Asbestos Cancer Update 2010

 The epothilones and their analogs constitute a novel class of antineoplastic agents, produced by the myxobacterium Sorangium cellulosum. These antimicrotubule agents act in a similar manner to taxanes, stabilizing microtubules and resulting in arrested tumor cell division and apoptosis. Unlike taxanes, however, epothilones and their analogs are macrolide antibiotics, with a distinct tubulin binding mode and reduced susceptibility to a range of common tumor resistance mechanisms that limit the effectiveness of taxanes and anthracyclines. While natural epothilones A and B show potent antineoplastic activity in vitro, these effects were not seen in preclinical in vivo models due to their poor metabolic stability and unfavorable pharmacokinetics. A range of epothilone analogs was synthesized, therefore, with the aim of identifying those with more favorable characteristics. Here, we describe the preclinical characterization and selection of ixabepilone, a semi-synthetic epothilone B analog, among many other epothilone analogs. Ixabepilone demonstrated superior preclinical characteristics, including high metabolic stability, low plasma protein binding and low susceptibility to multidrug resistance protein-mediated efflux, all of which were predictive of potent in vivo cell-killing activity. Ixabepilone also demonstrated in vivo antitumor activity in a range of human tumor models, several of which displayed resistance to commonly used agents such as anthracyclines and taxanes. These favorable preclinical characteristics have since translated to the clinic. Ixabepilone has shown promising phase II clinical efficacy and acceptable tolerability in a wide range of cancers, including heavily pretreated and drug-resistant tumors. Based on these results, a randomized phase III trial was conducted in anthracycline-pretreated or resistant and taxane-resistant metastatic breast cancer to evaluate ixabepilone in combination with capecitabine. Ixabepilone combination therapy showed significantly superior progression-free survival and tumor responses over capecitabine alone.

PURPOSE: The epothilones are effective antitumor medications for patients with breast cancer, including patients who have been previously treated with or are resistant to anthracyclines or the taxanes. SUMMARY: With the best currently available therapies, the median survival time for patients with metastatic breast cancer is only 2-3 years, and many patients develop resistance to taxanes or other chemotherapy drugs. The epothilones are a novel class of antitumor medications, similar to the taxanes in some respects, but that also possess several advantages. Like taxanes, epothilones are believed to produce antitumor effects by binding to and stabilizing intracellular microtubules, which are essential in DNA replication and cell division.

Several in vitro and animal studies have shown that the epothilones are more potent microtubule stabilizers than the taxanes, they are effective against cancer cell lines with high levels of drug resistance, and they induce the regression of taxane-resistant human tumors. Preclinical studies also have demonstrated synergistic increases in tumor cell killing when the epothilones are combined with other antitumor medications. Epothilone B (patupilone) has been evaluated in a series of phase I and II clinical trials, which demonstrated disease stabilization or objective responses in patients with a variety of cancers, including ovarian, prostate, breast, colon, stomach, and kidney cancers. This agent is currently being evaluated in phase III clinical trials. A second epothilone, ixabepilone, was recently approved by the FDA for the treatment of metastatic breast cancer. Ixabepilone was evaluated as monotherapy for the treatment of breast cancer in phase II clinical trials of previously untreated patients and in taxane-experienced and taxane-resistant disease. A phase III clinical trial demonstrated that the combination of ixabepilone and capecitabine was superior to capecitabine alone in heavily pretreated, taxane-resistant patients. CONCLUSION: Ongoing clinical trials will continue to define the role of the epothilones in cancer therapy.

The search for novel chemotherapeutic agents in the treatment of breast cancer with lower susceptibility to resistance mechanisms than current agents has led to the discovery of the epothilones and their analogues. Epothilones stabilize microtubules in a manner similar to taxanes but are structurally distinct. Ixabepilone, an epothilone B analogue, having demonstrated high antimicrotubule activity in preclinical studies, has shown notable efficacy in phase II trials in patients with early-stage and metastatic breast cancer. Of particular note, single-agent ixabepilone is effective in tumors resistant to anthracyclines, taxanes, and capecitabine, for which there is currently no recommended therapy. Different mechanisms of action and the non-overlapping toxicities of ixabepilone with other agents provide the rationale for ixabepilone in combination as a valid therapeutic approach. Phase II results assessing ixabepilone in combination with capecitabine in anthracycline- and taxane-pretreated patients are promising. The investigation of ixabepilone in the neoadjuvant setting has also revealed potential biomarkers to predict ixabepilone response. Ixabepilone has demonstrated activity in patients with tumors that are estrogen receptor-, progesterone receptor-, and HER2-negative. The safety profile throughout the trials has been manageable, with peripheral neuropathy as one of the more notable adverse events, which has been mostly reversible. A phase III trial comparing ixabepilone plus capecitabine versus capecitabine alone demonstrated significant prolongation of median progression-free survival and reduction in relapse risk. Additionally, other members of the epothilone family, such as patupilone, ZK-EPO, BMS-310705, and KOS-862, have demonstrated efficacy against breast cancer in phase I clinical trials. Ongoing phase II/III trials continue to assess ixabepilone and other members of the epothilone family in breast cancer, particularly in combination regimens, as being valid treatment options in multidrug-resistant breast cancer.

