New insights into cancer cell^specific biological pathways are urgently needed to promote development of rationally targeted therapeutics. Reactive oxygen species (ROS) and their role in cancer cell response to growth factor signaling and hypoxia are emerging as verdant areas of exploration on the road to discovering cancer's Achilles heel. One of the distinguishing and nearuniversal hallmarks of cancer growth is hypoxia. Unregulated cellular proliferation leads to formation of cellular masses that extend beyond the resting vasculature, resulting in oxygen and nutrient deprivation. The resulting hypoxia triggers a number of critical adaptations that enable cancer cell survival, including apoptosis suppression, altered glucose metabolism, and an angiogenic phenotype. Ironically, recent investigations suggest that oxygen depletion stimulates mitochondria to elaborate increased ROS, with subsequent activation of signaling pathways, such as hypoxia inducible factor 1a, that promote cancer cell survival and tumor growth. Because mitochondria are key organelles involved in chemotherapy-induced apoptosis induction, the relationship between mitochondria, ROS signaling, and activation of survival pathways under hypoxic conditions has been the subject of increased study. Insights into mechanisms involved in ROS signaling may offer novel avenues to facilitate discovery of cancer-specific therapies. Preclinical and clinical evaluation of agents that modify ROS signaling in cancer offers a novel avenue for intervention. This review will cover recent work in ROS-mediated signaling in cancer cells and its potential as a target for developmental therapeutics.
totic phenotype in the transformed cell. This conceptual frameThe human melanocyte is continuously exposed to intrinsic and work offers testable steps to determine the role of redox extrinsic sources of reactive biochemical species, but is finely tuned via the intrinsic anti-oxidant and radical properties of alterations in the carcinogenic evolution, prevention and treatmelanin to suppress the build-up of an altered redox phenoment of melanoma and other diseases of the melanocyte. type. We propose that this control is lost during melanomageKey words: Transcription factor, NF-kB, AP-1, Reactive nesis and inappropriate redox-sensitive transcriptional factor oxygen species, Glutathione, Superoxide anion activations occur which result in enhancement of an anti-apopand glutathione (GSH), melanin as an anti-oxidant and cellular pro-oxidant, response of melanin to ultraviolet (UV) light, anti-oxidant levels and melanomagenesis, redox regulation of transcription factors, and a conceptual framework for the pathogenesis of melanoma based on altered redox control.In response to UV light an inflammatory response is generated involving the production of massive amounts of various cytokines and growth factors by keratinocytes, a vigorous inflammatory/immunologic host response, and in some cases angiogenesis. Each one of these responses generates or stimulates the production of reactive oxygen or nitrogen species. Additionally, UV light interacts directly with biochemical constituents of the melanocyte to generate intracellular reactive oxygen species (ROS), hydrogen peroxide and/or superoxide anion. The sum total of these alterations is that melanocytes are subjected to an panoply of redox changes with secondary effects on melanin synthesis and a variety of signaling cascades.We suggest that alterations in these processes are fundamentally involved in the pathogenesis of melanoma and perhaps other pathologic states. These observations encum-
A B S T R A C T PurposeMetastatic melanoma, a highly vascularized tumor with strong expression of vascular endothelial growth factor, has an overall poor prognosis. We conducted a placebo-controlled, double-blind phase II study of carboplatin plus paclitaxel with or without bevacizumab in patients with previously untreated metastatic melanoma. Patients and MethodsPatients were randomly assigned in a two-to-one ratio to carboplatin (area under the curve, 5) plus paclitaxel (175 mg/m 2 ) and bevacizumab (15 mg/kg; CPB) or placebo (CP) administered intravenously once every 3 weeks. Progression-free survival (PFS) was the primary end point. Secondary end points included overall survival (OS) and safety. ResultsTwo hundred fourteen patients (73% with M1c disease) were randomly assigned. With a median follow-up of 13 months, median PFS was 4.2 months for the CP arm (n ϭ 71) and 5.6 months for the CPB arm (n ϭ 143; hazard ratio [HR], 0.78; P ϭ .1414). Overall response rates were 16.4% and 25.5%, respectively (P ϭ .1577). With 13-month follow-up, median OS was 8.6 months in the CP arm versus 12.3 months in the CPB arm (HR, 0.67; P ϭ .0366), whereas in an evaluation 4 months later, it was 9.2 versus 12.3 months, respectively (HR, 0.79; P ϭ .1916). In patients with elevated serum lactate dehydrogenase (n ϭ 84), median PFS and OS were longer in the CPB arm (PFS: 4.4 v 2.7 months; HR, 0.62; OS: 8.5 v 7.5 months; HR, 0.52). No new safety signals were observed. ConclusionThe study did not meet the primary objective of statistically significant improvement in PFS with the addition of bevacizumab to carboplatin plus paclitaxel. A larger phase III study will be necessary to determine whether there is benefit to the addition of bevacizumab to carboplatin plus paclitaxel in this disease setting.
