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


: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.


Int J Cancer


Ramraj SK,Elayapillai SP,Pelikan RC,Zhao YD,Isingizwe ZR,Kennedy AL,Lightfoot SA,Benbrook DM




Has Abstract


2020-08-15 00:00:00












  • Antibiotic use and risk of non-Hodgkin lymphomas.

    abstract::Clinical case reports have suggested that specific bacterial infections are associated with certain non-Hodgkin lymphoma (NHL) subtypes. Epidemiological case-control studies have been conducted using antibiotics as a proxy for bacterial infections, but with inconclusive results. The aim of this study was, in a cohort ...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Rasmussen ML,Hjalgrim H,Mølgaard-Nielsen D,Wohlfahrt J,Melbye M

    更新日期:2012-10-01 00:00:00

  • Fifty years of cancer incidence: CI5 I-IX.

    abstract::The Cancer Incidence in Five Continents (CI5) series comprises nine volumes that bring together peer-reviewed results from population-based cancer registries worldwide. The aim of each is to make available comparable data on cancer incidence from as wide a range of geographical locations as possible. In addition, the ...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Parkin DM,Ferlay J,Curado MP,Bray F,Edwards B,Shin HR,Forman D

    更新日期:2010-12-15 00:00:00

  • High-grade tumor-specific immunity induced by L1210 leukemia variants obtained from the culture of L1210 cells fused with Lesch-Nyhan fibroblasts.

    abstract::A highly immunogenic variant of the murine L1210 leukemia cell (L1210/LN-1) for generation of tumor immunity has been obtained from culture of L1210 cells originally fused with human Lesch-Nyhan fibroblasts. In L1210/LN-1 cells, no human chromosomes were identified and chromosomes M1 and No. 1 carried by the parent L1...

    journal_title:International journal of cancer

    pub_type: 杂志文章


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  • Hypermethylation of the MYF-3 gene in colorectal cancers: associations with pathological features and with microsatellite instability.

    abstract::Myf-3 is the human homologue of the murine Myo-D1 gene involved in muscle-cell differentiation. Using Southern blot analysis, we examined methylation of Myf-3 in histologically normal colonic mucosae, adenomas and carcinomas from a large series of patients with primary colorectal cancer. Hypermethylation of this gene ...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Shannon B,Kay P,House A,Iacopetta B

    更新日期:1999-04-20 00:00:00

  • Uterine carcinosarcoma is derived from a single stem cell: an in vitro study.

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    journal_title:International journal of cancer

    pub_type: 杂志文章


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    journal_title:International journal of cancer

    pub_type: 杂志文章


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    pub_type: 杂志文章


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    journal_title:International journal of cancer

    pub_type: 杂志文章


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  • Familial aggregation of astrocytoma in northern Sweden: an epidemiological cohort study.

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    journal_title:International journal of cancer

    pub_type: 杂志文章


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  • Human melanoma cells express FGFR/Src/Rho signaling that entails an adhesion-independent caveolin-1 membrane association.

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    journal_title:International journal of cancer

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    journal_title:International journal of cancer

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  • Interval cancers in the Norwegian breast cancer screening program: frequency, characteristics and use of HRT.

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    journal_title:International journal of cancer

    pub_type: 杂志文章


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  • A novel copper complex of 3-benzoyl-alpha methyl benzene acetic acid with antitumor activity mediated via cyclooxygenase pathway.

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    journal_title:International journal of cancer

    pub_type: 杂志文章


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    journal_title:International journal of cancer

    pub_type: 杂志文章


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  • Protein content and functional characteristics of serum-purified exosomes from patients with colorectal cancer revealed by quantitative proteomics.

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    journal_title:International journal of cancer

    pub_type: 杂志文章


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  • Whole exome sequencing identifies PLEC, EXO5 and DNAH7 as novel susceptibility genes in testicular cancer.

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    journal_title:International journal of cancer

    pub_type: 杂志文章


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  • Enhancement of colorectal tumor targeting using a novel biparatopic monoclonal antibody against carcinoembryonic antigen in experimental radioimmunoguided surgery.

    abstract::Biparatopic CEA, carcinoembryonic antigen (MAb) was newly designed and tested as to whether it enhanced the accuracy of tumor detection by reducing non-specific binding in experimental radioimmunoguided surgery. Biparatopic MAb was prepared by using cross-linking of reduced Fab' fragments from PR1A3 and T84.66. Fifty-...

    journal_title:International journal of cancer

    pub_type: 杂志文章


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    abstract::The relationship between breast cancer-associated fatty acid synthase (FAS; oncogenic antigen-519) and chemotherapy-induced cell damage has not been studied. We examined the ability of C75, a synthetic slow-binding inhibitor of FAS activity, to modulate the cytotoxic activity of the microtubule-interfering agent Taxol...

    journal_title:International journal of cancer

    pub_type: 杂志文章


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  • Type I IFNs induce anti-tumor polarization of tumor associated neutrophils in mice and human.

    abstract::The importance of tumor associated neutrophils (TANs) in cancer development is in the meantime well established. Numerous of clinical data document the adverse prognostic effects of neutrophil infiltration in solid tumors. However, certain tumor therapies need functional neutrophils to be effective, suggesting altered...

    journal_title:International journal of cancer

    pub_type: 杂志文章


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    abstract::Pancreatic cancer remains the fourth most common cause of cancer related death in the United States. Therefore, novel strategies for the prevention and treatment are urgently needed. Genistein is a prominent isoflavonoid found in soy products and has been proposed to be responsible for lowering the rate of pancreatic ...

    journal_title:International journal of cancer

    pub_type: 杂志文章,收录出版


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  • Hematologic toxicity assessment in solid tumor patients treated with cetuximab: a pooled analysis of 18 randomized controlled trials.

