Ovarian cancer is the most common cause of mortality of tumors from gynecologic origin and is often diagnosed after patients have already progressed to advanced disease stage. The current standard of care for treatment of ovarian cancer includes cytoreductive surgery followed by adjuvant chemotherapy. Unfortunately, many patients will recur and ultimately die from their disease. Targeted therapies have been evaluated in ovarian cancer as a method to overcome resistant disease. Angiogenesis inhibitors have shown success in many tumor types and have also demonstrated promise in trials involving patients with ovarian cancer. PARP inhibitors may be potentially active agents in patients with BRCA-associated ovarian cancer. Trials that have evaluated combinations of targeted agents have often revealed untoward toxicities, thus tempering enthusiasm for this approach.

Resveratrol, a naturally occurring polyphenol, has been reported to be an anti-tumor and chemopreventive agent. Recent data show that it may also exert anti-angiogenic effects. We hypothesized that the anti-angiogenic activity of resveratrol may be caused by modulation of tumor cell release of thrombospondin-1 (TSP1) and vascular endothelial growth factor (VEGF) into the extracellular matrix, leading to vascular endothelial cell (VEC) apoptosis. We therefore evaluated the effects of resveratrol on melanoma cell lines co-cultured with vascular endothelial cells in monolayer and in three dimensional spheroids. We found that resveratrol stimulated isolated VEC proliferation, while it caused growth inhibition of VECs grown with melanoma cells in three-dimensional co-culture. This effect was associated with increased melanoma cell expression of tumor suppressor protein 53 and matrix protein TSP1, as well as decreased hypoxia-driven expression of hypoxia inducible factor-1α and inhibition of VEGF production.

Purpose

Metastatic melanoma patients have a poor prognosis. No chemotherapy regimen has improved overall survival. More effective treatments are needed. Docetaxel has clinical activity in melanoma and may be more active when combined with vinorelbine. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown activity as an adjuvant melanoma therapy. We carried out a phase II study of these agents in patients with stage IV melanoma.

Methods

Patients had documented stage IV melanoma and may have had prior immuno or chemotherapy. Previously treated brain metastases were allowed. Docetaxel (40 mg/m(2) IV) and vinorelbine (30 mg/m(2) IV) were administered every 14 days, followed by GM-CSF (250 mg/m2 SC on days 2 to 12). The primary endpoint of the study was 1-year overall survival (OS). Secondary objectives were median overall survival, response rate (per RECIST criteria), and the toxicity profiles.

Results

Fifty-two patients were enrolled; 80% had stage M1c disease. Brain metastases were present in 21%. Fifty-two percent of patients had received prior chemotherapy, including 35% who received prior biochemotherapy. Toxicity was manageable. Grade III/IV toxicities included neutropenia (31%), anemia (14%), febrile neutropenia (11.5%), and thrombocytopenia (9%). DVS chemotherapy demonstrated clinical activity, with a partial response in 15%, and disease stabilization in 37%. Six-month PFS was 37%. Median OS was 11.4 months and 1-year OS rate was 48.1%.

Conclusions

The DVS regimen was active in patients with advanced, previously treated melanoma, with manageable toxicity. The favorable 1-year overall survival and median survival rates suggest that further evaluation of the DVS regimen is warranted.

Docetaxel is currently the most effective drug for the treatment of castration-resistant prostate cancer (CRPC), but it only extends life by an average of 2 months. Lycopene, an antioxidant phytochemical, has antitumor activity against prostate cancer (PCa) in several models and is generally safe. We present data on the interaction between docetaxel and lycopene in CRPC models. The growth-inhibitory effect of lycopene on PCa cell lines was positively associated with insulin-like growth factor I receptor (IGF-IR) levels. In addition, lycopene treatment enhanced the growth-inhibitory effect of docetaxel more effectively on DU145 cells with IGF-IR high expression than on those PCa cell lines with IGF-IR low expression. In a DU145 xenograft tumor model, docetaxel plus lycopene caused tumor regression, with a 38% increase in antitumor efficacy (P = .047) when compared with docetaxel alone. Lycopene inhibited IGF-IR activation through inhibiting IGF-I stimulation and by increasing the expression and secretion of IGF-BP3. Downstream effects include inhibition of AKT kinase activity and survivin expression, followed by apoptosis. Together, the enhancement of docetaxel's antitumor efficacy by lycopene supplementation justifies further clinical investigation of lycopene and docetaxel combination for CRPC patients. CRPC patients with IGF-IR-overexpressing tumors may be most likely to benefit from this combination.

