Moneo V.,PharmaMar R and D |
Serelde B.G.,Spanish National Cancer Center |
Blanco-Aparicio C.,Spanish National Cancer Center |
Diaz-Uriarte R.,Spanish National Cancer Center |
And 6 more authors.
BMC Cancer | Year: 2014
Background: Zalypsis® is a marine compound in phase II clinical trials for multiple myeloma, cervical and endometrial cancer, and Ewing's sarcoma. However, the determinants of the response to Zalypsis are not well known. The identification of biomarkers for Zalypsis activity would also contribute to broaden the spectrum of tumors by selecting those patients more likely to respond to this therapy.Methods: Using in vitro drug sensitivity data coupled with a set of molecular data from a panel of sarcoma cell lines, we developed molecular signatures that predict sensitivity to Zalypsis. We verified these results in culture and in vivo xenograft studies.Results: Zalypsis resistance was dependent on the expression levels of PDGFRα or constitutive phosphorylation of c-Kit, indicating that the activation of tyrosine kinase receptors (TKRs) may determine resistance to Zalypsis. To validate our observation, we measured the levels of total and active (phosphorylated) forms of the RTKs PDGFRα/β, c-Kit, and EGFR in a new panel of diverse solid tumor cell lines and found that the IC50 to the drug correlated with RTK activation in this new panel. We further tested our predictions about Zalypsis determinants for response in vivo in xenograft models. All cells lines expressing low levels of RTK signaling were sensitive to Zalypsis in vivo, whereas all cell lines except two with high levels of RTK signaling were resistant to the drug.Conclusions: RTK activation might provide important signals to overcome the cytotoxicity of Zalypsis and should be taken into consideration in current and future clinical trials. © 2014 Moneo et al.; licensee BioMed Central Ltd.
Steiner N.,Innsbruck Medical University |
Ribatti D.,University of Bari |
Ribatti D.,Italian National Cancer Institute |
Willenbacher W.,Innsbruck Medical University |
And 11 more authors.
Oncotarget | Year: 2015
Purpose: The prognosis of patients with multiple myeloma (MM) is still dismal despite recent improvements achieved by introducing new therapeutic agents. However, there remains an urgent need for progress in myeloma drug development. We here show that novel marine-derived compounds can exert potent anti-myeloma activity. Experimental Design: Nine marine-derived compounds were applied at low nM concentrations (0.1-100 nM) to MM cell lines (OPM-2, NCI-H929, U266, RPMI-8226), to primary human myeloma cells and to peripheral blood mononuclear cells. Apoptosis was determined by flow cytometry. In addition, eGFP-transgenic MM cell lines growing with mesenchymal cells from bone marrow were used to visualize tumors by fluorescence stereomicroscopy. Anti-myeloma activities were studied in vitro in 3D spheroids and in vivo in myeloma xenografts on chicken embryos. Tumor size was analyzed by measuring GFP content with a GFP ELISA. Anti-angiogenic activities of compounds were tested in an in vivo gelatin sponge assay with conditioned media from primary bone marrow-derived endothelial cells. Results: We identified a subset of marine compounds with strong anti-myeloma activity in vitro and in vivo. Moreover, some of the compounds inhibited myeloma-related angiogenesis in the in vivo gelatin sponge assay. They merit further drug development to improve treatment options for MM.
Vidal L.,Royal Marsden Hospital |
Magem M.,08907 Lhospitalet Of Llobregat |
Barlow C.,Royal Marsden Hospital |
Pardo B.,08907 Lhospitalet Of Llobregat |
And 7 more authors.
Investigational New Drugs | Year: 2012
Purpose: This study intended to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RD) of trabectedin combined with carboplatin in patients with advanced solid tumors. Patients and methods: Carboplatin-pretreated patients received carboplatin AUC 4 (Group 1), whereas carboplatin-naïve patients received carboplatin AUC 5 (Group 2) as a 1-h i.v. infusion followed by trabectedin at dose range from 0.5-1.2 mg/m 2 in the schedule of 3-h/every-3-weeks. Pharmacokinetic (PK) sampling was performed in the first 2 cycles. Results: Forty-four patients were treated and evaluable for safety and dose-limiting toxicities (DLTs). In Group 1, at trabectedin 1.0 mg/m 2, cumulative hematological toxicity was found in all patients and 1/10 patients had DLTs. The RD was considered trabectedin 0.8 mg/m 2 combined with carboplatin AUC 4. Although no DLT occurred at this dose level, frequent dose delays (28.6%) and the 4-week cycle re-scheduling (66.7%) were required. In Group 2, DLTs occurred at trabectedin 0.8 mg/m 2 (3/8 patients), 1.0 mg/m 2 (3/10 patients) and 1.2 mg/m 2 (2/2 patients) with cumulative hematological toxicity associated with an important number of transfusions. In this group, neither the MTD nor the RD were established. Promising antitumor activity was found for this carboplatin/trabectedin combination; especially in patients with advanced ovarian cancer and soft tissue sarcoma. No significant PK drug-drug interaction occurred. Conclusions: This study established a trabectedin dose of 0.8 mg/m 2 combined with carboplatin AUC 4 and given every 4 weeks as the most feasible schedule in carboplatin-pretreated patients. Dose and cycle recommendations for carboplatin-naïve patients warrant further evaluation. © Springer Science+Business Media, LLC 2010.
Barboza N.M.,University of New Brunswick |
Medina D.J.,University of New Brunswick |
Budak-Alpdogan T.,University of New Brunswick |
Aracil M.,PharmaMar R and D |
And 3 more authors.
Cancer Biology and Therapy | Year: 2012
Plitidepsin (Aplidin), an antitumor agent of marine origin, presently is undergoing phase II/III clinical trials, and has shown promise for the treatment of lymphoma. Here, we describe the antitumor effects of plitidepsin alone and in combination with rituximab and investigated the effects of each drug and the combination on the cell cycle and mechanism of cell death. Several Diffuse Large Cell Lymphoma (DLCL) lines and Burkitt cell lines were tested for sensitivity to plitidepsin and rituximab. All DLCL and Burkitt lymphoma cell lines were inhibited by plitidepsin in nanomolar concentrations, while rituximab sensitivity varied among different cell lines. Ramos and the RL cell lines proved sensitive to rituximab and were used to test the effects of each of the two drugs. The two agents exhibited synergism at all tested concentrations. For in vivo studies, irradiated athymic nude mice were engrafted with the Ramos lymphoma. Treatment was initiated when the tumors were ~0.5 cm in diameter, and toxic and therapeutic effects were monitored. In the in vivo study, additive effects of the combined two drugs, was demonstrated without an increase in host toxicity. The in vitro synergy and the in vivo additive antitumor effects without an increase in host toxicity with two relatively non-marrow suppressive agents encourages further development of this combination for treatment of aggressive B-cell lymphomas. © 2012 Landes Bioscience.