Purpose: To evaluate if diastolic blood pressure (dBP) !90 mm Hg during axitinib treatment is a marker of efficacy.Experimental Design: The relationship between dBP !90 mm Hg and efficacy was retrospectively explored across 5 phase II studies of single-agent axitinib for the treatment of 4 different tumor types. All patients had baseline BP 140/90 mm Hg and were stratified into 2 groups based on in-clinic BP measurements after initiating therapy: those with dBP <90 mm Hg throughout therapy and those with at least 1 dBP !90 mm Hg. Median overall survival (mOS), median progression-free survival (mPFS), objective response rate (ORR), and adverse events were evaluated by dBP group in individual and pooled analyses.Results: Two-hundred thirty patients were evaluated. Patients with dBP !90 mm Hg had a significantly lower relative risk of death than those with dBP <90 mm Hg [adjusted HR (95% CI) ¼ 0.55 (0.39, 0.77); P < 0.001]. The relative risk of progression was also lower in patients with dBP !90 mm Hg [HR (95% CI) ¼ 0.76 (0.54, 1.06), P ¼ 0.107], and ORR was significantly higher (43.9% vs. 12.0%; P < 0.001). In an 8-week landmark analysis, mOS (25.8 vs. 14.9 months) and mPFS (10.2 vs. 7.1 months) were greater for patients in the !90 mm Hg group. Adverse events were similar between groups.Conclusions: Axitinib efficacy correlated with dBP !90 mm Hg. Further investigation of dBP as a predictive biomarker of efficacy in patients receiving axitinib is warranted.
Purpose:To investigate the association between parameters obtained from dynamic contrast enhanced MRI (DCE-MRI) of breast cancer using different analysis approaches, as well as their correlation with angiogenesis biomarkers (vascular endothelial growth factor and vessel density).Materials and Methods: DCE-MRI results were obtained from 105 patients with breast cancer (108 lesions). Three analysis methods were applied: 1) whole tumor analysis, 2) regional hot-spot analysis, and 3) intratumor pixel-by-pixel analysis. Early enhancement intensities and fitted pharmacokinetic parameters were studied. Paraffin blocks of 71 surgically resected specimens were analyzed by immunohistochemical staining to measure microvessel counts (with CD31) and vascular endothelial growth factor (VEGF) expression levels.Results: MRI parameters obtained from the three analysis methods showed significant correlations (P Ͻ 0.0001), but a substantial dispersion from the linear regression line was noted (r ϭ 0.72-0.97). The entire region of interest (ROI) vs. pixel population analyses had a significantly higher association compared to the entire ROI vs. hot-spot analyses. Cancer specimens with high VEGF expression had significantly higher CD31 microvessel densities than did specimens with low VEGF levels (P Ͻ 0.005). No significant association was found between MRI parameters obtained from the three analysis strategies and IHC based measurements of angiogenesis. Conclusion:A consistent analysis strategy was important in the DCE-MRI study. In this series, none of these strategies yielded results for MRI based quantitation of tumor vascularity that were associated with IHC based measurements. Therefore, different analyses could not account for the lack of association.
Nearly 30% of women with early-stage breast cancer develop recurrent disease attributed to resistance to systemic therapy. Prevailing models of chemotherapy failure describe three resistant phenotypes: cells with alterations in transmembrane drug transport, increased detoxification and repair pathways, and alterations leading to failure of apoptosis. Proliferative activity correlates with tumor sensitivity. Cell-cycle status, controlling proliferation, depends on local concentration of oxygen and nutrients. Although physiologic resistance due to diffusion gradients of these substances and drugs is a recognized phenomenon, it has been difficult to quantify its role with any accuracy that can be exploited clinically. We implement a mathematical model of tumor drug response that hypothesizes specific functional relationships linking tumor growth and regression to the underlying phenotype. The model incorporates the effects of local drug, oxygen, and nutrient concentrations within the three-dimensional tumor volume, and includes the experimentally observed resistant phenotypes of individual cells. We conclude that this integrative method, tightly coupling computational modeling with biological data, enhances the value of knowledge gained from current pharmacokinetic measurements, and, further, that such an approach could predict resistance based on specific tumor properties and thus improve treatment outcome. [Cancer Res 2009;69(10):4484-92]
The successful treatment of melanoma has been hampered by the unique biology of this cancer. Fortunately, research to further our understanding of how melanoma cells differ from normal tissues has led to the discovery of potential new avenues of attack. One promising strategy relates to targeting the excess free radicals produced by melanomas. Melanocyte transformation into cancer is associated with significant structural alterations in the melanosome. In addition to pigment production, melanosomes also protect the cell by scavenging free radicals generated by sunlight and cellular metabolism. In melanoma, the disrupted and disorganized melanosome structure reverses this process. Melanosomes found in melanoma produce free radicals, such as hydrogen peroxide, furthering DNA damage. Melanosome generation of reactive oxygen species (ROS), in tandem with those generated by cancer metabolism, activate cellular signal transduction pathways that prevent cell death. ROS activation of proto-oncogene pathways in melanoma contributes to their resistance to chemotherapy. Fortunately, it may be possible to target these free radicals, just as Paris was able to successfully target Achilles' heel. The use of agents that block ROS scavenging, such as ATN-224 and disulfiram, have been explored clinically. A recent randomized Phase II trial with elesclomol, an agent that generates ROS, in combination with paclitaxel led to improved patient survival, suggesting that this may be a viable approach to advance the treatment of melanoma.
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.
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