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.

journal_name

Int J Cancer

authors

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

doi

10.1002/ijc.32830

subject

Has Abstract

pub_date

2020-08-15 00:00:00

pages

1086-1097

issue

4

eissn

0020-7136

issn

1097-0215

journal_volume

147

pub_type

杂志文章
  • 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

    doi:10.1002/ijc.27626

    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

    doi:10.1002/ijc.25517

    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

    doi:10.1002/ijc.2910320419

    authors: Kawashima K,Nagura E,Watanabe E,Mizoguchi K,Saga S,Isobe K,Nakashima I,Yamada K,Oikawa T,Kojima K

    更新日期:1983-10-15 00:00:00

  • 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

    doi:10.1002/(sici)1097-0215(19990420)84:2<109::aid-ijc

    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.

    abstract::Expression of intermediate filaments (IFs) has been suggested to be a reliable marker for differentiating epithelial and non-epithelial tumors. Moreover, the c-erbB-2 and p53 genes are considered to be involved relatively early in the process of human carcinogenesis. In order to elucidate the origin of uterine carcino...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/(sici)1097-0215(19970904)72:5<821::aid-ijc

    authors: Gorai I,Yanagibashi T,Taki A,Udagawa K,Miyagi E,Nakazawa T,Hirahara F,Nagashima Y,Minaguchi H

    更新日期:1997-09-04 00:00:00

  • p53 gene mutations in oropharyngeal carcinomas: a comparison of solitary and multiple primary tumours and lymph-node metastases.

    abstract::Despite the steadily increasing number of patients suffering from squamous-cell carcinomas of the oropharyngeal region, little is known about the molecular steps involved in the induction of these neoplasms. We investigated oropharyngeal cancers from 38 patients for mutations in the p53 tumour-suppressor gene. The maj...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.2910560608

    authors: Zariwala M,Schmid S,Pfaltz M,Ohgaki H,Kleihues P,Schäfer R

    更新日期:1994-03-15 00:00:00

  • Alcohol consumption and risk of gastric cardia adenocarcinoma and gastric noncardia adenocarcinoma: A 16-year prospective analysis from the NIH-AARP diet and health cohort.

    abstract::The role of alcoholic beverages in the etiology of gastric cancer is unclear. Recent summaries showed a positive association between higher alcohol intake and gastric cancer risk, but the magnitude of association is small, there is moderate heterogeneity among studies, and most cases were from Asian populations. We pr...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.31740

    authors: Wang S,Freedman ND,Loftfield E,Hua X,Abnet CC

    更新日期:2018-12-01 00:00:00

  • Inhibitory effects of the standardized extract (DA-9601) of Artemisia asiatica Nakai on phorbol ester-induced ornithine decarboxylase activity, papilloma formation, cyclooxygenase-2 expression, inducible nitric oxide synthase expression and nuclear transc

    abstract::Artemisia asiatica Nakai has been used in traditional Asian medicine for the treatment of inflammatory and other disorders. Previous studies have revealed that the formulated ethanol extract (DA-9601) of A. asiatica has pronounced antioxidative and antiinflammatory activities and exhibits cytoprotective effects agains...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.10489

    authors: Seo HJ,Park KK,Han SS,Chung WY,Son MW,Kim WB,Surh YJ

    更新日期:2002-08-01 00:00:00

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

    abstract::This population-based cohort study investigated the occurrence of familial astrocytoma among first-degree relatives of patients with astrocytoma diagnosed between 1985 and 1993 in the northern region of Sweden. The 432 cases received a questionnaire. They were asked to provide names and cancer diagnoses of first-degre...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/(sici)1097-0215(19990505)81:3<366::aid-ijc

    authors: Malmer B,Grönberg H,Bergenheim AT,Lenner P,Henriksson R

    更新日期:1999-05-05 00:00:00

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

    abstract::Caveolae have been indicated as a center of cytoskeleton regulation for Src kinase/Rho GTPase signaling. In addition, Src recruitment on intact cortical actin cytoskeleton appears to be required for bFGF/FGFR signal activation. Recently, we established a relationship between caveolin-1 (Cav-1) expression and cell migr...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.26092

    authors: Fecchi K,Travaglione S,Spadaro F,Quattrini A,Parolini I,Piccaro G,Raggi C,Fabbri A,Felicetti F,Carè A,Fiorentini C,Sargiacomo M

    更新日期:2012-03-15 00:00:00

  • Androgen receptor-interacting protein HSPBAP1 facilitates growth of prostate cancer cells in androgen-deficient conditions.

    abstract::Hormonal therapies targeting androgen receptor (AR) are effective in prostate cancer (PCa), but often the cancers progress to fatal castrate-resistant disease. Improved understanding of the cellular events during androgen deprivation would help to identify survival and stress pathways whose inhibition could synergize ...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.29303

    authors: Saeed K,Östling P,Björkman M,Mirtti T,Alanen K,Vesterinen T,Sankila A,Lundin J,Lundin M,Rannikko A,Nordling S,Mpindi JP,Kohonen P,Iljin K,Kallioniemi O,Rantala JK

    更新日期:2015-06-01 00:00:00

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

    abstract::Breast cancers diagnosed between screening examinations among women who attend a breast cancer screening program are defined as interval cancers. The Norwegian Breast Cancer Screening Program started as a pilot project in 1996, and data from the first 2-year interval are available. Our study quantifies interval cancer...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.1511

    authors: Wang H,Bjurstam N,Bjørndal H,Braaten A,Eriksen L,Skaane P,Vitak B,Hofvind S,Thoresen SØ

