Doxorubicin In Soft Tissue Sarcoma Research Articles

Synergistic activities of Panobinostat and doxorubicin in soft tissue sarcomas

BackgroundSoft tissue sarcomas (STS) are rare diseases typically arising from connective tissues in children and adults. However, chemotherapies involved in the treatment of STS may cause toxic side effects and multi-drug chemoresistance, making the treatment even more challenging. Histone deacetylase inhibitors (HDACi) are epigenetic agents which have shown anti-tumor effects as single agent as well as combination use with other drugs. Our project intends to prove the same effects in STS. MethodsPanobinostat (LBH589) plus doxorubicin was selected for investigations based on our previous research. Tumor xenografts were tried in an epithelioid sarcoma model to validate good synergy effects in vivo and a leiomyosarcoma model was used as a negative comparison group. Gene profile changes were studied afterwards. The possible pathway changes caused by HDACi were explored and validated by several assays. ResultsSynergy effect of LBH589 plus doxorubicin was successfully validated in STS cell lines and an epithelioid sarcoma mice model. We tried to reduce the dose of doxorubicin to a lower level and found the drug combination can still inhibit tumor size in mice. Furthermore, gene profile changes caused by LBH589 was studied by RNA-Sequencing analysis. Results showed LBH589 can exert effects on a group of target genes which can regulate potential biological functions especially in the cell cycle pathway.

Best Overall Response-Associated Signature to Doxorubicin in Soft Tissue Sarcomas: A Transcriptomic Analysis from ANNOUNCE.

This exploratory analysis evaluated the tumor samples of the patients treated with doxorubicin (with or without olaratumab) in a negative phase III ANNOUNCE trial to better understand the complexity of advanced soft tissue sarcomas (STS) and to potentially identify its predictive markers. RNA sequencing was performed on pretreatment tumor samples (n = 273) from the ANNOUNCE trial to evaluate response patterns and identify potential predictive treatment markers for doxorubicin. A BOR-associated signature to doxorubicin (REDSARC) was created by evaluating tumors with radiographic response versus progression. An external cohort of doxorubicin-treated patients from the Spanish Group for Research on Sarcomas (GEIS) was used for refinement and validation. A total of 259 samples from the trial were considered for analysis. Comparative analyses by the treatment arm did not explain the negative trial. However, there was an association between the BOR signature and histologic subtype (χ2P = 2.0e-7) and grade (P = 0.002). There were no associations between the BOR signature and gender, age, ethnicity, or stage. Applied to survival outcomes, REDSARC was also predictive for progression-free survival (PFS) and overall survival (OS). Using the GEIS cohort, a refined 25-gene signature was identified and applied to the ANNOUNCE cohort, where it was predictive of PFS and OS in leiomyosarcoma, liposarcoma, and other sarcoma subtypes, but not in undifferentiated pleomorphic sarcoma. The refined REDSARC signature provides a potential tool to direct the application of doxorubicin in sarcomas and other malignancies. Validation and further refinement of the signature in other potentially subtype specific prospective cohorts is recommended.

Economic evaluation of the GENESIS-SEFH report of olaratumab with doxorubicin in soft tissue sarcoma in advanced stages

ObjectiveThe economic evaluation of the drug olaratumab is carried out in the treatment of soft tissue sarcoma. MethodThe data were analyzed following the recommendations contained in the MADRE program of the GENESIS-SEFH report model. ResultsProgression free survival and overall survival results published in the pivotal clinical trial; Tap WD et al. (2016) were improvement of 2.5 months in median progression free survival (primary endpoint) HR = 0.672; IC95% (0.442-1.021) and gain of 11.8 months in median OS (secondary endpoint) HR = 0.463; IC95% (0.301-0.710).A cost-effectiveness analysis was performed considering 2 scenarios; scenario 1: with use of whole vials and scenario 2: use of whole vials and associating non-pharmacological costs (day hospital visits, mucositis, neutropenia and dexrazoxane use). In both cases we considered the cost of drugs and the efficacy data of the pivotal clinical trial. In Scenario 1, we would have an Incremental-Cost-Effectiveness-Ratio of €28,443.81/ month of progression-free survival and €72,560.74 per year of life gained and in scenario 2 we would have an incremental-cost-effectiveness-ratio of €30,879.79/ progression-free survival and €78,774.99/ year of life gained.The budgetary impact of this drug would range from €61,759,592 to €92,639,388 estimated to be 800 to 1,200 patients likely to receive treatment in Spain. ConclusionsOlaratumab is a drug that provides a significant benefit in overall survival but not in progression free survival.To be used in soft tissue sarcoma and to be cost-effective, the acquisition cost of the 500 mg vial should be between €101.91 and €506.54 and that of the 190 mg vial between €39.31 and €195.37.

