Targeting survivin as a potential new treatment for chondrosarcoma of bone

Chondrosarcomas are malignant cartilage-forming bone tumors, which are intrinsically resistant to chemo- and radiotherapy, leaving surgical removal as the only curative treatment option. Therefore, our aim was to identify genes involved in chondrosarcoma cell survival that could serve as a target for therapy. siRNA screening for 51 apoptosis-related genes in JJ012 chondrosarcoma cells identified BIRC5, encoding survivin, as essential for chondrosarcoma survival. Using immunohistochemistry, nuclear as well as cytoplasmic survivin expression was analyzed in 207 chondrosarcomas of different subtypes. Nuclear survivin has been implicated in cell-cycle regulation while cytoplasmic localization is important for its anti-apoptotic function. RT-PCR was performed to determine expression of the most common survivin isoforms. Sensitivity to YM155, a survivin inhibitor currently in phase I/II clinical trial for other tumors, was examined in 10 chondrosarcoma cell lines using viability assay, apoptosis assay and cell-cycle analysis. Survivin expression was found in all chondrosarcoma patient samples. Higher expression of nuclear and cytoplasmic survivin was observed with increasing histological grade in central chondrosarcomas. Inhibition of survivin using YM155 showed that especially TP53 mutant cell lines were sensitive, but no caspase 3/7 or PARP cleavage was observed. Rather, YM155 treatment resulted in a block in S phase in two out of three chondrosarcoma cell lines, indicating that survivin is more involved in cell-cycle regulation than in apoptosis. Thus, survivin is important for chondrosarcoma survival and chondrosarcoma patients might benefit from survivin inhibition using YM155, for which TP53 mutational status can serve as a predictive biomarker.Toxicolog

A screening-based approach identifies cell cycle regulators AURKA, CHK1 and PLK1 as targetable regulators of chondrosarcoma cell survival

Chondrosarcomas are malignant cartilage tumors that are relatively resistant towards conventional therapeuticapproaches. Kinase inhibitors have been investigated and shown successful for several different cancer types. Inthis study we aimed at identifying kinase inhibitors that inhibit the survival of chondrosarcoma cells and therebyserve as new potential therapeutic strategies to treat chondrosarcoma patients.An siRNA screen targeting 779 different kinases was conducted in JJ012 chondrosarcoma cells in parallelwith a compound screen consisting of 273 kinase inhibitors in JJ012, SW1353 and CH2879 chondrosarcoma celllines. AURKA, CHK1 and PLK1 were identified as most promising targets and validated further in a morecomprehensive panel of chondrosarcoma cell lines. Dose response curves were performed using tyrosine kinaseinhibitors: MK-5108 (AURKA), LY2603618 (CHK1) and Volasertib (PLK1) using viability assays and cell cycleanalysis. Apoptosis was measured at 24 h after treatment using a caspase 3/7 assay. Finally, chondrosarcomapatient samples (N = =34) were used to examine the correlation between AURKA, CHK1 and PLK1 RNAexpression and documented patient survival.Dose dependent decreases in viability were observed in chondrosarcoma cell lines after treatment with MK-5108, LY2603618 and volasertib, with cell lines showing highest sensitivity to PLK1 inhibition. In additionincreased sensitivity to conventional chemotherapy was observed after CHK1 inhibition in a subset of the celllines. Interestingly, whereas AURKA and CHK1 were both expressed in chondrosarcoma patient samples, PLK1expression was found to be low compared to normal cartilage. Analysis of patient samples revealed that highCHK1 RNA expression correlated with a worse overall survival.AURKA, CHK1 and PLK1 are identified as important survival genes in chondrosarcoma cell lines. Althoughfurther research is needed to validate these findings, inhibiting CHK1 seems to be the most promising potentialtherapeutic target for patients with chondrosarcoma.Toxicolog

Genome-Wide Meta-Analysis Identifies Variants in DSCAM and PDLIM3 that correlate with efficacy outcomes in metastatic renal cell carcinoma patients treated with sunitinib

Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in CYP3A5 and ABCB1. Our aim is to provide novel insights into biological mechanisms underlying sunitinib action. We included mRCC patients from the European EuroTARGET consortium (n = 550) and the RIKEN cohort in Japan (n = 204) which were analysed separately and in a meta-analysis of genome-wide association studies (GWAS). SNPs were tested for association with progression-free survival (PFS) and overall survival (OS) using Cox regression. Summary statistics were combined using a fixed effect meta-analysis. SNP rs28520013 in PDLIM3 and the correlated SNPs rs2205096 and rs111356738 both in DSCAM, showed genome-wide significance (p Personalised Therapeutic

Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome

Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). We report somatic heterozygous mutations in IDH1 (c.394C>T encoding an R132C substitution and c.395G>A encoding an R132H substitution) or IDH2 (c.516G>C encoding R172S) in 87% of enchondromas (benign cartilage tumors) and in 70% of spindle cell hemangiomas (benign vascular lesions). In total, 35 of 43 (81%) subjects with Ollier disease and 10 of 13 (77%) with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Fourteen of 16 subjects had identical mutations in separate lesions. Immunohistochemistry to detect mutant IDH1 R132H protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors were associated with hypermethylation and downregulated expression of several genes. Mutations were also found in 40% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines, which will enable functional studies to assess the role of IDH1 and IDH2 mutations in tumor formation

Update on Targets and Novel Treatment Options for High-Grade Osteosarcoma and Chondrosarcoma

Molecular tumour pathology - and tumour genetic

An orthotopic mouse model for chondrosarcoma of bone provides an in vivo tool for drug testing

Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

Cartilage tumour progression is characterized by an increased expression of heparan sulphate 6O-sulphation-modifying enzymes

Molecular tumour pathology - and tumour genetic

Src kinases in chondrosarcoma chemoresistance and migration: dasatinib sensitises to doxorubicin in TP53 mutant cells

Molecular tumour pathology - and tumour genetic

Bcl-xl as the most promising Bcl-2 family member in targeted treatment of chondrosarcoma

MTG6Molecular tumour pathology - and tumour genetic

Restoration of chemosensitivity for doxorubicin and cisplatin in chondrosarcoma in vitro: BCL-2 family members cause chemoresistance

Molecular tumour pathology - and tumour genetic