therapeutic target.
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