Comparison between trabectedin and doxorubicin in soft-tissue sarcomas: a systematic review and meta-analysis.

BackgroundThis study sought to evaluate the differences between trabectedin and doxorubicin in the treatment of soft-tissue sarcoma (STS).MethodsMultiple databases, including PubMed, Web of Science, Cochrane Library, and China National Knowledge Infrastructure, were searched to retrieve relevant articles. Ultimately, the full text of 10 studies involving the use of trabectedin and doxorubicin in STS were reviewed. Review Manager 5.2 was used to evaluate the heterogeneity of the results of the selected articles. Forest plot, bias, and sensitivity analyses were carried out on the included articles.ResultsTen papers that met the criteria were included in this analysis. STS patients receiving trabectedin had longer progression-free survival than those receiving doxorubicin [overall mean difference (MD) =1.36, 95% confidence interval (CI): 1.04, 1.68, I2=6%, fixed-effects model]. The experimental group also had a longer overall survival period than the control group (MD =3.92, 95% CI: 0.23, 7.60, P=0.04 and I2=83%, random-effects model), and the experimental group had a better disease control rate than the control group (relative risk =1.2, P=0.03 and I2=45%, fixed-effects model). From the publication bias analysis and sensitivity analysis, we can guarantee the results are robust and unbiased.DiscussionOur research showed that STS patients who received trabectedin had better clinical effects and a longer survival time than those who received doxorubicin.

1402PD - Exposure-response of olaratumab for survival outcomes and safety when combined with doxorubicin in soft tissue sarcoma (STS) patients

1402PD - Exposure-response of olaratumab for survival outcomes and safety when combined with doxorubicin in soft tissue sarcoma (STS) patients

Down-Regulation of AKT Signalling by Ursolic Acid Induces Intrinsic Apoptosis and Sensitization to Doxorubicin in Soft Tissue Sarcoma.

Several important biological activities have been attributed to the pentacyclic triterpene ursolic acid (UA), being its antitumoral effect extensively studied in human adenocarcinomas. In this work, we focused on the efficacy and molecular mechanisms involved in the antitumoral effects of UA, as single agent or combined with doxorubicin (DXR), in human soft tissue sarcoma cells. UA (5–50 μM) strongly inhibited (up to 80%) the viability of STS cells at 24 h and its proliferation in soft agar, with higher concentrations increasing apoptotic death up to 30%. UA treatment (6–9 h) strongly blocked the survival AKT/GSK3β/β-catenin signalling pathway, which led to a concomitant reduction of the anti-apoptotic proteins c-Myc and p21, altogether resulting in the activation of intrinsic apoptosis. Interestingly, UA at low concentrations (10–15 μM) enhanced the antitumoral effects of DXR by up to 2-fold, while in parallel inhibiting DXR-induced AKT activation and p21 expression, two proteins implicated in antitumoral drug resistance and cell survival. In conclusion, UA is able to induce intrinsic apoptosis in human STS cells and also to sensitize these cells to DXR by blocking the AKT signalling pathway. Therefore, UA may have beneficial effects, if used as nutraceutical adjuvant during standard chemotherapy treatment of STS.

A four-arm randomized phase II trial with NGR-hTNF given at low or high dose with or without doxorubicin in soft tissue sarcomas (STS).

10525 Background: NGR-hTNF, a tumor targeted antivascular agent, exhibits a biphasic dose-response curve with activity shown at low dose (LD) or high dose (HD). Vascular effects at LD are driven by...

