Sarcoma treatment in the era of molecular medicine.

Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling.

Kaposiform hemangioendothelioma and tufted angioma - (epi)genetic analysis including genome-wide methylation profiling.

Kaposiform hemangioendothelioma (KHE) is a locally aggressive vascular condition of childhood and is clinicopathologically related to tufted angioma (TA), a benign skin lesion. Due to their rarity molecular data are scarce. We investigated 7 KHE and 3 TA by comprehensive mutational analysis and genome-wide methylation profiling and compared the clustering, also with vascular malformations.

Targeting Cyclin-Dependent Kinases in Synovial Sarcoma: Palbociclib as a Potential Treatment for Synovial Sarcoma Patients.

Background: In synovial sarcomas alterations in the cyclin D1-CDK4/6-Rb axis have been described. Also, β-catenin, a cyclin D1 regulator, is often overexpressed. Additionally, studies have shown that the t(X;18) translocation influences tumor behavior partly through cyclin D1 activation.

Next generation sequencing in synovial sarcoma reveals novel gene mutations.

Over 95% of all synovial sarcomas (SS) share a unique translocation, t(X;18), however, they show heterogeneous clinical behavior. We analyzed multiple SS to reveal additional genetic alterations besides the translocation. Twenty-six SS from 22 patients were sequenced for 409 cancer-related genes using the Comprehensive Cancer Panel (Life Technologies, USA) on an Ion Torrent platform.

The role of AXL and the in vitro activity of the receptor tyrosine kinase inhibitor BGB324 in Ewing sarcoma.

New targets for Ewing sarcoma (ES) patients are urgently needed. Therefore, we investigated the expression and genetic aberrations of the oncogenic receptor tyrosine kinase (RTK) AXL in ES and determined the efficacy of AXL targeting on cell viability and migration. First, AXL and Gas6 (ligand) mRNA expression was determined by RT-PCR on 29 ES samples.

Solitary fibrous tumor - clinicopathologic, immunohistochemical and molecular analysis of 28 cases.

Background: Solitary fibrous tumor is a mesenchymal tumor of fibroblastic type, which can affect any region of the body. Recently, a recurrent gene fusion NAB2-STAT6 has been identified as molecular hallmark. The NAB2-STAT6 fusion leads to EGR1 activation and transcriptional deregulation of EGR1-dependent target genes and is a driving event in initiation of SFT.

Temsirolimus combined with cisplatin or bevacizumab is active in osteosarcoma models.

Mammalian target of rapamycin (mTOR) is a new promising oncological target. However, most clinical studies reported only modest antitumor activity during mTOR-targeted monotherapies, including studies in osteosarcomas, emphasizing a need for improvement. We hypothesized that the combination with rationally selected other therapeutic agents may improve response.

Theranostic applications of antibodies in oncology.

Targeted therapies, including antibodies, are becoming increasingly important in cancer therapy. Important limitations, however, are that not every patient benefits from a specific antibody therapy and that responses could be short-lived due to acquired resistance. In addition, targeted therapies are quite expensive and are not completely devoid of side-effects.

Anti-angiogenic therapy, a new player in the field of sarcoma treatment.

Sarcomas encompass a heterogeneous family of mesenchymal malignancies. In metastatic disease improvement in outcome has been limited and there is a clear need for the development of new therapies. One potential target is angiogenesis, already an accepted target for treatment of more prevalent cancers.

Targeting receptor tyrosine kinases in osteosarcoma and Ewing sarcoma: current hurdles and future perspectives.

Osteosarcoma (OS) and Ewing sarcoma (ES) are the two most common types of primary bone cancer, which mainly affect children and young adults. Despite intensive multi-modal treatment, the survival of both OS and ES has not improved much during the last decades and new therapeutic options are awaited. One promising approach is the specific targeting of transmembrane receptor tyrosine kinases (RTKs) implicated in these types of bone cancer.

IGF signaling pathway analysis of osteosarcomas reveals the prognostic value of pAKT localization.

Aim: The aim of this study was to examine the expression of the IGF signaling pathway components in osteosarcoma samples before and after chemotherapy with special emphasis on their prognostic value.

Materials & Methods: Tumor material and follow-up data of 58 osteosarcoma patients were analyzed. Immunohistochemical staining was carried out to identify proteins related to the IGF pathway.

Simultaneous targeting of insulin-like growth factor-1 receptor and anaplastic lymphoma kinase in embryonal and alveolar rhabdomyosarcoma: a rational choice.

