The molecular genetic basis of ovarian cancer and its roadmap towards a better treatment

Despierre, Evelyn; Lambrechts, Diether; Neven, Patrick; Amant, Frédéric; Lambrechts, Sandrijne; Vergote, Ignace

doi:10.1016/j.ygyno.2010.02.012

Cited by 52 publications

(36 citation statements)

References 78 publications

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“…Activation of Akt is observed in up to 70% of ovarian cancers (4) due to a variety of causes, including PIK3CA mutations (8%-12%) or amplification (3%-8%) and/or PTEN loss (27%) or mutations (3-8%) (1,(5)(6)(7)(8)(9)(10). Loss of Pten (11,12) or overexpression of activated PI3K in the mouse ovarian surface epithelium (OSE) (13) do not lead to tumor formation; however, the ability of mutant Pik3ca to initiate tumorigenesis or drive tumor progression has not been established.…”

Section: Introductionmentioning

confidence: 99%

An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice

et al. 2012

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Section: Introductionmentioning

confidence: 99%

An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice

et al. 2012

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“…For example, polyethylene glycol (PEG)ylation has been extensively employed to increase the accumulation of liposomes in tumor tissues via enhanced permeability and retention (EPR) effects (i.e., passive targeting) (11). To increase the specificity of the interactions between liposomes and tumor cells, various studies have focused on the development of active tumor-targeted liposomes modified with specific ligands, including transferrin (12), folic acid (13), peptides (14)(15)(16)(17)(18) or antibodies (19)(20)(21). These modified liposomes are able to selectively recognize and bind to specific receptors overexpressed on tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Effect of integrin receptor-targeted liposomal paclitaxel for hepatocellular carcinoma targeting and therapy

et al. 2015

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Abstract. The major aim of the present study was to develop an integrin receptor-targeted liposomal paclitaxel (PTX) to enhance the targeting specificity and therapeutic effect of PTX on hepatocellular carcinoma (HCC) cells. The specific Arg-Gly-Asp (RGD) ligand was conjugated to 1,2-distearoylphosphatidylethanolamine-polyethylene glycol 2000 to prepare the RGD-modified liposomes (RGD-LP). Furthermore, physicochemical characteristics of RGD-LP, including particle size, ζ potential, encapsulation efficiency and in vitro PTX release, were evaluated. RGD-modified liposomes were selected as the carrier for the present study, as they exhibit good biocompatibility and are easy to modify using RGD. The cellular uptake efficacy of RGD-LP by HepG2 cells was 3.3-fold higher than that of liposomes without RGD, indicating that RGD-LP may specifically target HepG2 cells by overexpressing integrin αvβ3 receptors. The RGD modification appeared to enhance the anti-proliferative activity of LP-PTX against HepG2 cells, with the extent of anti-proliferative activity dependent on the concentration of PTX and the incubation time. Additionally, evaluation of the homing specificity and anticancer efficacy of RGD-LP on the tumor spheroids indicated that solid tumor penetration was enhanced by the modification of RGD. In agreement with these in vitro findings, in vivo investigations demonstrated that RGD-LP-PTX exhibited a greater inhibitory effect on tumor growth in HepG2-bearing mice than LP-PTX or free PTX. Thus, RGD-LPs may represent an efficient targeted PTX delivery system for the treatment of patients with HCC.

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“…Although progress has been made in its treatment with the introduction of platinumtaxane-based chemotherapy since the 1980s, the mortality rate remains largely unchanged in the past 2 decades (1). The overall 5-year survival rate is only 29%, possibly due to infrequent early diagnosis coupled with the emergence of drug resistance in recurrent disease (2). The current gold standard for chemotherapy targeting ovarian cancer is a combination of carboplatin, a platinum-based compound, together with paclitaxel, an antimitotic drug.…”

Section: Introductionmentioning

confidence: 99%

The Molecular Basis of Synergism between Carboplatin and ABT-737 Therapy Targeting Ovarian Carcinomas

Jain

Meyer‐Hermann

2011

Cancer Research

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Resistance to standard chemotherapy (carboplatin þ paclitaxel) is one of the leading causes of therapeutic failure in ovarian carcinomas. Emergence of chemoresistance has been shown to be mediated in part by members of the Bcl family of proteins including the antiapoptotic protein Bcl-x L , whose expression is correlated with shorter disease-free intervals in recurrent disease. ABT-737 is an example of one of the first small-molecule inhibitors of Bcl-2/Bcl-x L that has been shown to increase the sensitivity of ovarian cancer cells to carboplatin. To exploit the therapeutic potential of these two drugs and predict optimal doses and dose scheduling, it is essential to understand the molecular basis of their synergistic action. Here, we build and calibrate a mathematical model of ABT-737 and carboplatin action on an ovarian cancer cell line (IGROV-1). The model suggests that carboplatin treatment primes cells for ABT-737 therapy because of an increased dependence of cells with DNA damage on Bclx L for survival. Numerical simulations predict the existence of a threshold of Bcl-x L below which these cells are unable to recover. Furthermore, co-plus posttreatment of ABT-737 with carboplatin is predicted to be the best strategy to maximize synergism between these two drugs. A critical challenge in chemotherapy is to strike a balance between maximizing cell-kill while minimizing patient drug load. We show that the model can be used to compute minimal doses required for any desired fraction of cell kill. These results underscore the potential of the modeling work presented here as a valuable quantitative tool to aid in the translation of novel drugs such as ABT-737 from the experimental to clinical setting and highlight the need for close collaboration between modelers and experimental scientists. Cancer Res; 71(3); 705-15. Ó2010 AACR.

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The molecular genetic basis of ovarian cancer and its roadmap towards a better treatment

Cited by 52 publications

References 78 publications

An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice

An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice

Effect of integrin receptor-targeted liposomal paclitaxel for hepatocellular carcinoma targeting and therapy

The Molecular Basis of Synergism between Carboplatin and ABT-737 Therapy Targeting Ovarian Carcinomas

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