Javier Martin-Broto

RG7112, a Small-Molecule Inhibitor of MDM2, Enhances Trabectedin Response in Soft Tissue Sarcomas

ABSTRACT MDM2 is a critical negative regulator of the p53 tumor suppressor protein. Selected sarcoma subtypes are being treated with Trabectedin in second line, which promotes DNA damage and p53-dependent apoptosis. The aim of this study was to evaluate the improvement of Trabectedin response with MDM2 inhibitors in soft tissue sarcomas. The antitumor effects of Trabectedin, Nutlin-3A and RG7112 as single agents or in combination were examined in vitro. RG7112 significantly synergized with Trabectedin in MDM2-amplified liposarcoma cells, representing a promising new therapeutic strategy for the treatment of sarcomas with MDM2 amplification.

Efficacy of bortezomib in sarcomas with high levels of MAP17 (PDZK1IP1)

Sarcomas are malignant tumors accounting for a high percentage of cancer morbidity and mortality in children and young adults. Surgery and radiation therapy are the accepted treatments for most sarcomas; however, patients with metastatic disease are treated with systemic chemotherapy. Many tumors display marginal levels of chemoresponsiveness, and new treatment approaches are needed. MAP17 is a small non-glycosylated membrane protein overexpressed in carcinomas. The levels of MAP17 could be used as a prognostic marker to predict the response to bortezomib in hematological malignancies and in breast tumors. Therefore, we analyzed the expression of this oncogene in sarcomas and its relationship with clinico-pathological features, as well as tested whether it can be used as a new biomarker to predict the therapeutic response to bortezomib and new therapies for sarcomas. We found that the levels of MAP17 were related to clinical features and poor survival in a cohort of 69 patients with different sarcoma types, not being restricted to any special subtype of tumor. MAP17 expression is associated with poor overall survival (p<0.001) and worse disease-free survival (p=0.002). Cell lines with high levels of MAP17 show a better response to bortezomib in vitro. Furthermore, patient-derived xenografts (PDX) with high levels of MAP17 respond to bortezomib in vivo. Our results showed that this response is due to the lower levels of NFκB and autophagy activation. Therefore, we suggest that MAP17 is a new biomarker to predict the efficacy of bortezomib as a new therapy for sarcomas.

Trabectedin clinical cases: use according to indication in diverse clinical scenarios

BACKGROUND Key distinguishing characteristics of trabectedin in the treatment of advanced soft tissue sarcoma are its prolonged tumor control activity in multiple histological subtypes, positive outcomes in translocation-related sarcomas, maintenance of response, option to rechallenge after treatment interruption and lack of cumulative toxicity. Trabectedin is indicated for use in advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide, or as front-line treatment in patients unsuited to receive these agents. METHODS In this review, cases studies are presented in which trabectedin was used according to its indication but in diverse clinical settings. RESULTS As second-line treatment of uterine leiomyosarcoma, trabectedin produced prolonged tumor control with good quality of life. In treatment of recurrent synovial sarcoma, the best objective response (partial response) and longest disease control (37 months) was achieved under treatment with trabectedin. As neoadjuvant treatment of undifferentiated pleomorphic sarcoma in a patient unsuited to receive doxorubicin-based chemotherapy, trabectedin induced a pathological response with 85% of necrosis. CONCLUSION These cases illustrate the broad range of indications for trabectedin in advanced soft tissue sarcoma and highlight how its unique characteristics can be optimized to achieve maximum clinical benefit.

Activity of Pazopanib and Trabectedin in Advanced Alveolar Soft Part Sarcoma

BACKGROUND Alveolar soft part sarcoma (ASPS) is an exceedingly rare and orphan disease, without active drugs approved in the front line. Pazopanib and trabectedin are licensed for sarcoma treatment from second-line, but very little and contradictory data are available on their activity in ASPS. Lacking ongoing and/or planned clinical trials, we conducted a multi-institutional study involving the reference sites for sarcoma in Europe, U.S., and Japan, within the World Sarcoma Network, to investigate the efficacy of pazopanib and trabectedin. MATERIALS AND METHODS From May 2007, 14 of the 27 centers that were asked to retrospectively review their databases had identified 44 advanced ASPS patients treated with pazopanib and/or trabectedin. Response was evaluated by Response Evaluation Criteria in Solid Tumors 1.1. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method. RESULTS Among 30 patients who received pazopanib, 18 were pretreated (13 with other antiangiogenics). Response was evaluable in 29/30 patients. Best responses were 1 complete response, 7 partial response (PR), 17 stable disease (SD), and 4 progressions. At a 19-month median follow-up, median PFS was 13.6 months (range: 1.6-32.2+), with 59% of patients progression-free at 1 year. Median OS was not reached.Among 23 patients treated with trabectedin, all were pretreated and evaluable for response. Best responses were 1 PR, 13 SD, and 9 progressions. At a 27-month median follow-up, median PFS was 3.7 months (range: 0.7-109), with 13% of patients progression-free at 1 year. Median OS was 9.1 months. CONCLUSION The value of pazopanib in advanced ASPS is confirmed, with durable responses, whereas the value of trabectedin appears limited. These results are relevant to defining the best approach to advanced ASPS. IMPLICATIONS FOR PRACTICE This retrospective study, conducted among the world reference centers for treatment of sarcoma, confirms the value of pazopanib in patients with advanced alveolar soft part sarcoma (ASPS), with dimensional and durable responses, whereas trabectedin shows a limited activity. Alveolar soft part sarcoma is resistant to conventional cytotoxic chemotherapy. Pazopanib and trabectedin are licensed for treatment of sarcoma from second line; in the lack of prospective clinical trials, these results are relevant to defining ASPS best management and strongly support initiatives aimed at obtaining the approval of pazopanib in the front line of the disease.