Background: Rhabdomyosarcoma (RMS) is an aggressive soft tissue tumour mainly affecting children and adolescents. Since survival of high-risk patients remains poor, new treatment options are awaited. The aim of this study is to investigate anaplastic lymphoma kinase (ALK) and insulin-like growth factor-1 receptor (IGF-1R) as potential therapeutic targets in RMS.

αB-crystallin expression is correlated with phospho-ERK1/2 expression in human breast cancer.

αB-crystallin is regarded as a biomarker for triple-negative and/or basal-like breast cancer. In normal breast cells, overexpression of αB-crystallin leads to neoplastic-like changes, which likely relate to enhanced expression of phosphorylated ERK1/2 (pERK1/2). In this study, we investigated whether αB-crystallin expression is correlated to pERK1/2 expression in breast cancer.

The strength of small: improved targeting of insulin-like growth factor-1 receptor (IGF-1R) with F(ab')₂-R1507 fragments in Ewing sarcomas.

Purpose: To investigate whether F(ab')₂-fragments of the monoclonal Insulin-like Growth Factor-1 Receptor (IGF-1R) antibody R1507 (F(ab')₂-R1507) can successfully target IGF-1R in Ewing sarcomas (ES).

Materials And Methods: BALB/c nude mice were subcutaneously implanted with IGF-1R-expressing human ES xenografts (EW-5 and EW-8) which previously showed heterogeneous or no uptake of indium-111-labelled R1507 IgG ((111)In-R1507), respectively. Mice were injected with (111)In-F(ab')₂-R1507 or (111)In-R1507 as a reference.

Hypoxia regulation of phosphokinases and the prognostic value of pAKT in breast cancer.

Tumor hypoxia results in poor treatment response and is an indicator of poor outcome in cancer patients. TRIB3 is a hypoxia-upregulated protein involved in the ability of breast cancer cells to survive in hypoxic conditions. It is also involved in the prognosis of cancer patients, possibly by affecting several kinase-signaling pathways.

Expression and clinical relevance of MET and ALK in Ewing sarcomas.

Because novel therapeutic options are limited in Ewing sarcomas (ES), we investigated the expression, genetic aberrations and clinical relevance of MET and anaplastic lymphoma kinase (ALK) in ES and determined the relevance of targeting these receptors. MET and ALK protein expression was determined immunohistochemically in 31 (50 samples) and 36 (59 samples) ES patients, respectively. Samples included primary tumors, postchemotherapy resections, metastases and relapses.

Anaplastic lymphoma kinase aberrations in rhabdomyosarcoma: clinical and prognostic implications.

Purpose: The aim of this study is to investigate anaplastic lymphoma kinase (ALK) protein expression and underlying genetic aberrations in rhabdomyosarcoma (RMS), with special attention to clinical and prognostic implications.

Patients And Methods: A total of 189 paraffin-embedded RMS tumor specimens from 145 patients were collected on tissue microarray. ALK protein expression was evaluated by immunohistochemistry.

Predicting IGF-1R therapy response in bone sarcomas: immuno-SPECT imaging with radiolabeled R1507.

Purpose: To investigate whether indium-111-labeled R1507 ((111)In-R1507) immuno-SPECT (single-photon emission computed tomography), a novel noninvasive, in vivo screening method to visualize membranous insulin-like growth factor 1 receptor (IGF-1R) expression and accessibility, can be used to predict IGF-1R treatment (R1507) response in bone sarcomas.

Experimental Design: BALB/c nude mice were subcutaneously implanted with IGF-1R-expressing human bone sarcoma xenografts (OS-1, EW-5, and EW-8) which showed high, modest, or no response, respectively, to R1507, a monoclonal antibody targeting the extracellular domain of IGF-1R. An IGF-1R-negative tumor (OS-33), unresponsive to IGF-1R inhibitors, was examined as well.

ImmunoSPECT and immunoPET of IGF-1R expression with the radiolabeled antibody R1507 in a triple-negative breast cancer model.

Unlabelled: The insulinlike growth factor 1 receptor (IGF-1R) is a new target for the treatment of breast cancer. Patients with breast cancer lesions that express IGF-1R may benefit from treatment with anti-IGF-1R antibodies. Therefore, the aim of the present study was to develop a noninvasive, in vivo imaging method, using radiolabeled antibodies, to visualize IGF-1R expression.