An Integrated Genomic-Based Approach to Individualized Treatment of Patients With Advanced-Stage Ovarian Cancer

Dressman, Holly K.; Berchuck, Andrew; Chan, Gina; Zhai, Jun; Bild, Andrea; Sayer, Robyn; Cragun, Janiel M.; Clarke, Jennifer; Whitaker, Regina S.; Li, Li Hua; Gray, Jonathan; Marks, Jeffrey R.; Ginsburg, Geoffrey S.; Potti, Anil; West, Mike; Nevins, Joseph R.; Lancaster, Johnathan M.

doi:10.1200/jco.2006.06.3743

Cited by 246 publications

(238 citation statements)

References 32 publications

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“…It is tempting to speculate that under certain circumstances, E2F activity might aid in the development of drug resistance through stimulating FA pathway activity and DNA repair. Interestingly, gene expression signatures of platinum-resistant advanced stage ovarian cancers revealed activation of E2F3 pathways, and the targeting of E2F pathways with roscovitine could be exploited for improved response to chemotherapy in vitro (Dressman et al, 2007). Additionally, high levels of activating relative to repressing E2Fs have recently been shown to be clinical predictors of poor response to chemotherapy in ovarian cancer patients (Reimer et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway

et al. 2008

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Fanconi anemia (FA) is a genome instability syndrome that is characterized by progressive bone marrow failure and a high risk of cancer. FA patients are particularly susceptible to leukemia as well as squamous cell carcinomas (SCCs) of the head and neck, anogenital region and skin. Thirteen complementation groups and the corresponding FA genes have been identified, and their protein products assemble into nuclear core complexes during DNA-damage responses. Much progress has been made in our understanding of post-translational FA protein modifications and physical interactions. By contrast, little is known about the control of protein availability at the level of transcription. We report here that multiple FA proteins were downregulated during the proliferative arrest of primary human keratinocytes and HeLa cells, and that the observed regulation was at a transcriptional level. Proliferative stimuli such as expression of HPV16 E7 as well as E2F1 overexpression in primary cells resulted in coordinate FA upregulation. To define the underlying mechanism, we examined the endogenous FANCD2 promoter, and detected regulated binding of members of the E2F/Rb family in chromatin immunoprecipitation assays. Finally, a 1 kb promoter fragment was sufficient to confer E2F/Rb regulation in reporter assays. Taken together, our data demonstrate FA gene co-regulation in synchrony with the cell cycle and suggest that deregulated expression of individual FA genes-in addition to FA gene mutation-may promote FA-related human cancer.

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Section: Discussionmentioning

confidence: 99%

Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway

et al. 2008

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“…Importantly, aberrant expression and activation of the SFKs have been described in human ovarian cancer cell lines (Budde et al, 1994) and clinical samples (Wiener et al, 2003). A recent study used gene expression signatures that define the status of Src signalling pathways to predict the probability of Src pathway activation in 119 patients with ovarian cancer (Dressman et al, 2007). Approximately half of the tumours examined in this study showed Src pathway deregulation.…”

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confidence: 99%

Activity of the multikinase inhibitor dasatinib against ovarian cancer cells

Glas

Dering

et al. 2009

Br J Cancer

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BACKGROUND: Here, we explore the therapeutic potential of dasatinib, a small-molecule inhibitor that targets multiple cytosolic and membrane-bound tyrosine kinases, including members of the Src kinase family, EphA2, and focal adhesion kinase for the treatment of ovarian cancer. METHODS: We examined the effects of dasatinib on proliferation, invasion, apoptosis, cell-cycle arrest, and kinase activity using a panel of 34 established human ovarian cancer cell lines. Molecular markers for response prediction were studied using gene expression profiling. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions with chemotherapeutic drugs. RESULTS: Concentration-dependent anti-proliferative effects of dasatinib were seen in all ovarian cancer cell lines tested, but varied significantly between individual cell lines with up to a 3 log-fold difference in the IC 50 values (IC 50 range: 0.001 -11.3 mmol l À1 ). Dasatinib significantly inhibited invasion, and induced cell apoptosis, but less cell-cycle arrest. At a wide range of clinically achievable drug concentrations, additive and synergistic interactions were observed for dasatinib plus carboplatin (mean CI values, range: 0.73 -1.11) or paclitaxel (mean CI values, range: 0.76 -1.05). In this study, 24 out of 34 (71%) representative ovarian cancer cell lines were highly sensitive to dasatinib, compared with only 8 out of 39 (21%) representative breast cancer cell lines previously reported. Cell lines with high expression of Yes, Lyn, Eph2A, caveolin-1 and 2, moesin, annexin-1, and uPA were particularly sensitive to dasatinib. CONCLUSIONS: These data provide a clear biological rationale to test dasatinib as a single agent or in combination with chemotherapy in patients with ovarian cancer.

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“…It might then be possible to study physiological processes in one type of cancer and extrapolate the results predictively to another type through commonalities in their molecular constitutions. More recently, several studies have demonstrated that genomic biomarkers can be used to predict chemotherapeutic responses of human cancer patients (6)(7)(8).…”

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confidence: 99%

A strategy for predicting the chemosensitivity of human cancers and its application to drug discovery

Lee

Havaleshko

Cho

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

280

272

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An Integrated Genomic-Based Approach to Individualized Treatment of Patients With Advanced-Stage Ovarian Cancer

Abstract: We have defined a strategy for treatment of patients with advanced-stage ovarian cancer that uses therapeutic stratification based on predictions of response to chemotherapy, coupled with prediction of oncogenic pathway deregulation, as a method to direct the use of targeted agents.

Cited by 246 publications

References 32 publications

Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway

Coordinate regulation of Fanconi anemia gene expression occurs through the Rb/E2F pathway

Activity of the multikinase inhibitor dasatinib against ovarian cancer cells

A strategy for predicting the chemosensitivity of human cancers and its application to drug discovery

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