Tumor cells from four established human ovarian carcinoma cell lines were analyzed for their expression of surface antigens including MHC Class I, Class II, ICAM-1, and the tumor-associated antigens CA 125 and Her2-neu before and after exposure to high doses of gamma irradiation. All four ovarian cell IInes expressed variable levels of MHC Class I and Her2-neu. ICAM-1 antigens were expressed in only two cell lines and Class II and CA 125 surface antigens were absent in all the cell lines evaluated. Exposure to high doses of gamma irradiation (i.e., 5000 to 10,000 cGy) significantly and consistently increased the expression of all surface antigens present on the cells prior to irradiation. Importantly, the irradiation-induced upregulation was persistent and lasted until all the cells died. Irradiation was unable to induce neoexpression of antigens previously not expressed by the cells (i.e., MHC Class II or ICAM-1). These findings may partially explain the increased immunogenicity of tumor cells following irradiation and may suggest enhanced immune recognition in tumor tissue in patients receiving radiation therapy.

Purpose

This phase II study evaluated the safety and clinical activity of pazopanib, a potent and mutlitargeted tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFRs)-1, -2 and -3, platelet-derived growth factor receptor (PDGFR)-α and β, and cKit, in combination with metronomic paclitaxel in patients with metastatic melanoma.

Experimental design

Sixty chemotherapy-naive patients received pazopanib at a starting dose of 800 mg daily in combination with metronomic dosing of paclitaxel 80 mg/m² weekly thrice every 4 weeks. The primary endpoint was 6-month progression-free survival (PFS) rate, while secondary endpoints included 1-year overall survival rate, RECIST response rates, progression-free survival rates and median overall survival. Prior BRAF-targeted therapy or checkpoint inhibitors were permitted.

Results

The 6-month PFS rate was 68%, with a 1-year OS rate of 48%. Objective response rate was 37% comprising one complete and 20 partial responses. Stable disease at 8 weeks was noted in 32 patients (55%) with an overall clinical benefit rate of 93%. Six-month median progression-free survival was 8 months and median OS was 12.7 months. The most frequently (> 15%) reported non-hematologic, treatment-related adverse events were fatigue, diarrhea, hypertension, transaminitis and peripheral neuropathy. Treatment-related non-fatal bowel perforation, a known class effect, occurred in one patient. No significant association was noted between plasma levels of pazopanib and response.

Conclusions

The combination of pazopanib and metronomic paclitaxel was well-tolerated, demonstrating significant activity in metastatic melanoma. Further evaluation of this combination is warranted.

We carried out a phase II study to investigate the activity of docetaxel plus lycopene in advanced castrate resistant adenocarcinoma of the prostate. Patients were chemotherapy and biological therapy naive. Docetaxel 75 mg/m² was given every 21 days with daily oral lycopene 30 mg. The primary endpoint was a ≥50% reduction in PSA. Secondary endpoints were median time to PSA progression, duration of response and overall survival. Thirteen patients were initiated on protocol therapy. Median age was 77 (range 55-90). Twelve patients (92%) had bone metastases. Four patients (30%) had both bone and visceral metastases. PSA response was seen in 10 patients (76.9% [95% confidence interval (CI), 46.2-94.9%]). Two patients had stable disease (SD), yielding a disease control rate of 92%. Median time to PSA progression was 8 months [95% CI, 3.5-8.7]. Median duration of response (DOR) was 7.3 months [95% CI, 4.8-13.2]. Median overall survival at 5 years was 35.1 months [95% CI 25.7-57.7]. No new safety signals were noted. No patients experienced grade 3 or above anemia. One patient (7%) experienced febrile neutropenia. A PSA response rate of 76.9% and median survival of 35.1 months compares favorably to the 45% PSA response rate and 17.4 months median survival reported for the TAX 237 trialists. While our study was limited due to small sample size, our results suggest that the combination of docetaxel and lycopene merits further study.

