HIF Inactivation of p53 in Ovarian Cancer Can Be Reversed by Topotecan, Restoring Cisplatin and Paclitaxel Sensitivity.

Ovarian cancer growth under hypoxic conditions results in hypoxia-inducible factor-1α (HIF1α) stabilization. HIF1α is an adverse prognostic factor that may contribute to worse outcomes via its capacity to bind to p53, potentially blocking p53-mediated apoptosis. We determined whether HIF1α-p53 binding occurred in hypoxic ovarian cancer cell lines, and if this blocked p53 transcriptional activity. Topotecan (TPT), used in the treatment of ovarian cancer, inhibits HIF1α translation via a topoisomerase-1 (TOPO1)-dependent mechanism. We examined if TPT knockdown of HIF1α restored p53 transcriptional function. TPT effects on HIF1α and p53-related transcriptional targets were assessed by PCR. Associations between TPT effects and TOPO1 expression levels were examined by Western blots and knockdown by siRNA. RNA-binding protein immunoprecipitation was used to assess if TOPO1 was resident on HIF1α mRNA. We determined if sublethal doses of TPT, used to knockdown HIF1α, reversed hypoxia-related cisplatin and paclitaxel resistance (XTT assay). Flow cytometry was used to assess HIF1α-mediated upregulation of ABCB1 and ABCB5 efflux pump expression. We found that HIF1α binding to, and inhibition of, p53 transcriptional activity in hypoxic ovarian cancer cells was associated with drug resistance. TPT-mediated downregulation of HIF1α in hypoxic cells required TOPO1 resident on HIF1α mRNA, restored p53 transcriptional activity, downregulated ABCB1/ABCB5 cell surface expression, and reversed hypoxia-related cisplatin and paclitaxel resistance. IMPLICATIONS: TPT-mediated reduction of HIF1α accumulation in hypoxic ovarian cancer cell lines restores p53 tumor-suppressor function, offering a novel approach to reverse chemoresistance. Further clinical investigation is warranted.

Phase II study of pazopanib in combination with paclitaxel in patients with metastatic melanoma.

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 ß, 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.

Lycopene enhances docetaxel's effect in castration-resistant prostate cancer associated with insulin-like growth factor I receptor levels.

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.

Anti-angiogenic effects of resveratrol mediated by decreased VEGF and increased TSP1 expression in melanoma-endothelial cell co-culture.

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.

Predictive and prognostic angiogenic markers in a gynecologic oncology group phase II trial of bevacizumab in recurrent and persistent ovarian or peritoneal cancer.

OBJECTIVE: Potential predictive/prognostic angiogenic markers were prospectively examined in a phase II trial of bevacizumab in epithelial ovarian cancer (EOC)/primary peritoneal cancer (PPC). METHODS: Recurrent/persistent EOC/PPC patients were treated with bevacizumab (15 mg/kg IV q21days) until disease progression. Validated-immunohistochemistry (IHC) assays were performed on pre-cycle 1/4 tumor biopsies for CD31-microvessel density (MVD), VEGF-histoscore (HS), p53-HS, and TSP1 image analysis score (IA). Pre-cycle 1/4 serum and plasma VEGF were quantified using a validated-ELISA. RESULTS: CD31-MVD and serum VEGF, evaluated pre-cycle 1 in 41/61 and 51/61 eligible patients, respectively, did not appear to be correlated. High CD31-MVD, categorized at the median, appeared to be associated with tumor response, a 13-month shorter median survival, and an increased risk of death (unadjusted hazard ratio [HR] = 2.2, 95% confidence interval [CI] = 1.067-4.467). In addition, each standard deviation (SD) increase in CD31-MVD appeared to be associated with worse survival in unadjusted and adjusted analyses. IHC and plasma biomarkers did not change with bevacizumab treatment except for serum VEGF, which appeared to decrease during bevacizumab treatment. This decrease was not associated with response. High pre-cycle 1 serum VEGF, categorized at the median, was associated with 22-month shorter median survival and an increased risk of death (unadjusted HR = 2.7, 95% CI = 1.369-5.191). Categorized p53 appeared to be associated with unadjusted survival and each SD increase in TSP1-IA appeared to be associated with a decreased risk of progression in unadjusted and adjusted analyses. CONCLUSIONS: Despite the limitations in sample size and exploratory nature of the study, angiogenic markers in tumor and serum may provide prognostic value in recurrent/persistent EOC/PPC, and are being prospectively evaluated in the GOG phase III trial of carboplatin, paclitaxel and bevacizumab/placebo in previously untreated EOC/PPC.