Dovitinib in patients with gastrointestinal stromal tumour refractory and/or intolerant to imatinib

Background:This multicentre phase II trial (DOVIGIST) evaluated the antitumour activity of dovitinib as second-line treatment of patients with gastrointestinal stromal tumour (GIST) refractory to imatinib or who do not tolerate imatinib.Methods:Patients received oral dovitinib 500 mg day−1, 5 days on/2 days off, until GIST progression or unacceptable toxicity, with an objective to evaluate efficacy, assessed as the disease control rate (DCR) at 12 weeks. Tumour assessment and response to dovitinib therapy were evaluated by Response Evaluation Criteria In Solid Tumours (RECIST v1.1) and the Choi criteria. Secondary objectives included assessment of progression-free survival (PFS), safety and tolerability, and DCR at the end of treatment.Results:Thirty-eight of the 39 patients enrolled had histologically confirmed GIST. The DCR at 12 weeks was 52.6% (90% confidence interval (CI), 38.2–66.7%) meeting the preset efficacy criterion for the primary end point. The objective response rate (complete response+partial response) was 2.6% (1 of 38; 90% CI, 0.1–11.9%), and 5.3% (n=2; 90% CI, 0.9–15.7%) at the end of the study. The median PFS was 4.6 months (90% CI, 2.8–7.4 months). Dose interruption was required in 26 patients (66.7%), of which 18 (69.2%) were due to adverse events. The most frequently observed grade 3 adverse events included hypertension (n=7), fatigue (n=5), vomiting (n=4), hypertriglyceridaemia (n=4), and γ-glutamyltransferase increase (n=4).Conclusions:Dovitinib is an active treatment for patients with GIST who are intolerant to imatinib or whose GIST progresses on imatinib.

Gemcitabine plus sirolimus for relapsed and progressing osteosarcoma patients after standard chemotherapy: a multicenter, single-arm phase II trial of Spanish Group for Research on Sarcoma (GEIS).

Background Patients with relapsed unresectable osteosarcoma represents an unmet need, so active and safe systemic treatments are required. Fas cell surface death receptor and mammalian target of rapamycin pathways are implicated in progressing osteosarcoma, and we had preclinical and clinical experience with a scheme that targets both pathways. Therefore, we designed a phase II trial with gemcitabine plus rapamycin, to determine the efficacy and safety, in this subset of patients. Patients and methods A multicenter, single-arm phase II trial was sponsored by the Spanish Group for Research on Sarcoma. Osteosarcoma patients, relapsed or progressing after standard chemotherapy and unsuitable for metastasectomy received gemcitabine and rapamycin p.o. 5 mg/day except for the same day of gemcitabine administration, and the day before. The main end point was 4-month progression-free survival rate (PFSR), with the assumption that rates higher than 40% would be considered as an active regimen. Translational research aimed to correlate biomarkers with the clinical outcome. Results Thirty-five patients were enrolled and received at least one cycle. PFSR at 4 months was 44%, and after central radiologic assessment, 2 partial responses and 14 stabilizations (48.5%) were reported from 33 assessable patients. The most frequent grade 3-4 adverse events were: neutropenia (37%), thrombocytopenia (20%), anemia (23%), and fatigue (15%); however, only three patients had febrile neutropenia. Positive protein expression of RRM1 significantly correlated with worse PFS and overall survival, while positivity of P-ERK1/2 was correlated with significant better overall survival. Conclusion Gemcitabine plus sirolimus exhibits satisfactory antitumor activity and safety in this osteosarcoma population, exceeding the prespecified 40% of 4-month PFSR. The significant correlation of biomarkers with clinical outcome encourages further prospective investigation.

Targeted treatments of sarcomas and connective tumors beside gastrointestinal stromal tumor.

Purpose of review Sarcoma is a heterogeneous group of malignancies historically treated with classic cytotoxic chemotherapy. This review updates the recent advances in targeted therapies in soft-tissue sarcoma, bone sarcoma and other connective diseases with local aggressiveness. Recent findings Platelet-derived growth factor receptor (PDGFR) inhibitors, antiangiogenics, cell cycle inhibitors and immunomodulatory agents are the main targeted therapies in development in sarcoma. PDGFR&agr; inhibitor olaratumab is being evaluated in a phase III trial in combination with doxorubicin against doxorubicin in monotherapy and, in case of positive results, it could change the standard in the first-line setting. Immunotherapy is still in the early phases of development, although some data in synovial sarcoma are promising. Targeted agents are also in development in other mesenchymal neoplasms, such as the inhibitor of colony stimulating factor 1 receptor for pigmented villonodular synovitis. Summary Several targeted therapies are in development in sarcoma and could be added to the therapeutic armamentarium in the near future. However, predictive factors still need to be identified to better select the target population of these new drugs.

