Search

Objective To assess the cost-effectiveness of a strategy employing genomic-based tumor testing to guide therapy for platinum-resistant ovarian cancer. Methods A decision model was created to compare standard of care (SOC) cytotoxic chemotherapy to a genomic-based treatment strategy. The genomic arm included tumor testing with treatment directed at targets identified. Overall survival was assumed to be similar between strategies; quality of life (QOL) was assumed superior during targeted therapy compared to chemotherapy. Pertinent uncertainties (cost of targeted therapy and genomic testing, response to targeted therapy, probability of a tumor having a targetable alteration, and impact on QOL) were evaluated in a series of one-and two-way sensitivity analyses. Results The genomic testing strategy was more expensive ($90,271 vs. $74,926) per patient than SOC. The incremental cost-effectiveness ratio (ICER) of the genomic strategy was $479,303 per quality-adjusted life year saved (QALY). Model results were insensitive to the cost of genomic testing, differences in QOL, and the probability of identifying a targetable alteration. However, the model was sensitive to the cost of targeted therapy. For example, when the cost of targeted therapy was reduced to 56% of its current cost (or $6400/cycle), the genomic strategy became more cost-effective with an ICER of $96,612/QALY. Conclusions Genomic-based tumor testing and targeted therapy in patients with platinum-resistant ovarian cancer is not cost-effective compared with SOC. However, reducing the cost of targeted therapy (independently, or in combination with reducing the cost of the genomic test) provides opportunities for improved value in cancer care. [ABSTRACT FROM AUTHOR]

Targeting the human epidermal growth factor receptor 2 (HER2) has yielded major advances in breast cancer treatment. Accordingly, it has generated interest in targeting HER2 to treat gynecologic malignancies. Multiple studies have evaluated the rates of HER2 overexpression and/or amplification in ovarian and uterine cancers. HER2 has also been studied as a prognostic factor but resulting data has been contradictory. Moreover, clinical trials of HER2-directed therapies, including trastuzumab, pertuzumab, and lapatinib in ovarian and uterine cancers have been largely disappointing. Current research on HER2 in gynecologic malignancies has focused on identifying mechanisms of resistance and looking further into how HER2 signaling in gynecologic cancers differs from breast cancer. In this review, we highlight the existing data of targeting HER2 in ovarian and uterine carcinomas, many dating back more than a decade, and discuss future directions in pursuing HER2 as a potential target in these diseases. [ABSTRACT FROM AUTHOR]

Abstract: Epigenetic drugs have been shown to enhance gene expression and drug sensitivity in ovarian cancer cell lines and animal models. Based on promising preclinical studies, DNA methylation inhibitors in combination with existing chemotherapeutic agents have the potential for overcoming acquired drug resistance, laying the foundation for this specific class of epigenetic drug in ovarian cancer clinical trials. The recent completion of phase I trials of decitabine has yielded important information on dosing schedules and biological endpoints for evaluating patient responses. In addition, epigenetic drug effects on pharmacodyamic targets are beginning to emerge, and predictive epigenetic biomarkers and next generation epigenome therapeutics are being developed for application in clinical settings for ovarian cancer patients. [Copyright &y& Elsevier]

Abstract: Objectives. : Current virotherapy strategies for ovarian cancer have been hampered by limitations in target cell infectivity and nonspecific tissue replication. In an effort to circumvent these limitations, we evaluated various CRAds modified to incorporate novel capsid targeting motifs (RGD and chimeric Ad5/3) with a novel tissue-specific promoter (CXCR4). Methods. : Two novel CRAds (Ad5-CXCR4-F5/3 and Ad5-CXCR4-RGD) were constructed via homologous recombination and verified by PCR and DNA sequencing. The infectivity and viral replication rates of these two CRAds were analyzed via quantitative real-time PCR (QRT-PCR) in cell line experiments using three ovarian cancer cell lines (SKOV3.ip1, Hey, and OV4) and compared to that achieved with a clinical grade CRAd (Δ24-RGD) to be evaluated in a Phase I trial. Cytocidal effects were determined by crystal violet staining in these same cell lines infected with different concentrations of viral particles per cell (0, 0.1, 1, 10, 100, and 500). Additionally, viral replication was evaluated by QRT-PCR in primary ovarian cancer tissue slices from multiple patients with ovarian cancer as well as in primary human normal liver tissue slices in order to establish CRAd selectivity. All experiments incorporated appropriate controls and repeated in triplicate. Results. : Compared to RGD-capsid CRAds (Δ24-RGD and CXCR4-RGD), the F5/3-capsid CRAd (CXCR4-F5/3) demonstrated significant improvements in infection rates (p =0.025, 0.006, and 0.006) in all ovarian cancer cell lines tested (SKOV3.ip1, Hey, and OV4, respectively). In addition to improved transduction of virus into the cells, the TSP CXCR4-based CRAds demonstrated improved viral replication. Specifically, CXCR4-F5/3 further enhanced viral replication 89-fold (p =0.009, 0.010, 0.003) in the same cancer cell lines. Furthermore, CXCR4-F5/3 showed a 4-log improvement in oncolytic potential over Δ24-RGD. In the ex vivo primary ovarian tissue slices, CXCR4-F5/3 showed a 58-fold improvement in viral replication (p =0.005) compared to the clinical grade Δ24-RGD. Both CXCR4-F5/3 and CXCR4-RGD demonstrated significant reduction of viral replication in normal liver slices (p =0.001). Conclusions. : These data suggest that a dual targeted approach is feasible for the combined enhancement of infectivity and replication in ovarian cancer with a specificity that was attenuated in normal liver tissues. In fact, CXCR4-F5/3 outperformed our best CRAd agent to date nearly 60-fold in our most stringent ex vivo model of primary ovarian cancer tissue slices and suggests that this novel agent could be useful for the treatment of ovarian cancer. [Copyright &y& Elsevier]

