Inhibition of gamma-secretase activity in combination with paclitaxel to reduce platinum-resistant ovarian tumor growth

• Published in: Journal of clinical oncology Vol. 31; no. 15_suppl; p. 5578
• Main Authors: Groeneweg, Jolijn W, DiGloria, Celeste M, Growdon, Whitfield Board, Sathyanarayanan, Sriram, Foster, Rosemary, Rueda, Bo R
• Format: Journal Article
• Language: English
• Published: 20.05.2013
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/jco.2013.31.15_suppl.5578

Abstract only 5578 Background: Ovarian cancer (OvCa) is the most lethal gynecologic malignancy in the United States. Chemotherapy is effective but seldom curative, mainly due to the development of chemoresistant recurrent disease. Our current research investigates the efficacy of inhibiting the Notch pathway with a gamma-secretase inhibitor (GSI), MRK-003, in an OvCa xenograft model as a single agent therapy and in combination with standard chemotherapy. Methods: Mice bearing xenografts derived from clinically platinum sensitive human ovarian serous carcinomas were treated with GSI or vehicle, or with either vehicle, GSI alone, paclitaxel and carboplatinum (T/C) alone, or the combination of GSI and T/C. In addition, mice bearing xenografts derived from patients with clinically platinum resistant disease were given GSI with or without paclitaxel. Gene transcript levels of several factors in the Notch pathway were analyzed using RT-PCR. Notch1 and Notch3 protein levels were evaluated by western blotting. The Wilcoxon rank-sum test was used to assess significance between the different treatment groups. Results: Expression of Notch1 and Notch3 was highly variable across all analyzed OvCa samples. Treatment with GSI alone significantly decreased tumor growth in 3 of 4 platinum sensitive ovarian tumors (all p < 0.05), as well as in 1 of 3 platinum resistant tumors (p = 0.04). Furthermore, the combination of GSI and paclitaxel was significantly more effective than GSI alone and paclitaxel alone in all platinum resistant ovarian tumors (all p < 0.05). The addition of GSI did not alter the effect of T/C in platinum sensitive tumors. Although the response of each tumor to GSI did not correlate with its endogenous level of Notch expression, 2 of the 3 tumors resistant to paclitaxel but sensitive to the combination of GSI and paclitaxel showed elevated Notch activity by RT-PCR. Conclusions: Inhibition of the Notch signaling cascade with a gamma-secretase inhibitor reduces tumor growth in vivo, most notably in combination with paclitaxel in a platinum resistant setting. These promising findings underscore the need for further investigation of the preclinical and clinical effectiveness of Notch inhibitors in OvCa.