Opportunities and challenges in ovarian cancer research, a perspective from the 11th Ovarian cancer action/HHMT Forum, Lake Como, March 2007

Ashworth, Alan; Balkwill, Frances R.; Bast, Robert C.; Berek, Jonathan S.; Kaye, Allyson; Boyd, J.; Mills, Gordon B.; Weinstein, John N.; Woolley, Katie; Workman, Paul

doi:10.1016/j.ygyno.2007.11.014

Cited by 22 publications

(19 citation statements)

References 29 publications

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“…If detected while still confined to the ovaries (Stage I) or to the pelvis (Stage II), 5-year survival rates are 90% and 70% respectively. Once the disease has spread to the peritoneal cavity (Stage III) or beyond (Stage IV), the 5-year survival decreases sharply to less than 20% (2-4). Computer simulation suggests that earlier detection could reduce mortality by as much as 43% (5).…”

Section: Introductionmentioning

confidence: 99%

Elevation of TP53 Autoantibody Before CA125 in Preclinical Invasive Epithelial Ovarian Cancer

Yang

Gentry‐Maharaj

Simmons

et al. 2017

Clinical Cancer Research

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Purpose The TP53 tumor suppressor gene is mutated in >95% of high grade serous ovarian cancers. Detecting an autologous antibody response to TP53 might improve early detection. Experimental design An immunoassay was developed to measure TP53 autoantibody in sera from 378 cases of invasive epithelial ovarian cancer and in 944 age-matched healthy controls from the United States, Australia and the United Kingdom. Serial preclinical samples from cases and controls were also assayed from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Results Using a cut-off of 78 U/mL to achieve a specificity of 97.4%, TP53 autoantibody were elevated in 30% of 50 cases from MD Anderson, 21.3% of 108 cases from the Australian Ovarian Cancer Study and 21% of 220 cases from the UKCTOCS. Among 164 cases with rising CA125 detected with the UKCTOCS risk of ovarian cancer algorithm (ROCA), 20.7% had elevated TP53 autoantibody. In cases missed by the ROCA, 16% of cases had elevated TP53 autoantibody. Of the 34 ovarian cancer cases detected with the ROCA, TP53 autoantibody titers were elevated 11.0 months prior to CA125. In the 9 cases missed by the ROCA, TP53 autoantibody was elevated 22.9 months before cancer diagnosis. Similar sensitivity was obtained using assays with specific mutant and wild-type TP53. Conclusion TP53 autoantibody levels provide a biomarker with clinically significant lead time over elevation of CA125 or an elevated ROCA value. Quantitative assessment of autoantibodies in combination with CA125 hold promise for earlier detection of invasive epithelial ovarian cancer.

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Section: Introductionmentioning

confidence: 99%

Elevation of TP53 Autoantibody Before CA125 in Preclinical Invasive Epithelial Ovarian Cancer

Yang

Gentry‐Maharaj

Simmons

et al. 2017

Clinical Cancer Research

Self Cite

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“…The success rate of anti-cancer therapies translating from in vitro culture systems into the clinic is about 5%. 1 The vast majority of drugs that show promising results in vitro fail to replicate in an in vivo model system and even fewer make it into clinical trials. Nonetheless testing drugs in cell culture models is a vital part of any drug development process.…”

mentioning

confidence: 99%

A three-dimensional microenvironment alters protein expression and chemosensitivity of epithelial ovarian cancer cells in vitro

Lee

Mhawech‐Fauceglia

Lee

et al. 2013

Laboratory Investigation

269

125

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For many cancers, there is a real need for more effective therapies. Although many drugs show promising results in vitro, most fail to translate into an in vivo model system, and only B5% show anti-tumor activity in clinical trials. It remains a significant challenge to accurately replicate in vitro the complex in vivo microenvironment in which cancers thrive, but this will be key to increasing the success of translating novel therapies into clinical practice. Three-dimensional (3D) cell culture models may better mimic primary tumors in vivo than traditional two-dimensional (2D) cultures. Therefore, we established and characterized 3D in vitro models of 31 epithelial ovarian cancer (EOC) cell lines, compared their biological and molecular features with 2D cultures and primary tumors, and tested their efficacy as models for evaluating chemoresponse. When cultured in 3D using polyhydroxoethylamethacrylate-coated plastics, EOC lines formed multicellular aggregates that could be classified as 'large dense', 'large loose', and 'small', based on size, light permeability, and proportion of cells incorporated into the complex structures. Features of histological differentiation characteristic of primary tumors that were not present in 2D cultures were restored in 3D. For many cell lines, the transition from a 2D to 3D microenvironment induced changes in the expression of several biomarkers relevant to disease. Generally, EOC cell lines proliferated more slowly and were more chemoresistant in 3D compared with 2D culture. In summary, 3D models of EOCs better reflect the histological, biological, and molecular features of primary tumors than the same cells cultured using traditional 2D techniques; 3D in vitro models also exhibit different sensitivities to chemotherapeutic agents compared with 2D models, which may have a significant impact on the success of drug testing pipelines for EOC. These findings could also impact in vitro modeling approaches and drug development strategies for other solid tumor types. The success rate of anti-cancer therapies translating from in vitro culture systems into the clinic is about 5%. 1 The vast majority of drugs that show promising results in vitro fail to replicate in an in vivo model system and even fewer make it into clinical trials. Nonetheless testing drugs in cell culture models is a vital part of any drug development process. It is likely that a major contributing factor to the low rates of in vivo translation of new therapeutic agents is the widespread use of two-dimensional (2D) monolayer culture systems used for in vitro drug discovery and development. 2D cultures fail to recapitulate the gradients of drugs, nutrients, gases, and waste products that characterize tumors in vivo; all are important factors influencing response to therapy. 2,3 Moreover, many of the signaling pathways involved in chemoresponsiveness are differentially activated in monolayer cultures, and as a result, 2D cultures are often more sensitive to drug therapies yielding many false-positive results in 2D dr...

