Abstract LB-244: Prevention of ovarian cancer tumor establishment with mortalin targeting and p53 reactivator drugs
Authors: Satish Kumar Ramraj, Zitha Redempta Isingizwe, Sugantha Priya Elayapillai, Amy L. Bosley, Yan Daniel Zhao, Doris M. Benbrook
Journal: Cancer Research (2019)

Abstract Background: The majority of high-grade serous ovarian cancer patients are diagnosed at late stage and recur after primary chemotherapy and cytoreductive surgery. Our objective was to test low-toxicity drug combinations to prevent ovarian cancer tumor establishment. SHetA2 is a novel small molecule drug that exhibited in vivo colorectal cancer prevention activity, reasonable oral bioavailability and pharmacokinetics and lack of toxicity in extensive preclinical studies. SHetA2 binding to its HSPA9 target (mortalin) causes release and nuclear accumulation of p53, which contributes to the mechanism of cancer cell death because ovarian cancer cells with missense p53 mutations are more resistant to SHetA2. Thus, we hypothesized that combination of SHetA2 with a p53 reactivator drug, PRIMA1MET would synergistically prevent ovarian cancer tumor establishment as a model of recurrence. Methods: Effects of SHetA2 and PRIMA1MET alone and in combination were evaluated in ovarian cancer cell lines with different TP53 gene mutation status. Immunocompromised mice were injected IP with MES-OV TP53 R282W ovarian cancer cells. Drug treatment was initiated 5 weeks prior to development of ascites as observed in a pilot study and in this intervention experiment. Animals were randomized to treatment groups (N=12: Controls, PRIMA1MET, SHetA2, SHETA2+PRIMA1MET) based on body weight. After 5 weeks treatment, animals were sacrificed and necropsied. Tissues are being evaluated for toxicity and to verify drug mechanism. Statistical Analysis (SAS 9.4) used tumor development as the primary outcome. Univariate Fisher’s exact test was used to compare outcome among groups. Multiple logistic regression models with, or without, interaction was used to assess synergistic and additive effects between the two drugs. Results: In cell culture studies, combinations of SHetA2 and PRIMA1MET exhibited synergy in the presence of missense p53 mutations and additive or synergistic activity in cultures with wild type or null p53. In the animal model, tumor-free rates were 0% in the control, 25% in the PRIMA1MET, 42% in the SHetA2, and 67% in the combination group. Univariate Fisher’s exact test revealed a significant difference between the control and SHetA2 groups (p=0.037) only. Logistic regression indicated that the interaction between SHetA2 and PRIMA1MET was not significantly synergistic (p=0.973). However, a subsequent additive model showed that SHetA2 (p=0.004, OR=10.384, 95% CI: 2.158, 48.965) and PRIMA1MET (p=0.048, OR=4.464, 95% CI: 1.014, 19.655) functioned additively in preventing tumor development. No evidence of gross toxicity was observed. Conclusion: SHetA2 alone, and in combination with PRIMA1MET, significantly prevented ovarian cancer tumor establishment without evidence of toxicity warranting further study in clinical trials. Funding: R01 CA196200, FWC-Ovarinnovate: Ovarcome Research Excellence Award Citation Format: Satish Kumar Ramraj, Zitha Redempta Isingizwe, Sugantha Priya Elayapillai, Amy L. Bosley, Yan Daniel Zhao, Doris M. Benbrook. Prevention of ovarian cancer tumor establishment with mortalin targeting and p53 reactivator drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-244.