epothilone-a and Glioblastoma

Common care for glioblastoma multiforme (GBM) is a surgical resection followed by radiotherapy and temozolomide- (TMZ-) based chemotherapy. Unfortunately, these therapies remain inadequate involving severe mortality and recurrence. Recently, new approaches discovering combinations of multiple inhibitors have been proposed along with the identification of key driver mutations that are specific to each patient. To date, this approach is still limited by the lack of effective therapy. Hopefully, novel compounds derived from natural products are suggested as potential solutions. Inhibitory effects of natural products on angiogenesis and metastasis and cancer suppressive effect of altering miRNA expression are provident discoveries.

Topics: Angelica sinensis; Animals; Antineoplastic Agents; Apoptosis; Benzopyrans; Epothilones; Glioblastoma; Humans; MicroRNAs; RNA, Neoplasm; Serratia marcescens

Patients with glioblastoma (GBM) inevitably develop recurrent or progressive disease after initial multimodal treatment and have a median survival of 6-9 months from time of progression. To date, there is no accepted standard treatment for GBM relapse or progression. Patupilone (EPO906) is a novel natural microtubule-stabilizing cytotoxic agent that crosses the blood-brain barrier and has been found to have preclinical activity in glioma models.. This is a single-institution, early-phase I/II trial of GBM patients with tumor progression who qualified for second surgery with the goal of evaluating efficacy and safety of the single-agent patupilone (10 mg/m(2), every 3 weeks). Patients received patupilone 1 week prior to second surgery and every 3 weeks thereafter until tumor progression or toxicity. Primary end points were progression-free survival (PFS) and overall survival (OS) at 6 months as well as patupilone concentration in tumor tissue. Secondary end points were toxicity, patupilone concentration in plasma and translational analyses for predictive biomarkers.. Nine patients with a mean age of 54.6 ± 8.6 years were recruited between June 2008 and April 2010. Median survival and 1-year OS after second surgery were 11 months (95% CI, 5-17 months) and 45% (95% CI, 14-76), respectively. Median PFS was 1.5 months (95% CI, 1.3-1.7 months) and PFS6 was 22% (95% CI, 0-46), with 2 patients remaining recurrence-free at 9.75 and 22 months. At the time of surgery, the concentration of patupilone in tumor tissue was 30 times higher than in the plasma. Tumor response was not predictable by the tested biomarkers. Treatment was generally well tolerated with no hematological, but cumulative, though reversible sensory neuropathy grade ≤3 was seen in 2 patients (22%) at 8 months and grade 4 diarrhea in the 2nd patient (11%). Non-patupilone-related peri-operative complications occurred in 2 patients resulting in discontinuation of patupilone therapy. There were no neurocognitive changes 3 months after surgery compared to baseline.. In recurrent GBM, patupilone can be given safely pre- and postoperatively. The drug accumulates in the tumor tissue. The treatment results in long-term PFS in some patients. Patupilone represents a valuable novel compound which deserves further evaluation in combination with radiation therapy in patients with GBM.

Topics: Aged; Antineoplastic Agents; Apoptosis; Brain Neoplasms; Central Nervous System Neoplasms; Combined Modality Therapy; Epothilones; Glioblastoma; Humans; Ki-67 Antigen; Middle Aged; Neoplasm Recurrence, Local; Treatment Outcome; Tubulin

Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models.. Patients with first recurrence/progression of glioblastoma were eligible for this early phase II and pharmacokinetic study exploring single-agent sagopilone (16 mg/m(2) over 3 h every 21 days). Primary end point was a composite of either tumor response or being alive and progression free at 6 months. Overall survival, toxicity and safety and pharmacokinetics were secondary end points.. Thirty-eight (evaluable 37) patients were included. Treatment was well tolerated, and neuropathy occurred in 46% patients [mild (grade 1) : 32%]. No objective responses were seen. The progression-free survival (PFS) rate at 6 months was 6.7% [95% confidence interval (CI) 1.3-18.7], the median PFS was just over 6 weeks, and the median overall survival was 7.6 months (95% CI 5.3-12.3), with a 1-year survival rate of 31.6% (95% CI 17.7-46.4). Maximum plasma concentrations were reached at the end of the 3-h infusion, with rapid declines within 30 min after termination.. No evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected. Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administration.

