Abstract 2323: Tarextumab (Anti-NOTCH2/3) reverses NOTCH2 and NOTCH3-dependent tumorigenicity and metastases in small cell lung cancer
Authors: Shah Jalpa , O'Young Gilbert , Wei Jie , Fischer Marcus , Yen Wan-Ching , Cancilla Belinda , Kapoun Ann , Lewicki John , Cain Jennifer , Hoey Timothy 
Published: August 2015

Abstract
Small cell lung cancer (SCLC) is marked by early metastatic spread and, despite high initial response rates to therapy, long term survival is poor. We have previously shown that inhibition of NOTCH2 and NOTCH3 using a blocking antibody (OMP-59R5: Tarextumab) that inhibits both human and murine receptor signaling suppresses the growth of patient-derived SCLC tumor xenografts (PDXs) and delays tumor recurrence following chemotherapy-induced tumor regression. We therefore reasoned that NOTCH2 and NOTCH3 might sustain a chemorefractory population of cells with high tumorigenic potential and the capacity to seed distant metastases.
In order to directly evaluate the tumorigenic potential of NOTCH2 and NOTCH3 expressing cells, we isolated NOTCH2+,NOTCH3+, and NOTCH2&3+ cells from treatment naïve SCLC PDX tumors and transplanted them into secondary recipient mice. Tumor incidence was 100% in each of the NOTCH2+, NOTCH3+ and NOTCH2&3+ groups. This decreased by half in the NOTCH2-, NOTCH3-, and NOTCH2&3- groups, suggesting that expression of each of the two receptors is associated with increased tumorigenicity in SCLC.
We then evaluated the effect of 59R5 treatment upon tumorigenic potential of SCLC PDX cells. We first treated mice with either 59R5 or control antibody, with and without cisplatin/irinotecan. Upon study termination, we harvested tumor cells, serially transplanted them into treatment naïve mice and assessed the incidence of tumors in serially transplanted mice. We observed that tumorigenic cell frequency was doubled in the chemotherapy-treated cohort but was decreased more than 10-fold in the 59R5+chemotherapy treated group relative to control antibody.
Finally, we evaluated the effect of 59R5 treatment upon tumor cell dissemination and metastases in therapeutic efficacy experiments. In one SCLC PDX model, 59R5 decreased the frequency of circulating tumor cells (CTCs) in the blood. In a second SCLC PDX model, 59R5 reduced the frequency of disseminated tumor cells (DTCs) as well as metastases to the adrenal glands, liver, lungs and brain. The ability of 59R5 to decrease metastases was independent from the effect on primary tumor volume, suggesting a mechanistically distinct effect upon tumorigenicity and metastatic spread relative to that of tumor growth.
In summary, NOTCH2+ and NOTCH3+ cell populations are enriched for cells with tumorigenic potential and NOTCH2/3 inhibition in SCLC PDX models reduced tumorigenic cell frequency as well as the incidence of CTCs, DTCs and metastases to distant organs. Taken together, these data strongly implicate both NOTCH2 and NOTCH3 in the maintenance of SCLC cells with high tumorigenic potential and the capacity to seed and promote distant metastatic growth. A Phase 1b/2 clinical trial of OMP-59R5 in Combination With Etoposide and Cisplatin in Subjects With Untreated Extensive Stage Small Cell Lung Cancer (PINNACLE) is underway.
Citation Format: Jalpa Shah, Gilbert O'Young, Jie Wei, Marcus Fischer, Wan-Ching Yen, Belinda Cancilla, Ann Kapoun, John Lewicki, Jennifer Cain, Timothy Hoey. Tarextumab (Anti-NOTCH2/3) reverses NOTCH2 and NOTCH3-dependent tumorigenicity and metastases in small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2323. doi:10.1158/1538-7445.AM2015-2323