Salinomycin increases chemosensitivity to the effects of doxorubicin in soft tissue sarcomas

BackgroundChemotherapy for soft tissue sarcomas remains unsatisfactory due to their low chemosensitivity. Even the first line chemotherapeutic agent doxorubicin only yields a response rate of 18-29%. The antibiotic salinomycin, a potassium ionophore, has recently been shown to be a potent compound to deplete chemoresistant cells like cancer stem like cells (CSC) in adenocarcinomas. Here, we evaluated the effect of salinomycin on sarcoma cell lines, whereby salinomycin mono- and combination treatment with doxorubicin regimens were analyzed.MethodsTo evaluate the effect of salinomycin on fibrosarcoma, rhabdomyosarcoma and liposarcoma cell lines, cells were drug exposed in single and combined treatments, respectively. The effects of the corresponding treatments were monitored by cell viability assays, cell cycle analysis, caspase 3/7 and 9 activity assays. Further we analyzed NF-κB activity; p53, p21 and PUMA transcription levels, together with p53 expression and serine 15 phosphorylation.ResultsThe combination of salinomycin with doxorubicin enhanced caspase activation and increased the sub-G1 fraction. The combined treatment yielded higher NF-κB activity, and p53, p21 and PUMA transcription, whereas the salinomycin monotreatment did not cause any significant changes.ConclusionsSalinomycin increases the chemosensitivity of sarcoma cell lines - even at sub-lethal concentrations - to the cytostatic drug doxorubicin. These findings support a strategy to decrease the doxorubicin concentration in combination with salinomycin in order to reduce toxic side effects.

Nilotinib Counteracts P-Glycoprotein-Mediated Multidrug Resistance and Synergizes the Antitumoral Effect of Doxorubicin in Soft Tissue Sarcomas

The therapeutic effect of doxorubicin (DXR) in the treatment of soft tissue sarcomas (STS) is limited by its toxicity and the development of multidrug resistance (MDR), the latter mainly induced by high expression of efflux pumps (e.g., P-glycoprotein [P-gp]). Therefore, the search for alternative therapies, which sensitize these tumors to chemotherapy while maintaining a low toxicity profile, is a rational approach. We assessed efficacy and molecular mechanisms involved in the antiproliferative effects of the tyrosine kinase inhibitors, nilotinib and imatinib, as single agents or in combination with DXR, in human synovial sarcoma SW982 and leiomyosarcoma SK-UT-1 cells. As single compound nilotinib (1–10 µM) was more potent than imatinib inhibiting the growth of SK-UT-1 and SW982 cells by 33.5–59.6%, respectively. Importantly, only nilotinib synergized the antitumoral effect of DXR (0.05–0.5 µM) by at least 2-fold, which clearly surpassed the mere sum of effects according to isobolographic analysis. Moreover, nilotinib in combination with DXR had a sustained effect on cell number (−70.3±5.8%) even 12 days after withdrawal of drugs compared to DXR alone. On the molecular level, only nilotinib fully blocked FBS-induced ERK1 and p38 MAPK activation, hence, reducing basal and DXR-induced up-regulation of P-gp levels. Moreover, efflux activity of the MDR-related proteins P-gp and MRP-1 was inhibited, altogether resulting in intracellular DXR retention. In high-risk STS tumors 53.8% and 15.4% were positive for P-gp and MRP-1 expression, respectively, with high incidence of P-gp in synovial sarcoma (72.7%). In summary, nilotinib exhibits antiproliferative effects on cellular models of STS and sensitizes them to DXR by reverting DXR-induced P-gp-mediated MDR and inhibiting MRP-1 activity, leading to a synergistic effect with potential for clinical treatment.

Phase I/II study of TH-302 combined with doxorubicin in soft tissue sarcoma.

