In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 3048-3048
Abstract:
Small cell lung cancer (SCLC) is a devastating disease with very poor prognosis and few treatment options. We have established patient derived xenografts from SCLC tumors and determined that Notch pathway target genes are up-regulated in this disease relative to normal lung tissues and relative to other tumor types. We examined the in vivo efficacy of OMP-59R5, an antibody that was initially identified by binding to Notch2 and was subsequently shown to block signaling of both human and mouse Notch2 and Notch3. We performed in vivo growth inhibition and tumorigenicity studies with this Notch2/3 antibody alone or in combination with chemotherapeutic agents in a panel of six patient-derived SCLC xenograft models. We found that OMP-59R5 treatment significantly reduced tumor recurrence in combination with chemotherapy in five of the six models. Through a serial transplantation study from a sensitive tumor, we found that OMP-59R5 in combination with chemotherapy (cisplatin plus irinotecan) profoundly reduced the cancer stem cell (CSC) frequency. In contrast, treatment with chemotherapeutic agents alone had the opposite effect and increased CSC frequency. In minimal residual disease models, we analyzed the ability of OMP-59R5 to delay tumor recurrence following chemotherapy-induced tumor regression. While chemotherapeutic agent-treated tumors re-grew rapidly following treatment termination, the growth of recurrent tumors was delayed by OMP-59R5. We also evaluated changes in gene expression post treatment and found that OMP-59R5 modulated the expression of Notch pathway, epithelial-to-mesenchymal transition, stromal and vasculature genes. Furthermore, we observed an increase in expression of neuroendocrine differentiation markers after OMP-59R5 treatment in sensitive tumors. Following up on these preclinical findings, OMP-59R5 is currently being evaluated for safety and efficacy in combination with cisplatin and etoposide for treatment of SCLC in an ongoing Phase 1b/2 clinical trial (PINNACLE). Citation Format: Marcus M. Fischer, Jalpa Shah, Jennifer Cain, Belinda Cancilla, James W. Evans, Christopher L. Murriel, Tracy Tang, Jie Wei, Wan-Ching Yen, Chun Zhang, Austin Gurney, John Lewicki, Ann M. Kapoun, Timothy Hoey. OMP-59R5 (Anti-Notch2/3) inhibits tumor growth and reduces cancer stem cell frequency in patient derived SCLC xenografts. [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 3048. doi:10.1158/1538-7445.AM2014-3048
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2014-3048
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