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Health Informatics Research Group, Department of Information Studies, University of Sheffield, Sheffield, UK.

The aim of this study was to develop a tool for evaluating the quality of breast cancer information on the Internet from the perspective of patients and their families. A specific tool, Breast Cancer tool (BC tool), was developed based on the information needs of women with breast cancer and their families reported in the literature. The BC tool and other 3 generic tools (HON, IQ tool, Discern) were used to assess 40 breast cancer websites. The reliability and validity of each tool was examined and the time spent reviewing the websites was measured. The four tools were shown to have acceptable reliability (Cronbach’s alpha>0.7), convergent validity, especially the BC tool which was capable of distinguishing whether a website offers sufficient information for women and their families. However, the BC tool took more time than the other tools to use, suggesting relatively low feasibility. The results of this study reinforce the importance of developing specific tools from perspectives of patients and their family members.

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Departments of Cancer Biology and.

Oncogene-mediated signaling to the host environment induces a subset of cytokines and chemokines. The Drosophila Dac gene promotes migration of the morphogenetic furrow during eye development. Expression of the cell-fate determination factor Dachshund (DACH1) was lost in poor prognosis invasive breast cancer. Mouse embryo fibroblasts derived from Dach1(-/-) mice demonstrated endogenous Dach1 constitutively represses cellular migration. DACH1 inhibited cellular migration and invasion of oncogene (Ras, Myc, ErbB2, c-Raf)-transformed human breast epithelial cells. An unbiased proteomic analysis identified and immunoneutralizing antibody and reconstitution experiments demonstrated IL-8 is a critical target of DACH1 mediating breast cancer cellular migration and metastasis in vivo. DACH1 bound the endogenous IL-8 promoter in ChIP assays and repressed the IL-8 promoter through the AP-1 and NF-kappaB binding sites. Collectively, our data identify a pathway by which an endogenous cell-fate determination factor blocks oncogene-dependent tumor metastasis via a key heterotypic mediator.

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University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, 600 Highland Avenue K4/6 CSC, Madison, WI, 53792, USA, hhbailey@facstaff.wisc.edu.

PURPOSE: Perillyl alcohol (POH) is a naturally occurring lipid with preclinical activity against mammary carcinomas. We conducted a phase II multi-institutional study of oral POH administered four times daily in women with advanced treatment-refractory breast cancer. METHODS: Eligible women were treated with POH four times daily at 1,200-1,500 mg m(-2) dose(-1) on a 28-day cycle. Patients tolerating 1,200 mg m(-2) day(-1) four times daily after one cycle were dose-escalated to 1,500 mg/m(2). The primary endpoint was 1-year freedom-from-progression (FFP) rate. Secondary endpoints were response rate, tolerability and correlative evaluations. RESULTS: Twenty-nine cycles of POH were administered to 14 women. Three patients were dose-escalated to 1,500 mg/m(2). Grade 1 and grade 2 gastrointestinal effects and fatigue were predominant toxicities. Of seven patients receiving up to one cycle, three stopped therapy due to intolerance. Only two patients received more than two cycles, with disease stabilization of 3 and 8 months. Thirteen patients were evaluable for response. One-year FFP rate was zero. No objective responses were seen. The median time to progression was 35 days (95% CI, 29-123 days). Median overall survival was 389 days (95% CI, 202-776 days). Pharmacokinetic parameters were similar to previous investigations. The ability to correlate plasma TGF-beta1 levels with outcome was limited by lack of clinical benefit and inter- and intra-patient variability. CONCLUSIONS: Enrollment was suspended short of planned accrual because of lack of response and poor tolerance to POH. This regimen does not appear to provide benefit in advanced treatment-refractory breast carcinoma.

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Breast Center, Beijing Cancer Hospital and Institute, Peking University School of Oncology, 100036 Beijing, People’s Republic of China.

In vitro studies suggest that p53 codon 72 genotype alters the apoptotic capacity of p53 protein, with the 72 arginine (R) form of wild-type p53 harboring a greater apoptosis-inducing potential than the 72 proline (P) variant. The aim of this study was to investigate whether the association between the p53 codon 72 genotype and breast cancer survival was modified by p53 gene status. In our study, we examined the p53 codon 72 genotype and p53 mutations (through exons 4-9) in paraffin-embedded specimens from 414 breast cancer patients with a median follow-up of 8.2 years. We report that the p53 codon 72 genotype was significantly associated with disease-free survival (DFS, p = 0.02) but not with disease-specific survival (DSS, p = 0.24) in the entire study population (n = 414). In contrast, the codon 72 genotype was strongly associated with both DFS (p = 0.001) and DSS (p = 0.04) among patients with a wild-type p53 tumor (n = 346), patients with the P/P variant had worse DFS and DSS than did those with the P/R or R/R variant in this subgroup of patients. More importantly, as compared with the P/R or R/R variant, the P/P variant remained an independent prognostic factor of DFS among patients with a wild-type p53 tumor (HR = 2.5; 95%CI = 1.4-4.4; p = 0.003). We conclude that the effect of p53 codon 72 genotype on breast cancer survival is dependent on p53 gene status, the P/P variant is strongly associated with poor prognosis among patients with a wild-type p53 tumor. (c) 2008 Wiley-Liss, Inc.

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