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“…při screeningu nových léči-vých přípravků. Na druhou stranu však úspěšnost potenciálních protinádoro-vých léků, které se ukazovaly jako velmi slibné v rámci testování v in vitro 2D kultivačních systémech, bývá v klinické praxi jen okolo 5-10 % [32][33][34]. Využití zvířecích modelů, které obvykle předsta-vuje navazující fázi v rámci preklinického testování, je naopak finančně i časově značně náročné a navíc ani tyto modelové systémy plně neodpovídají lidské fyziologii [35].…”

Section: Historie Testování Chemosenzitivity Nádorových Onemocněníunclassified

New Approaches for Chemosensitivity Testing in Malignant Diseases

Sommerová¹,

Michalová²,

Hrstka³

2018

Klin Onkol

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Východiska: Vzhledem k nezastupitelné úloze chemoterapie při léčbě nádorových onemocnění se onkologický výzkum zaměřil na zvýšení účinnosti jednotlivých léčiv a maximální zmírnění, ne-li kompletní potlačení nežádoucích účinků. Vhodná léčba je primárně volena podle základních klinicko-patologických dia gnostických kritérií, jako je velikost nádoru, stupeň diferenciace a přítom-nost či absence standardních markerů. Situaci však komplikuje variabilita mezi jednotlivými pacienty spolu se značnou heterogenitou vlastního nádoru. Detailní charakterizace intratumorální heterogenity a získání spolehlivějších ukazatelů účinnosti léčiv by tak mělo vést k posílení personalizované terapie. Vývoj a výběr spolehlivých modelů tudíž představuje důležitou otázku ve vý-zkumu zaměřeném na predikci citlivosti nádorových buněk k léčbě. Cíl: Práce shrnuje poznatky o testovacích systémech zaměřených na stanovení citlivosti či rezistence nádorových buněk k chemoterapii a jejich zavádění do onkologické praxe od prvních dnes již historických pokusů až po současnost se snahou posoudit jejich uplatnění ve stávající klinické praxi či blízké budoucnosti. Značný důraz je kladen na porovnání 2D a 3D in vitro buněčných modelů, neboť jejich význam a popularita konstantně narůstá. Pozornost je též věnovaná systémům in vivo, které v poslední době zaznamenaly nemalý progres a jsou v rámci klinických studií testovány k predikci odpovědi na podávanou terapii. Závěr: Práce uvádí stručný přehled testů chemosenzitivity a hodnotí význam jednotlivých testů vzhledem k jejich zapojení do rozhodovacího procesu a stratifikace pacientů s cílem predikovat klinickou odpověď konkrétních pacientů a přispět tak k rozvoji cílené personalizované terapie. Klíčová slovatechniky tkáňových kultur -individualizovaná medicína -screening léčiv -bio logické modely -nádorové buněčné linie -karcinom -cytotoxické testy SummaryBackground: Due to the irreplaceable role of chemotherapy in cancer treatment, research has focused on improving the efficacies of individual drugs and minimizing, or completely suppressing, their negative side effects. Based on long-term experience and the results of clinical trials, the selection of appropriate treatment is currently based on classical clinical dia gnostic criteria, such as tumor size, grade, and the presence or absence of standard markers. However, complications arise due to variability between patients and tumor heterogeneity. Characterization of intratumoral heterogeneity and acquisition of more reliable drug performance indicators should improve personalized therapy. Development and selection of suitable models are therefore important issues in cancer research focused on predicting sensitivity to therapy. Aim: This work provides an overview of various chemosensitivity tests that have been previously employed and those that are currently used. Great emphasis is placed on comparing 2D and 3D cell culture models, since their importance and popularity are increasing. Particular attention is paid to in vivo systems, which have significantl...

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Opportunities and challenges in ovarian cancer research, a perspective from the 11th Ovarian cancer action/HHMT Forum, Lake Como, March 2007

Cited by 22 publications

References 29 publications

Elevation of TP53 Autoantibody Before CA125 in Preclinical Invasive Epithelial Ovarian Cancer

Elevation of TP53 Autoantibody Before CA125 in Preclinical Invasive Epithelial Ovarian Cancer

A three-dimensional microenvironment alters protein expression and chemosensitivity of epithelial ovarian cancer cells in vitro

New Approaches for Chemosensitivity Testing in Malignant Diseases

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