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.

中文翻译：

---

新型针对卵巢癌的卵巢癌维持疗法，主要针对mortalin和p53突变体。

当前的卵巢癌维持疗法受到毒性的限制，并且没有证明对总体存活率有影响。为了研究针对错义突变体p53的维持策略，我们假设SHetA2药物抑制mortalin释放突变体p53，再结合PRIMA-1 ^MET药物重新激活突变体p53，在突变体p53中协同抑制生长和肿瘤形成。依赖方式。评估了癌基因组图谱（TCGA）数据和浆液性卵巢肿瘤的TP53和HSPA9 / mortalin状态。SHetA2和PRIMA-1 ^MET使用等效线描图，荧光细胞计数，Western印迹和ELISA在卵巢癌细胞系和输卵管分泌上皮细胞中进行了检测。腹膜注射MESOV突变体p53卵巢癌细胞后，并在肿瘤建立之前，将药物施用于小鼠，这通过logistic回归进行评估。TPGA突变中58％的TP53突变是错义的，并且在TCGA高度浆液性卵巢癌中没有mortalin突变。浆液性良性，交界性和癌性肿瘤中的Mortalin水平依次升高。SHetA2在癌症细胞中引起p53核和线粒体积累，但在健康细胞中却没有。内源或外源突变体p53增加SHetA2抵抗力。PRIMA-1^气象降低了这种抗性，并在突变型和野生型表达p53的细胞系中与SHetA2协同相互作用，并增加了活性氧/ ATP比率。动物无瘤率分别为0％（对照组），25％（PRIMA1 ^MET），42％（SHetA2）和67％（组合）。SHetA2（p = 0.004）和PRIMA1 ^MET（p = 0.048）在预防肿瘤发展方面具有附加作用，没有观察到毒性。这些结果证明单独开发SHetA2和PRIMA-1 ^MET并联合用于卵巢癌维持治疗是合理的。