    更新日期:2001-11-01 00:00:00

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

    abstract::Pancreatic cancer (PC) is characterized as one of the deadliest malignancies and its treatment is a great challenge to clinical oncologists. Expression of COX-2 is detectable in 75% of PCs among which 50% showed overexpression, suggesting the importance of COX-2 enzyme and its metabolic product prostaglandin E2 (PGE(2...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.22383

    authors: Ahmed F,Adsule S,Ali AS,Banerjee S,Ali S,Kulkarni S,Padhye S,Sarkar FH

    更新日期:2007-02-15 00:00:00

  • Combined effects of cyclooxygenase-1 and cyclooxygenase-2 selective inhibitors on intestinal tumorigenesis in adenomatous polyposis coli gene knockout mice.

    abstract::As with cyclooxygenase (COX)-2, genetic disruption of COX-1 gene or pharmacologic inhibition of its activity has been shown to decrease the number of intestinal polyps in Apc gene-deficient mice. The present study was designed to investigate the combined effects of COX-1 and COX-2 selective inhibitors on spontaneous p...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.20012

    authors: Kitamura T,Itoh M,Noda T,Matsuura M,Wakabayashi K

    更新日期:2004-04-20 00:00:00

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

    abstract::Tumor cells of colorectal cancer (CRC) release exosomes into the circulation. These exosomes can mediate communication between cells and affect various tumor-related processes in their target cells. We present a quantitative proteomics analysis of the exosomes purified from serum of patients with CRC and normal volunt...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.30496

    authors: Chen Y,Xie Y,Xu L,Zhan S,Xiao Y,Gao Y,Wu B,Ge W

    更新日期:2017-02-15 00:00:00

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

    abstract::Testicular germ cell tumors (TGCTs) are a clinically and pathologically heterogeneous disease, and little is known of its genetic basis. Only low susceptibility risk loci have been identified for both sporadic and familial cases. Therefore, we tried to identify new susceptibility genes responsible for familial testicu...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.31604

    authors: Paumard-Hernández B,Calvete O,Inglada Pérez L,Tejero H,Al-Shahrour F,Pita G,Barroso A,Carlos Triviño J,Urioste M,Valverde C,González Billalabeitia E,Quiroga V,Francisco Rodríguez Moreno J,Fernández Aramburo A,López C,Maroto

    更新日期:2018-10-15 00:00:00

  • 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

    doi:10.1002/ijc.1630

    authors: Kim JC,Roh SA,Koo KH,Ryu JH,Hong HK,Oh SJ,Ryu JS,Kim HJ,Bodmer WF

    更新日期:2002-02-01 00:00:00

  • Pharmacological and small interference RNA-mediated inhibition of breast cancer-associated fatty acid synthase (oncogenic antigen-519) synergistically enhances Taxol (paclitaxel)-induced cytotoxicity.

    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

    doi:10.1002/ijc.20754

    authors: Menendez JA,Vellon L,Colomer R,Lupu R

    更新日期:2005-05-20 00:00:00

  • 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

    doi:10.1002/ijc.29945

    authors: Andzinski L,Kasnitz N,Stahnke S,Wu CF,Gereke M,von Köckritz-Blickwede M,Schilling B,Brandau S,Weiss S,Jablonska J

    更新日期:2016-04-15 00:00:00

  • Inhibition of nuclear factor kappab activity by genistein is mediated via Notch-1 signaling pathway in pancreatic cancer cells.

    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

    doi:10.1002/ijc.21589

    authors: Wang Z,Zhang Y,Banerjee S,Li Y,Sarkar FH

    更新日期:2006-04-15 00:00:00

  • 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

    doi:10.1002/ijc.29045

    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

    doi:10.1002/ijc.30584

    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

    更新日期:2017-04-01 00:00:00

  • 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

    doi:10.1002/ijc.20172

    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

    doi:10.1002/(SICI)1097-0215(19960611)66:6<784::AID-IJC

    authors: Hewett PW,Murray C

    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

    doi:10.1002/ijc.25210

    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.

    abstract::Deletion of chromosome 5q is common in prostate cancer and is linked to aggressive disease. Most previous studies focused on 5q21 where CHD1 is located, but deletion of mapping studies has identified a second deletion hotspot at 5q13. To clarify the prevalence and clinical relevance of 5q13 deletions and to determine ...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.33344

    authors: Möller K,Kluth M,Ahmed M,Burkhardt L,Möller-Koop C,Büscheck F,Weidemann S,Tsourlakis MC,Minner S,Heinzer H,Huland H,Graefen M,Sauter G,Schlomm T,Dum D,Simon R

    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.

    abstract::To elucidate the mechanisms responsible for the development of anti-estrogen resistance, we have cloned and established 3 stable ICI-182,780-resistant sub-lines, MCF-7/182R-1, MCF-7/182R-6 and MCF-7/182R-7 from the estrogen-receptor(ER)-positive and estrogen-responsive human breast-cancer MCF-7 cell line by long-term ...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/(sici)1097-0215(19970917)72:6<1129::aid-ij

    authors: Larsen SS,Madsen MW,Jensen BL,Lykkesfeldt AE

    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

    doi:10.1002/ijc.10213

    authors: Smalley KS,Eisen TG

    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

    doi:10.1002/ijc.29434

    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

    doi:10.1002/ijc.2910630225

    authors: Moog-Lutz C,Bouillet P,Régnier CH,Tomasetto C,Mattei MG,Chenard MP,Anglard P,Rio MC,Basset P

    更新日期:1995-10-09 00:00:00