Topics: Adult; Aged; Antineoplastic Agents; Astrocytoma; Benzothiazoles; Brain Neoplasms; Disease Progression; Disease-Free Survival; Epothilones; Female; Glioblastoma; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Recurrence, Local; Young Adult

Invasion of normal brain tissue by tumor cells is a major contributing factor to the recurrence of glioblastoma and its resistance to therapy. Here, we have assessed the efficacy of the microtubule (MT) targeting agent Epothilone B (patupilone) on glioblastoma cell migration, a prerequisite for invasive tumor cell behavior. At non-cytotoxic concentrations, patupilone inhibited glioblastoma cell movement, as shown by transwell cell migration, random motility and spheroid assays. This anti-migratory effect was associated with a reduced accumulation of EB1 and other MT plus end tracking proteins at MT ends and with the induction of MT catastrophes, while the MT growth rate and other MT dynamic instability parameters remained unaltered. An increase in MT catastrophes led to the reduction of the number of MTs reaching the leading edge. Analysis of the effect of patupilone on MT dynamics in a reconstituted in vitro system demonstrated that the induction of MT catastrophes and an alteration of EB1 accumulation at MT plus end are intrinsic properties of patupilone activity. We have thus demonstrated that patupilone antagonizes glioblastoma cell migration by a novel mechanism, which is distinct from suppression of MT dynamic instability. Taken together, our results suggest that EB proteins may represent a new potential target for anti-cancer therapy in highly invasive tumors.

Topics: Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Epothilones; Glioblastoma; Humans; Microtubule-Associated Proteins; Microtubules; Tubulin Modulators

The clinical resistance of glioblastomas to chemotherapeutic agents can be attributed to drug efflux pumps, such as P-glycoprotein, which contributes to reduce drug efficacy. The present study examined the utility of epothilone B, which is not a substrate for P-glycoprotein, on glioblastoma cells.. In vitro methods with glioblastoma cells varying in p53 status were used to assess the efficacy of epothilone B to induce anti-neoplastic responses. Immunofluorescence and ELISA procedures were used to examine levels of tubulin and survivin in epothilone B treated glioblastoma cells, while acridine orange labeling was used to detect the mode of epothilone B induced cell death.. A clinically achievable concentration of epothilone B induced a cytotoxic response in p53 mutant glioblastoma cells, as a consequence of survivin down-regulation and tubulin redistribution, while a cytostatic response was observed in p53 null glioblastoma cells with a modest increase in survivin expression post-epothilone B treatment. However, p53 wild-type glioblastoma cells did not sustain a positive anti-tumorigenic response to epothilone B.. Epothilone B, induced positive differential responses in glioblastoma cells with abnormal p53 status, but not in p53 wild-type cells. This suggests that epothilone B is a potential alternative to classic microtubule inhibiting agents (ie vincristine, paclitaxel) used to treat clinical glioblastomas with p53 mutations.

Topics: Apoptosis; Blotting, Western; Brain Neoplasms; Cell Proliferation; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Epothilones; Fluorescent Antibody Technique; Gentian Violet; Glioblastoma; Humans; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins; Mutation; Neoplasm Proteins; Survivin; Tubulin; Tubulin Modulators; Tumor Cells, Cultured; Tumor Stem Cell Assay; Tumor Suppressor Protein p53

The oncogenic epidermal growth factor receptor (EGFR) pathway triggers downstream phosphatidylinositol 3-kinase (PI3K)/RAS-mediated signaling cascades. In transgenic mice, glioblastoma cannot develop on single but only on simultaneous activation of the EGFR signaling mediators RAS and AKT. However, complete blockade of EGFR activation does not result in apoptosis in human glioblastoma cells, suggesting additional cross-talk between downstream pathways. Based on these observations, we investigated combination therapies using protein kinase inhibitors against EGFR, platelet-derived growth factor receptor, and mammalian target of rapamycin, assessing glioblastoma cell survival. Clinically relevant doses of AEE788, Gleevec (imatinib), and RAD001 (everolimus), alone or in combinations, did not induce glioblastoma cell apoptosis. In contrast, simultaneous inactivation of the EGFR downstream targets mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase and PI3K by U0126 and wortmannin triggered rapid tumor cell death. Blocking EGFR with AEE788 in combination with sublethal concentrations of the microtubule stabilizer patupilone also induced apoptosis and reduced cell proliferation in glioblastoma cells, accompanied by reduced AKT and ERK activity. These data underline the critical role of the PI3K/AKT and the RAS/RAF/mitogen-activated protein/ERK kinase/ERK signaling cascades in the cell-intrinsic survival program of sensitive glioblastoma cell lines. We conclude that drug combinations, which down-regulate both ERK and protein kinase B/AKT activity, may prove effective in overcoming cell resistance in a subgroup of glioblastoma.

Topics: Apoptosis; Benzamides; Blotting, Western; Cell Cycle; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epothilones; ErbB Receptors; Everolimus; Glioblastoma; Humans; Imatinib Mesylate; Immunosuppressive Agents; MAP Kinase Kinase 1; Microtubules; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phorbol Esters; Phosphatidylinositol 3-Kinases; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Purines; Pyrimidines; Signal Transduction; Sirolimus; Tumor Cells, Cultured