epothilone-a and Osteosarcoma

Systemic therapy has improved osteosarcoma event-free and overall survival, but 30-50% of patients originally diagnosed will have progressive or recurrent disease, which is difficult to cure. Osteosarcoma has a complex karyotype, with loss of p53 in the vast majority of cases and an absence of recurrent, targetable pathways. In this study, we explored 54 agents that are clinically approved for other oncologic indications, agents in active clinical development, and others with promising preclinical data in osteosarcoma at clinically achievable concentrations in 5 osteosarcoma cell lines. We found significant single-agent activity of multiple agents and tested 10 drugs in all permutations of two-drug combinations to define synergistic combinations by Chou and Talalay analysis. We then evaluated order of addition to choose the combinations that may be best to translate to the clinic. We conclude that the repurposing of chemotherapeutics in osteosarcoma by using an in vitro system may define novel drug combinations with significant in vivo activity. In particular, combinations of proteasome inhibitors with histone deacetylase inhibitors and ixabepilone and MK1775 demonstrated excellent activity in our assays.

Topics: Animals; Apoptosis; Bone Neoplasms; Cell Survival; Drug Synergism; Drug Therapy, Combination; Epothilones; Female; Histone Deacetylase Inhibitors; Humans; Mice; Mice, Inbred C57BL; Mice, Nude; Middle Aged; Osteosarcoma; Proteasome Inhibitors; Pyrazoles; Pyrimidines; Pyrimidinones; Transplantation, Heterologous; Tumor Cells, Cultured

Vinca alkaloids, agents that cause depolymerization of microtubules, are highly active in treatment of many pediatric cancers. In contrast, taxanes, agents that stabilize microtubules, are far less effective against the same cancer types. The purpose of the current study was to evaluate the antitumor activity of ixabepilone, an epothilone B derivative representing a new class of microtubule-stabilizing antimitotic agent in a wide variety of pediatric solid tumor models.. Ixabepilone was administered i.v. every 4 days for three doses to scid mice bearing s.c. human rhabdomyosarcoma (three lines), neuroblastoma (four), Wilms' tumors (six), osteosarcoma (four), or brain tumors (seven). Tumor diameters were measured weekly, and tumor growth or regressions were determined. Pharmacokinetic studies were done following a single administration of drug at the maximum tolerated dose (MTD) level (10 mg/kg).. At the MTD (10 mg/kg), ixabepilone induced objective responses (all tumors in a group achieved > or = 50% volume regression) in three of three rhabdomyosarcoma lines, three of five neuroblastomas, six of seven Wilms' tumor models, two of six osteosarcoma, and four of eight brain tumor models. However, the dose-response curve was steep with only 2 of 19 tumors models regressing (> or = 50%) at 4.4 mg/kg. In comparison, paclitaxel administered at the MTD on the same schedule failed to induce objective regressions of three tumor lines that were highly sensitive to treatment with ixabepilone. Pharmacokinetics following single i.v. administration of ixabepilone at its MTD (10 mg/kg) were biexponential with C(max) of 12.5 micromol/L, elimination half-life of 19.2 hours, and total area under the curve of 5.8 micromol/L-h. The achieved drug exposure of ixabepilone at this efficacious MTD dose level in mice is similar to those achieved in patients given the recommended phase II dose of 40 mg/m2 by either 1- or 3-hour infusion every 3 weeks, a regimen that has shown significant anticancer activity in phase II clinical trials in adult patients.. Administered at doses ranging from 66% to 100% of its MTD in mice, the epothilone B derivative ixabepilone shows broad spectrum activity against a panel of pediatric tumor xenograft models. Pharmacokinetic analysis indicates that the systemic ixabepilone exposure achieved in mice at its MTD is similar to that achieved in patients at the recommended phase II dose of 40 mg/m2 administered every 3 weeks. Importantly, the present results showed a clear distinction in sensitivity of pediatric solid tumors to this epothilone derivative compared with paclitaxel.

Topics: Animals; Area Under Curve; Brain Neoplasms; Cell Line, Tumor; Clinical Trials as Topic; Disease Models, Animal; Dose-Response Relationship, Drug; Epothilones; Female; Humans; Maximum Tolerated Dose; Mice; Mice, SCID; Microtubules; Mitosis; Models, Chemical; Neoplasm Transplantation; Neuroblastoma; Osteosarcoma; Paclitaxel; Rhabdomyosarcoma; Time Factors; Treatment Outcome; Vinca Alkaloids; Wilms Tumor