Novel ovarian cancer maintenance therapy targeted at mortalin and mutant p53.

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-1MET 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-1MET 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-1MET 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% (PRIMA1MET ), 42% (SHetA2) and 67% (combination). SHetA2 (p = 0.004) and PRIMA1MET (p = 0.048) functioned additively in preventing tumor development with no observed toxicity. These results justify the development of SHetA2 and PRIMA-1MET alone and in combination for ovarian cancer maintenance therapy.

• Authors: Satish K Ramraj, Sugantha P Elayapillai, Richard C Pelikan, Yan D Zhao, Zitha R Isingizwe, Amy L Kennedy, Stanley A Lightfoot, Doris M Benbrook
• Journal: International journal of cancer (Int J Cancer) Vol. 147 Issue 4 Pg. 1086-1097 (08 15 2020) ISSN: 1097-0215 [Electronic] United States
• PMID: 31845320 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 UICC.

Chemical References

• (((4-nitrophenyl)amino)(2,2,4,4-tetramethyl thiochroman-6-yl)amino) methane-1-thione
• Aza Compounds
• Bridged Bicyclo Compounds, Heterocyclic
• Chromans
• HSP70 Heat-Shock Proteins
• TP53 protein, human
• Thiones
• Tumor Suppressor Protein p53
• mortalin
• 2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one

Topics

• Animals
• Apoptosis (drug effects)
• Aza Compounds (pharmacology)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Line, Tumor
• Chromans (pharmacology)
• Female
• HSP70 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Humans
• Maintenance Chemotherapy (methods)
• Mice, Nude
• Molecular Targeted Therapy (methods)
• Mutation
• Ovarian Neoplasms (drug therapy, genetics, metabolism)
• Thiones (pharmacology)
• Tumor Suppressor Protein p53 (antagonists & inhibitors, genetics, metabolism)
• Xenograft Model Antitumor Assays (methods)