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Overcoming Chemoresistance with the Inhibition of the Wnt Pathway in Ovarian Cancer
Vol. 225, No. 4S2, October 2017
2 groups. Further study should investigate a larger sample size with a lengthier follow-up. Overcoming Chemoresistance with the Inhibition of the Wnt Pathway in Ovarian Cancer Cindy M Tawfik, Angelina I Londono, PhD, Bao Riyue, PhD, Ashwini Katre, Sara J Cooper, PhD, Michael J Straughn, MD, Donald J Buchsbaum, PhD, Lyse A Norian, PhD, Jason Luke, MD, Rebecca C Arend, MD University of Alabama at Birmingham, Birmingham, AL INTRODUCTION: Our objective was to assess the ability of the Wnt inhibitor, WNT974, to modulate the immune system and overcome paclitaxel (T) resistance in a syngeneic ovarian cancer (OVCA) mouse model. METHODS: Ascites cells from 53 OVCA patients were treated with 1 mM of WNT974. ATP levels were measured 7 days post treatment (tx) via ATPlite. RNA-Seq libraries were constructed for 40 samples (20 pre- and 20 post-tx) from “responders” (n¼10) and “non-responders” (n¼10). Gene expression patterns from pre-tx were compared with OVCA TCGA data (n ¼261)
Scientific Poster Presentations: 2017 Clinical Congress
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and patients were segregated into T cell-inflamed (hot) and nonT cell-inflamed (cold) groups. Genes were considered significant if FDR <0.5. C57BL-6 mice (n¼ 20) were injected subQ with ID8 cells and treated with vehicle control, T, WNT974, or a combination. WNT974 was given (5mg/kg) by oral gavage twice per day for 35 days. T was given (5mg/kg) IP 3 days on and 3 days off for 9 doses. RESULTS: WNT974 decreased ATP 19-97% in the responders; non responders had <10% decrease. Two Wnt pathway genes (AXIN2, FZD10) had decreased expression after tx (p< 0.05). One hundred eighty-seven pre-treated genes were significantly different between responders and non-responders. Ninety-three of these genes overlapped with the cold tumors in the TCGA OVCA cohort. In the syngeneic mouse model, WNT974 and T demonstrated a statistically significant inhibition of tumor growth compared to vehicle (p<0.0001), T alone (p¼0.0002) and WNT974 (p¼0.0003) alone. CONCLUSIONS: WNT974 creates an immunomodulatory effect, helping to overcome chemoresistance in OVCA patients and should be investigated further in combination with paclitaxel.
2 groups. Further study should investigate a larger sample size with a lengthier follow-up. Overcoming Chemoresistance with the Inhibition of the Wnt Pathway in Ovarian Cancer Cindy M Tawfik, Angelina I Londono, PhD, Bao Riyue, PhD, Ashwini Katre, Sara J Cooper, PhD, Michael J Straughn, MD, Donald J Buchsbaum, PhD, Lyse A Norian, PhD, Jason Luke, MD, Rebecca C Arend, MD University of Alabama at Birmingham, Birmingham, AL INTRODUCTION: Our objective was to assess the ability of the Wnt inhibitor, WNT974, to modulate the immune system and overcome paclitaxel (T) resistance in a syngeneic ovarian cancer (OVCA) mouse model. METHODS: Ascites cells from 53 OVCA patients were treated with 1 mM of WNT974. ATP levels were measured 7 days post treatment (tx) via ATPlite. RNA-Seq libraries were constructed for 40 samples (20 pre- and 20 post-tx) from “responders” (n¼10) and “non-responders” (n¼10). Gene expression patterns from pre-tx were compared with OVCA TCGA data (n ¼261)
Scientific Poster Presentations: 2017 Clinical Congress
e131
and patients were segregated into T cell-inflamed (hot) and nonT cell-inflamed (cold) groups. Genes were considered significant if FDR <0.5. C57BL-6 mice (n¼ 20) were injected subQ with ID8 cells and treated with vehicle control, T, WNT974, or a combination. WNT974 was given (5mg/kg) by oral gavage twice per day for 35 days. T was given (5mg/kg) IP 3 days on and 3 days off for 9 doses. RESULTS: WNT974 decreased ATP 19-97% in the responders; non responders had <10% decrease. Two Wnt pathway genes (AXIN2, FZD10) had decreased expression after tx (p< 0.05). One hundred eighty-seven pre-treated genes were significantly different between responders and non-responders. Ninety-three of these genes overlapped with the cold tumors in the TCGA OVCA cohort. In the syngeneic mouse model, WNT974 and T demonstrated a statistically significant inhibition of tumor growth compared to vehicle (p<0.0001), T alone (p¼0.0002) and WNT974 (p¼0.0003) alone. CONCLUSIONS: WNT974 creates an immunomodulatory effect, helping to overcome chemoresistance in OVCA patients and should be investigated further in combination with paclitaxel.