Disruption of TCF/β-Catenin Binding Impairs Wnt Signaling and Induces Apoptosis in Soft Tissue Sarcoma Cells

Soft tissue sarcomas (STS) are malignant tumors of mesenchymal origin and represent around 1% of adult cancers, being a very heterogeneous group of tumors with more than 50 different subtypes. The Wnt signaling pathway is involved in the development and in the regulation, self-renewal, and differentiation of mesenchymal stem cells, and plays a role in sarcomagenesis. In this study, we have tested pharmacologic inhibition of Wnt signaling mediated by disruption of TCF/β-catenin binding and AXIN stabilization, being the first strategy more efficient in reducing cell viability and downstream effects. We have shown that disruption of TCF/β-catenin binding with PKF118-310 produces in vitro antitumor activity in a panel of prevalent representative STS cell lines and primary cultures. At the molecular level, PKF118-310 treatment reduced β-catenin nuclear localization, reporter activity, and target genes, resulting in an increase in apoptosis. Importantly, combination of PKF118-310 with doxorubicin resulted in enhanced reduction of cell viability, suggesting that Wnt inhibition could be a new combination regime in these patients. Our findings support the usefulness of Wnt inhibitors as new therapeutic strategies for the prevalent STS. Mol Cancer Ther; 16(6); 1166–76. ©2017 AACR.

Current and future systemic treatment options for advanced soft-tissue sarcoma beyond anthracyclines and ifosfamide

Sarcomas are rare, life-threatening, malignant tumors. Surgery is the cornerstone of therapy in the localized setting. About one-third of patients develop distant metastasis. In the metastatic setting, systemic therapy is the mainstay of treatment, and several second-line options are available, proving a modest survival increase for these patients. Trabectedin is an active drug with several described mechanisms of action. Although the objective response rate is low, about one-third of patients achieve disease stabilizations and a prolonged disease control. Interestingly, it has no accumulative toxicities. Pazopanib is the only targeted therapy approved for soft-tissue sarcoma (STS), with the exception of adipocytic sarcoma. Eribulin represents a recently approved therapeutic option for liposarcoma. Other drugs such as gemcitabine combinations, dacarbazine, and taxanes have also shown activity in second lines in advanced STS. The selection should be based on histologic subtype, patient characteristics, and toxicity profile among other factors. This review will summarize clinical development of the current and future therapeutic options for this heterogeneous group of diseases.

GEIS-21: a multicentric phase II study of intensive chemotherapy including gemcitabine and docetaxel for the treatment of Ewing sarcoma of children and adults: a report from the Spanish sarcoma group (GEIS)

Background:First Spanish trial of Ewing sarcoma (ES) including adults and children with the aim to test the efficacy of Gemcitabine and Docetaxel (G/D) in newly diagnosed high-risk (HR) patients.Methods:This was a prospective, multicentric, non-randomised, open study for patients ⩽40 years with newly diagnosed ES. HR patients (metastatic, axial-pelvic primaries or bone marrow micrometastasis) received 2 window cycles of G/D. Patients with an objective response (OR) to G/D received 12 monthly cycles of G/D after completion of mP6. The primary end point was the OR rate to the G/D window phase and the event-free survival (EFS) and overall survival (OS) for all patients. The study is registered at ClinicalTrials.gov (identifier: NCT00006734).Results:Forty-three patients were enroled, median age 17 years (range, 3–40). After a median follow-up of 43.4 months, the 5-year OS rate is 55.0% (95% CI, 41–74%) with an EFS of 50.0% (95% CI, 36–68%). The 5-year OS and EFS rates for standard risk (SR) patients was 76.0% (95% CI, 57–100%) and 71.0% (CI, 54–94%); for HR 36.0% (CI, 20–65%) and 29.0% (CI, 15–56%). Twelve of 17 (70.6%) high-risk (HR) patients showed an OR (7 PR and 5 SD) to G/D window therapy. The 5-year OS rate for patients ⩽18 years of age was 74.0% (CI, 56–97%) and 31.0% for >18 years (95% CI, 15–66%), P<0.001. Grade 4 adverse events during mP6 occurred in 28/39 of patients (72%) and did not correlate with age. Multivariate survival analyses with <18 vs ⩾18 and risk groups significant differences, P<0.00001. Using a Cox model for OS, both age and risk group were statistically significant (P=0.0011 and P=0.0065, respectively).Conclusions:Age at diagnosis is an independent prognostic factor superior to the presence of metastases with 18 years as the strongest cut-off. The mP6 regimen provided survival curves that plateau at 3 years and G/D produced significant responses in HR-ES that is worth further exploring.