10036 Background: TH-302 is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard. TH-302 is activated in severe hypoxia, releasing Br-IPM. In preclinical sarcoma models, TH-302 was active alone and enhanced the activity of doxorubicin (Dox). A phase I/II study was performed to investigate the safety and activity of TH-302 in combination with Dox in soft tissue sarcoma (STS). Methods: Eligible patients (pts) had ECOG ≤1, advanced or metastatic STS (AJCC grade 3 or 4), ≤2 prior chemotherapies, evaluable by RECIST, and acceptable hematologic, liver, renal and cardiac function. TH-302 was administered IV over 30-60 minutes on Day 1 and 8 and full dose Dox (75 mg/m2) as IV bolus 2 hours later on Day 1 of a 21-day cycle. A standard 3+3 design was used with phase II expansion in first-line pts at the combination MTD. TH-302 starting dose was 240 mg/m2. Results: 22 pts with STS (6 liposarcoma, 6 leiomyosarcoma, 5 pleomorphic NOS, 2 synovial, 3 other) were treated at TH-302 doses of 240 (6 pts), 300 (12) or 340 (4). 18 pts were first-line; 4 pts had received prior chemo. Median age: 58 (range 19-85); 10 M/12 F. 8 pts are ongoing, 6 completed study (4 received extra cycles TH-302 alone), 8 discontinued prior to Cycle 6 (AE/QOL-4, PD-3, pt decision-1). After Gr4 neutropenia at 240 mg/m2, all later pts received growth factor (GCSF) on Day 8. DLTs were Gr4 thrombocytopenia and Gr3 infection with Gr4 neutropenia at 340 mg/m2. The combination MTD of TH-302 is 300 mg/m2. 12 pts were treated at MTD with 1 DLT (Gr3 febrile neutropenia). Skin toxicities were reported in 11 pts (one Gr 3 cellulitis); mucosal toxicities were reported in 12 pts (one Gr 3 vaginitis). Nonhematologic AEs are Gr 1/2: fatigue (59%), nausea (45%), alopecia (41%). Gr3/4 hematologic toxicity: neutropenia (45%), thrombocytopenia (23%) and anemia (32%). There was no PK interaction between TH-302 and Dox. Best response assessments in 20 pts: 5 PRs (25%), 12 SDs (60%) and 3 PDs; excluding pt with post cycle 6 pathology confirmed enlarging necrotic tumor, 6 month progression-free rate is 56%. Conclusions: TH-302 may be administered in combination with full dose Dox in STS. Myelosuppression is dose limiting with the effects partially obviated by use of GCSF. Antitumor activity is encouraging. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Threshold Pharmaceuticals Threshold Pharmaceuticals Threshold Pharmaceuticals Threshold Pharmaceuticals

Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL®/CAELYX®) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group

CAELYX®/DOXIL®, pegylated liposomal doxorubicin, has shown antitumour activity and reduced toxicity compared with standard doxorubicin in other tumour types. In this prospective randomised trial, 94 eligible patients with advanced soft-tissue sarcoma (STS) were treated, 50 with CAELYX® (50 mg/m2 by a 1 h intravenous (i.v.) infusion every 4 weeks) and 44 with doxorubicin (75 mg/m2 by an i.v. bolus every 3 weeks). Histological subtypes were evenly matched, 33% were leiomyosarcoma (CAELYX®: 18; doxorubicin: 13). Primary disease sites were well matched. CAELYX® was significantly less myelosuppressive, only 3 (6%) patients had grade 3 and 4 neutropenia, versus 33 (77%) on doxorubicin; febrile neutropenia occurred in 7 (16%) patients given doxorubicin, but only 1 (2%) given CAELYX®. 37 (86%) patients on doxorubicin had grade 2–3 alopecia, but only 3 (6%) on CAELYX®, and the major toxicity with CAELYX® was to the skin. Palmar-plantar erythrodysesthesia with CAELYX® was grade 1: 4 (8%) patients, grade 2: 11 (22%) patients, grade 3: 9 (18%) patients and grade 4: 1 (2%) patient. Other non-haematological grade 3 and 4 toxicities were rare. Confirmed responses were observed with both agents: CAELYX®: complete response (CR) 1 (uterine), partial response (PR) 4 (response rate (RR) 10%); and doxorubicin: CR 1, PR 3 (RR of 9%); with the best response being stable disease (NC) in 16 and 18 patients, respectively. The reason for the low response rate is unknown, but it may be due partly to a high proportion of gastrointestinal stromal tumours. In conclusion, CAELYX® has equivalent activity to doxorubicin in STS with an improved toxicity profile and should be considered for further investigation in combination with other agents such as ifosfamide.