Purpose

The aim of this study was to compare the overexpression of specific biomarkers in primary advanced and recurrent epithelial ovarian cancers.

Methods

Biomarker expression by epithelial ovarian cancer specimens from primary and metastatic sites was examined by immunohistochemistry and flow cytometry. Biomarker expression by subpopulations of tissues consisting of matched pairs of synchronous and metachronous lesions was also studied.

Results

A total of 3173 epithelial ovarian cancer specimens were retrieved from women with FIGO Stage III/IV disease. These included lesions from 1036 primary and 2137 metastatic sites. The percentages of biomarker expression for primary and metastatic lesions, respectively, were MDR1, 12 and 10%; p53, 55 and 60%; HER2, 12 and 11%; EGF-R, 26 and 33%; increased microvessel counts (CD31), 21 and 36%. Approximately 73% of both primary and metastatic specimens were aneuploid, and approximately 57% of both sets had an S-phase fraction >7%. Only EGF-R and CD31 expression were found to be significantly different between the primary and metastatic tumors (P < 0.05). Of the paired synchronous cases (n = 48) evaluated, 88% of aneuploid primary lesions were associated with aneuploid metastases. Similarly, the distributions for MDR1, HER2, and p53 expression did not vary significantly between primary and metastatic sites. Pairings of metachronous cases (n = 66) revealed that nearly 80% of primary aneuploid tumors (n = 39) retained their aneuploid status at the time of relapse. Furthermore, there were no significant changes in MDR1, p53, or HER2 expression at relapse.

Conclusions

With the exception of EGF-R and CD31, clonal divergence of the biomarkers evaluated in this study probably does not play a significant role in imparting clinical heterogeneity during the advanced and recurrent stages of epithelial ovarian cancer. These particular genes likely undergo alterations early in the tumorigenesis process before metastases have become established.

Tumor cells from 7 freshly isolated human ovarian tumors and 2 continuous human ovarian cancer cell lines were analyzed for their surface expression of MHC class-1, class 11 and ICAM-1 surface antigens before and after exposure to gamma-irradiation and/or the cytokines TNF-alpha plus IFN-gamma. All 7 fresh tumors expressed high levels of MHC class 1 and 1CAM-1 antigens, and levels were markedly up-regulated after exposure to TNF-alpha plus IFN-gamma Similarly, class-11 antigens were either induced (3 out of 7 tumors) or significantly up-regulated by TNF-alpha plus IFN-gamma. Exposure to high doses of gamma-irradiation also increased the expression of MHC class-1 and ICAM-1 antigens, albeit to a modest degree. MHC class 1 and ICAM-1 antigens expression was much lower on continuous human ovarian cell lines than on the fresh tumors. Exposure of these cells to TNF-alpha plus IFN-gamma markedly up-regulated antigen expression to levels comparable to those expressed on the freshly isolated tumors. With the established ovarian cell lines, removal of cytokines caused a rapid down-regulation of antigen expression to basal levels within 6 days, while in the fresh tumors a low level of up-regulation was still present at this time. In contrast, exposure to cytokines followed by high-dose gamma-irradiation resulted in a highly significant and long-lasting expression of each surface antigen which was either up-regulated or induced by the cytokines. These data indicated that the combination of these modalities may be beneficial in generating optimal antigen expression for use of tumor cells in vaccine studies.