In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 910-910
Abstract:
The Notch signaling pathway regulates key functions during embryonic development, stem cell maintenance and differentiation in adult tissues, and is implicated in many human cancers. OMP-59R5 is a ligand-blocking antibody targeting both the NOTCH2 and NOTCH3 receptors. We have developed a series of primary human xenograft models from patients with pancreatic cancer and used these models to examine efficacy response to OMP-59R5. We found that anti-NOTCH2/3, either as a single agent or in combination with chemotherapeutic agents, was efficacious in pancreatic tumor models. Expression of NOTCH3 mRNA by next-generation sequencing in ten baseline pancreatic tumors correlates with response to OMP-59R5, where growth of tumors with moderate to high expression of NOTCH3 was significantly reduced compared to tumors with low expression. We developed a Research-Use-Only (RUO) qPCR assay for measuring NOTCH3 mRNA expression using Formalin-Fixed, Paraffin-Embedded (FFPE) samples. This assay shows consistent NOTCH3 expression data with the next-generation sequencing data in the ten pancreatic xenograft tumors. Expression levels of NOTCH3 were also examined in ∼120 human metastatic pancreatic specimens to determine the reportable range of the assay and to identify association with clinical factors. This analysis showed that NOTCH3 gene expression maintained the same distribution across different specimen types, such as biopsy, surgical biopsy and surgical resection, etc. Samples with clinically relevant sites of recurrence also showed a similar range in NOTCH3 gene expression. Moreover, we developed an immunohistochemistry (IHC) assay for NOTCH3 protein expression. The correlation between the IHC assay and the qPCR assay was examined in both the metastatic pancreatic human specimens and the primary human pancreatic xenograft models. A significant correlation was found between the gene and protein levels, suggesting that both NOTCH3 gene expression and protein expression may predict the response to OMP-59R5 in pancreatic cancer. We are evaluating NOTCH3 levels and patient response in ALPINE, a Ph1b/2 Anti-NOTCH2/3 trial in first-line advanced pancreatic cancer patients. Citation Format: Belinda Cancilla, Wan-Ching Yen, Chun Zhang, Marcus M. Fischer, May Ji, Tracy Tang, Yu-Wang Liu, Raymond S. Tam, Min Wang, Austin Gurney, Timothy Hoey, John Lewicki, Ann M. Kapoun. NOTCH3 expression is predictive of efficacy in pancreas tumor models treated with OMP-59R5, a monoclonal antibody targeting the NOTCH2 and NOTCH3 receptors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 910. doi:10.1158/1538-7445.AM2014-910
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2014-910
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2014
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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