Abstract: Objectives. : Capsid-modified AAV vectors can mediate enhanced gene transfer to neoplasms characterized by low AAV receptor expression. Here we sought to determine the therapeutic potential of a capsid-modified AAV vector for gene therapy of ovarian carcinoma (OvCa). Methods. : We tested a panel of OvCa cell lines for AAV2-mediated gene transduction and for sensitivity to ganciclovir (GCV) following AAVHSVtk administration. Levels of AAV internalization and attachment receptor were assessed by flow cytometry and immunohistochemistry. The role of receptors in AAV-mediated gene transfer was assessed by competition assays. Finally, we examined the ability of a modified vector with an integrin-binding RGD motif inserted into the AAV capsid to improve gene delivery to OvCa and enhance AAVHSVtk/GCV-mediated killing by cytotoxicity assay. Results. : All OvCa cell lines were poorly transduced with AAV2 vectors and showed variably sensitive to AAVHSVtk/GCV. While OvCa cell lines expressed AAV2 internalization receptors (αv integrins), expression of the AAV2 attachment receptor, HSPG, was variable and not detected on many lines. Analysis of archived clinical specimens showed no detectable HSPG expression on approximately 45% of primary human tumors. Gene transfer to OvCa was increased several fold using the RGD-modified vector. Gene transfer was independent of HSPG and specific to the targeted receptor. Importantly, the RGD-modified capsid markedly increased the ability of the AAVHSVtk to kill OvCa cells in the presence of GCV. Conclusions. : The development of AAV vectors targeted to cell surface receptors other than HSPG will be critical to the advancement of AAV-mediated gene therapy for treating OvCa. [Copyright &y& Elsevier]

Abstract: Objective. : Icodextrin, a novel glucose polymer solution utilized for peritoneal dialysis, has been demonstrated to have prolonged intraperitoneal (IP) instillation volumes in comparison to standard PBS solutions. In an animal model of ovarian cancer, we explored whether a survival advantage exists utilizing icodextrin rather than PBS as a delivery solution for an infectivity enhanced virotherapy approach. Methods. : Initial experiments evaluated whether icodextrin would adversely affect replication of a clinical grade infectivity enhanced conditionally replicative adenovirus (Δ24-RGD). Virus was added to prepared blinded solutions of PBS or icodextrin (20%) and then evaluated in vitro in various human ovarian cancer cell lines (SKOV3.ip1, PA-1, and Hey) and in vivo in a SKOV3.ip1 human ovarian cancer IP murine model. Viral replication was measured by detecting adenovirus E4 gene levels utilizing QRT-PCR. Survival was subsequently evaluated in a separate SKOV3.ip1 ovarian cancer IP murine model. Cohorts of mice were treated in blinded fashion with PBS alone, icodextrin alone, PBS+Δ24-RGD, or icodextrin+Δ24-RGD. Survival data were plotted on Kaplan–Meier curve and statistical calculations performed using the log-rank test. Results. : There was no adverse affect of icodextrin on vector replication in the ovarian cancer cell lines nor murine model tumor samples evaluated. Median survival in the IP treated animal cohorts was 23 days for the PBS group, 40 days for the icodextrin group, 65 days for the PBS+Δ24-RGD group, and 105 days for icodextrin+Δ24-RGD (p =0.023). Of note, 5 of the 10 mice in the icodextrin+Δ24-RGD group were alive at the end of the study period, all without evidence of tumor (120 days). Conclusions. : These experiments suggest that the use of dialysates such as icodextrin may further enhance the therapeutic effects of novel IP virotherapy and other gene therapy strategies for ovarian cancer. Phase I studies utilizing icodextrin-based virotherapy for ovarian cancer are currently in development. [Copyright &y& Elsevier]

Objectives. The “suicide” gene therapy of cancer using promoters such as cytomegalovirus could cause severe toxicity to normal tissues due to a lack of specificity of prodrug activation. Therefore, we investigated gene therapy of ovarian cancer using ovarian-specific promoter (OSP1) to limit the synthesis of the prodrug activating enzyme HSVtk to ovarian cancer cells.Methods. The HSVtk expressing plasmid pOSP1–HSVtk was created and transfected into an ovarian cancer cell line OVCAR3. The ganciclovir (GCV) sensitivity of the stable transfectants was evaluated with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Tissue specificity of this promoter was evaluated by comparing the sensitivity to GCV between ovarian and nonovarian cancer cell lines after they were transfected with pOSP1–HSVtk. One transfectant sensitive to GCV was implanted intraperitoneally to immunocompromised mice which were treated subsequently with GCV. Furthermore, this ovarian cancer survival model was used to evaluate the in vivo efficacy of cationic lipid mediated pOSP1–HSVtk gene delivery followed by GCV treatment.Results. Stable transfectants of OVCAR3 cells bearing OSP1–HSVtk became more sensitive to GCV treatment compared to the parental cell line and vector transfected OVCAR3 cell line. OSP1–HSVtk could specifically sensitize the OVCAR3 ovarian cancer cell line to GCV. SCID mice transplanted with the OVCAR3 transfectant and treated with GCV survived longer than the mice without GCV treatment (P = 0.032). In vivo gene delivery mediated by a cationic lipid (GL67) followed by GCV treatment yielded a longer survival in the OVCAR3 survival model (P = 0.016).Conclusions. The OSP1 promoter can selectively direct suicide gene therapy of ovarian cancer and the in vivo efficacy is improved by using a cationic lipid GL67 as delivery vehicle as opposed to the direct injection of plasmid. [Copyright &y& Elsevier]