    abstract::The role of cetuximab in treatment-related hematologic toxicity is not clear. We performed a meta-analysis of published randomized controlled trials (RCTs) to determine the overall risk of ≥grade 3 hematologic toxicity events (HTEs) associated with cetuximab. PubMed, EMBASE, and Web of Knowledge databases as well as a...

    journal_title:International journal of cancer

    pub_type: 杂志文章,meta分析


    authors: Cui R,Chu L,Liu ZQ,Xiao YY,Zhu XL,Chen YJ,Xu Q

    更新日期:2015-02-15 00:00:00

  • Copy number variations in DCC/18q and ERBB2/17q are associated with disease-free survival in microsatellite stable colon cancer.

    abstract::We conducted a prospective study to assess the prognostic impact of selected copy number variations (CNVs) in Stage II-III microsatellite stable (MSS) colon cancer. A total of 401 patients were included from 01/2004 to 01/2009. The CNVs in 8 selected target genes, DCC/18q, EGFR/7p, TP53/17p, BLK/8p, MYC/8q, APC/5q, ER...

    journal_title:International journal of cancer

    pub_type: 杂志文章,多中心研究


    authors: Sefrioui D,Vermeulin T,Blanchard F,Chapusot C,Beaussire L,Armengol-Debeir L,Sesboué R,Gangloff A,Hebbar M,Copin MC,Houivet E,Schwarz L,Clatot F,Tuech JJ,Bénichou J,Martin L,Bouvier AM,Sabourin JC,Sarafan-Vasseur N,F

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  • Low-fat milk promotes the development of 7,12-dimethylbenz(A)anthracene (DMBA)-induced mammary tumors in rats.

    abstract::Commercial cow milk contains considerable amounts of estrogens. Our study assessed the effect of commercial low-fat milk on the development of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in rats. Eighty 6-week-old female Sprague-Dawley rats received a single oral dose of 5 mg DMBA. Twenty-four hours l...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Qin LQ,Xu JY,Wang PY,Ganmaa D,Li J,Wang J,Kaneko T,Hoshi K,Shirai T,Sato A

    更新日期:2004-07-01 00:00:00

  • Modulation of human endothelial cell procoagulant activity in tumour models in vitro.

    abstract::Several tumour-derived factors have recently been identified which induce tissue factor (TF) expression in endothelial cells in vitro. However, there is only limited evidence that endothelial cells lining tumour blood vessels express elevated procoagulant activity (PCA) in vivo. We have investigated the effects of hum...

    journal_title:International journal of cancer

    pub_type: 杂志文章


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    更新日期:1996-06-11 00:00:00

  • Flavokawain B, a kava chalcone, induces apoptosis via up-regulation of death-receptor 5 and Bim expression in androgen receptor negative, hormonal refractory prostate cancer cell lines and reduces tumor growth.

    abstract::Limited success has been achieved in extending the survival of patients with metastatic and hormone-refractory prostate cancer (HRPC). There is a strong need for novel agents in the treatment and prevention of HRPC. We have shown that flavokawain B (FKB), a kava chalcone, is about 4- to 12-fold more effective in reduc...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Tang Y,Li X,Liu Z,Simoneau AR,Xie J,Zi X

    更新日期:2010-10-15 00:00:00

  • Chromosome 5 harbors two independent deletion hotspots at 5q13 and 5q21 that characterize biologically different subsets of aggressive prostate cancer.

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    journal_title:International journal of cancer

    pub_type: 杂志文章


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    更新日期:2021-02-01 00:00:00

  • Resistance of human breast-cancer cells to the pure steroidal anti-estrogen ICI 182,780 is not associated with a general loss of estrogen-receptor expression or lack of estrogen responsiveness.

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    journal_title:International journal of cancer

    pub_type: 杂志文章


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    更新日期:1997-09-17 00:00:00

  • Farnesyl thiosalicylic acid inhibits the growth of melanoma cells through a combination of cytostatic and pro-apoptotic effects.

    abstract::Novel classes of drug that interfere with the signalling of the small G-protein Ras, the so-called Ras antagonists, are showing much promise as novel anti-cancer agents. In this study, we demonstrate that the novel Ras antagonist farnesylthiosalicylic acid (FTS) inhibits the growth of Colo 853 melanoma cells through a...

    journal_title:International journal of cancer

    pub_type: 杂志文章


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    更新日期:2002-04-01 00:00:00

  • Genetic variants in one-carbon metabolism genes and breast cancer risk in European American and African American women.

    abstract::Folate-mediated one-carbon metabolism plays critical roles in DNA synthesis, repair and DNA methylation. The impact of single nucleotide polymorphisms (SNPs) in folate-metabolizing enzymes has been investigated in risk of breast cancer among European or Asian populations, but not among women of African ancestry. We co...

    journal_title:International journal of cancer

    pub_type: 杂志文章


    authors: Gong Z,Yao S,Zirpoli G,David Cheng TY,Roberts M,Khoury T,Ciupak G,Davis W,Pawlish K,Jandorf L,Bovbjerg DH,Bandera EV,Ambrosone CB

    更新日期:2015-08-01 00:00:00

  • Comparative expression of the psoriasin (S100A7) and S100C genes in breast carcinoma and co-localization to human chromosome 1q21-q22.

    abstract::Using differential screening of a breast cancer cDNA library, we isolated a cDNA encoding the psoriasin (S100A7) protein, previously identified in psoriatic epidermis. In the present study, we demonstrate that the psoriasin gene is expressed in breast cancer cell lines and in cancer cells of some breast carcinomas but...

    journal_title:International journal of cancer

    pub_type: 杂志文章


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    更新日期:1995-10-09 00:00:00