Abstract B08: Overcoming cisplatin resistance in sinonasal undifferentiated carcinoma by inhibiting the TGFβ signaling pathway in vivo
Authors: Takahashi Yoko , Takahashi Hideaki , Amit Moran , Gleber-Netto Frederico O. , Bell Diana , Xie Tong-Xin , Roberts Dianna , Abdelmeguid Ahmed S. , Pickering Curtis , Myers Jeffrey N. , Hanna Ehab Y. 
Published: September 2020

Background: Sinonasal undifferentiated carcinoma (SNUC) is a rare, highly aggressive cancer that arises in the nasal cavity and paranasal sinuses. Despite aggressive multimodal therapy the prognosis remains poor. Because of the locally advanced nature of SNUC, we have used cisplatin-based induction chemotherapy before definitive surgery or radiation therapy in our institution. Unfortunately, about 30% of SNUC patients do not respond to this treatment, and the lack of response is associated with poor survival. Therefore, developing strategies to overcome resistance to induction chemotherapy is crucial. Our current gene expression analysis of SNUC specimens indicated that the TGFβ signaling pathway might be activated in nonresponders. Using the MDA8788-6 SNUC cell line established from a nonresponder, we found that TGFβ signaling is upregulated in an autocrine manner in the SNUC cell line. Since inhibition of the TGFβ pathway overcame cisplatin resistance in this cell line, we decided to examine the effects of TGFβ inhibition in vivo.

Materials and Methods: The MDA8788-6 SNUC cell line were cultured under serum-free condition overnight to induce TGFβ signaling. The cells were then resuspended in the serum-free conditioned medium collected from the same cell line to maintain activation of the pathway. Two million MDA8788-6 cells in the conditioned medium were inoculated into the flank of mice subcutaneously. On the same day of the inoculation, we started treatment with i) vehicle control, ii) cisplatin only (4 mg/kg, once per week, intravenously), iii) EW-7197 only (TGFβRI specific inhibitor, 40 mg/kg, five times per week, oral gavage), and iv) cisplatin plus EW-7197. After 5 courses of treatments, the mice were sacrificed. Average tumor volume of each treatment group 31 days after the cell inoculation was compared by Tukey’s multiple comparisons test. Area under the curve (AUC) was calculated according to the tumor growth curve of each mouse from 0 to 31 days after the cell inoculation. AUC of CDDP group and CDDP plus EW-7197 group was compared by unpaired, two-tailed t test with Welch’s correction.

Results: The EW-7197 treated group itself did not show antitumor growth effect compared to the control group. Comparison of AUC of the tumor volume showed significant difference between the cisplatin alone and cisplatin plus EW-7197; the combination of cisplatin and EW-7197 had better antitumor growth effect compared to cisplatin alone.

Conclusions: Our finding suggests that TGFβ inhibition may offer hope to SNUC patients struggling with chemoresistance.

Citation Format: Yoko Takahashi, Hideaki Takahashi, Moran Amit, Frederico O. Gleber-Netto, Diana Bell, Tong-Xin Xie, Dianna Roberts, Ahmed S. Abdelmeguid, Curtis Pickering, Jeffrey N. Myers, Ehab Y. Hanna. Overcoming cisplatin resistance in sinonasal undifferentiated carcinoma by inhibiting the TGFβ signaling pathway in vivo [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B08.