Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial

Grignani, Giovanni; Palmerini, Emanuela; Ferraresi, Virginia; D’Ambrosio, Lorenzo; Bertulli, Rossella; Asaftei, Sebastian Dorin; Tamburini, Angela; Pignochino, Ymera; Sangiolo, Dario; Marchesi, Emanuela; Capozzi, Federica; Biagini, R.; Gambarotti, Marco; Fagioli, Franca; Casali, Paolo G.; Picci, Piero; Ferrari, Stefano; Aglietta, Massimo

doi:10.1016/s1470-2045(14)71136-2

Cited by 279 publications

(242 citation statements)

References 45 publications

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“…Combination targeted therapy again may have merit: a phase II trial of sorafenib and everolimus combination therapy achieved 45% 6-month progression-free survival (PFS; ref. 70). Although falling just short of its prespecified primary endpoint (50% 6-month PFS), this result is well-above the widely accepted 20% 6-month PFS benchmark for sarcoma drug activity (71) and represents the first positive study for relapsed osteosarcoma in a quarter century.…”

Section: Sarcoma Treatment: Current and Future Prospectsmentioning

confidence: 80%

New Strategies in Sarcoma: Linking Genomic and Immunotherapy Approaches to Molecular Subtype

Lim

Poulin

Nielsen

2015

Clinical Cancer Research

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There are more than 100 sarcoma subtypes, each uncommon and diagnostically challenging. Conventional chemotherapy has little benefit for most soft-tissue sarcomas; new treatment strategies are needed. Multiple recent genomic studies have provided detailed insights into sarcoma biology, including more accurate classification by molecular subtype, identification of recurrent mutations in oncogenic pathways, and evidence of epigenetic dysregulation. Advances in immunotherapy (adoptive immune cell transfer, tumor vaccine strategies, and immune checkpoint inhibition) have also provided a better understanding of how immuno-oncology might best be applied to sarcoma treatment, including connections to oncogenic pathways that may support combination strategies with conventional and targeted therapies. In this article, we review the latest sarcoma genomic studies and immuno-oncology developments and discuss how the findings suggest potential strategies to improve diagnosis and treatment across multiple sarcoma subtypes.

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Section: Sarcoma Treatment: Current and Future Prospectsmentioning

confidence: 80%

New Strategies in Sarcoma: Linking Genomic and Immunotherapy Approaches to Molecular Subtype

Lim

Poulin

Nielsen

2015

Clinical Cancer Research

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“…Although 45% of the patients presented six months of progression-free survival, the target of 50% was not reached. 62 …”

Section: Pi3k/akt/mtor Pathwaymentioning

confidence: 99%

Deciphering signaling networks in osteosarcoma pathobiology

Adamopoulos

Gargalionis

Basdra

et al. 2016

Exp Biol Med (Maywood)

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Osteosarcoma is the most frequent type of primary bone tumors among children and adolescents. During the past years, little progress has been made regarding prognosis of osteosarcoma patients, especially for those with metastatic disease. Genomic instability and gene alterations are common, but current data do not reveal a consistent and repeatable pattern of osteosarcoma development, thus paralleling the tumor's high heterogeneity. Critical signal transduction pathways have been implicated in osteosarcoma pathobiology and are being evaluated as therapeutic targets, including receptor activator for nuclear factor-kB (RANK), Wnt, Notch, phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin, and mechanotransduction pathways. Herein, we recapitulate and discuss recent advances in the context of molecular mechanisms and signaling networks that contribute to osteosarcoma progression and metastasis, towards patient-tailored and novel-targeted treatments.

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“…In an effort to increase sorafenib's effects, one promising strategy is to combine sorafenib with other anticancer reagents (19,20). However, the outcomes of several of these studies were not desirable due to safety concerns or not achieving the expected end point such as improved overall survival (21,22).…”

Section: Introductionmentioning

confidence: 99%

Combination of wogonin and sorafenib effectively kills human hepatocellular carcinoma cells through apoptosis potentiation and autophagy inhibition

et al. 2017

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Abstract.The small molecule multi-kinase inhibitor sorafenib has become the standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC) and renal cell carcinoma. Similar to other kinase inhibitors, drug resistance hinders its clinical use; thus, combination therapy to improve sorafenib sensitivity is a promising approach. The present study shows for the first time that the combination of sorafenib and wogonin exerts a significant potentiation of cytotoxicity in a number of human HCC cell lines in a dose-dependent manner. Enhanced cell death was due to potentiation of apoptosis, which was demonstrated by increased apoptotic cell populations, caspase activation and suppression of cell death by the pan-caspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl. Sorafenib induced autophagy activation, which was shown by autophagic flux. Suppression of autophagy with the autophagy inhibitors chloroquine or 3-methyladenine significantly enhanced cytotoxicity, suggesting that sorafenib-induced autophagy is cytoprotective. Notably, wogonin effectively inhibited sorafenib-induced autophagy. Altogether, our results indicate that the combination of wogonin and sorafenib effectively kills human HCC cells. This occurs, at least in part, through autophagy inhibition, which potentiates apoptosis. Thus, wogonin could be an ideal candidate for increasing sorafenib's activity in HCC therapy, which warrants further investigation in vivo.

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Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial

Cited by 279 publications

References 45 publications

New Strategies in Sarcoma: Linking Genomic and Immunotherapy Approaches to Molecular Subtype

New Strategies in Sarcoma: Linking Genomic and Immunotherapy Approaches to Molecular Subtype

Deciphering signaling networks in osteosarcoma pathobiology

Combination of wogonin and sorafenib effectively kills human hepatocellular carcinoma cells through apoptosis potentiation and autophagy inhibition

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