Novel ovarian cancer maintenance therapy targeted at mortalin and mutant p53. Issue 4 (8th January 2020)

• Record Type: Journal Article
• Authors: Ramraj, Satish K.; Elayapillai, Sugantha P.; Pelikan, Richard C.; Zhao, Yan D.; Isingizwe, Zitha R.; Kennedy, Amy L.; Lightfoot, Stanley A.; Benbrook, Doris M.
• Is Part Of: International journal of cancer. Volume 147:Issue 4(2020)
• Page Start: 1086
• Page End: 1097
• Publication Date: 2020-01-08
• Subjects: p53 -- mortalin -- high‐grade serous ovarian cancer -- SHetA2 -- PRIMA‐1; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32830
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Current ovarian cancer maintenance therapy is limited by toxicity and no proven impact on overall survival. To study a maintenance strategy targeted at missense mutant p53, we hypothesized that the release of mutant p53 from mortalin inhibition by the SHetA2 drug combined with reactivation of mutant p53 with the PRIMA‐1 MET drug inhibits growth and tumor establishment synergistically in a mutant‐p53 dependent manner. The Cancer Genome Atlas (TCGA) data and serous ovarian tumors were evaluated for TP53 and HSPA9/mortalin status. SHetA2 and PRIMA‐1 MET were tested in ovarian cancer cell lines and fallopian tube secretory epithelial cells using isobolograms, fluorescent cytometry, Western blots and ELISAs. Drugs were administered to mice after peritoneal injection of MESOV mutant p53 ovarian cancer cells and prior to tumor establishment, which was evaluated by logistic regression. Fifty‐eight percent of TP53 mutations were missense and there were no mortalin mutations in TCGA high‐grade serous ovarian cancers. Mortalin levels were sequentially increased in serous benign, borderline and carcinoma tumors. SHetA2 caused p53 nuclear and mitochondrial accumulation in cancer, but not in healthy, cells. Endogenous or exogenous mutant p53 increased SHetA2 resistance. PRIMA‐1 MET decreased this resistance and interacted synergistically with SHetA2 in mutant and wild type p53‐expressing cell lines in association with elevated reactive oxygen species/ATP ratios. Tumor‐free rates in animals were 0% (controls), 25% (PRIMA1 MET ), 42% (SHetA2) and 67% (combination). SHetA2 ( p = 0.004) and PRIMA1 MET ( p = 0.048) functioned additively in preventing tumor development with no observed toxicity. These results justify the development of SHetA2 and PRIMA‐1 MET alone and in combination for ovarian cancer maintenance therapy. Abstract : What's new? Ovarian cancer patients need an effective maintenance therapy with minimal toxicity to prevent deadly recurrence of the disease. In this paper, the authors focused on reactivating missense mutant p53. Most high grade serous ovarian cancer contains mutations in p53, which can confer resistance to therapy. The authors tested SHetA2, a drug that frees p53 from sequestration by the protein mortalin, combined with a p53 activating drug, PRIMA‐1 MET . The two drugs combined achieved a 67% tumor‐free rate in mice, higher than either alone. This success fuels further testing of the two agents as combination therapy for ovarian cancer.