bims-myxlip 2022-02-20 papers

Issue of 2022–02–20
six papers selected by
Laura Mannarino, Humanitas Research

Cancers (Basel). 2022 Feb 05. pii: 814. [Epub ahead of print]14(3):

GPR64, Screened from Ewing Sarcoma Cells, Is a Potential Target for Antibody-Based Therapy for Various Sarcomas.

Koichi Nakamura, Kunihiro Asanuma, Takayuki Okamoto, Keisuke Yoshida, Yumi Matsuyama, Kouji Kita, Tomohito Hagi, Tomoki Nakamura, Akihiro Sudo.

Ewing sarcoma is an aggressive and the second most common bone tumor in adolescent and young adult patients. The 5-year survival rate is 60-70% for localized disease but 30% for patients with metastases. Here, we aimed to identify a therapeutic target for Ewing sarcoma and evaluate antibody-based therapeutic agents using in vitro and in vivo models. We identified G protein-coupled receptor 64 (GPR64) as a therapeutic target for Ewing sarcoma via next-generation RNA-sequencing. GPR64v205 mRNA was expressed in HTB166, A673, MG63, 143B, HS-Sy II, and HT1080 cell lines as well as in Ewing sarcoma, undifferentiated pleomorphic sarcoma, leiomyosarcoma, dedifferentiated liposarcoma, and synovial sarcoma tissues. GPR64 expression was observed in 62.5% of sarcoma cases and was overexpressed in 33.9% cases. GPR64-specific monoclonal antibodies were tested as near-infrared probes for in vivo imaging using subcutaneous tumor mouse xenografts. Fluorescence intensity was stronger for the AF700-labeled anti-GPR64 antibody than that for the AF700-labeled isotype control antibody. GPR64 was detected in engrafted tumors of A673, 143B, HT1080, and the epididymis but not in other resected tissues. The anti-GPR64 antibody showed excellent binding to GPR64-positive tumors but not to healthy tissues. This antibody has potential for drug delivery in the antibody-based treatment of sarcomas.

Keywords: Ewing sarcoma; GPR64; antibody-based therapeutics; epididymis; sarcomas

DOI: https://doi.org/10.3390/cancers14030814

Pathol Res Pract. 2022 Jan 24. pii: S0344-0338(22)00022-X. [Epub ahead of print]231 153779

Distinct histologic and genetic characteristics of round cell sarcoma with CIC-DUX4 fusion and comparison with ewing sarcoma.

Min Jeong Song, Kyung-Ja Cho, Tae-Im Kim, Wanlim Kim, Joon Seon Song.

CIC-DUX4 fusion gene associated sarcoma is a new emerging subgroup of round cell sarcoma with Ewing sarcoma-like morphology. Distinguishing these tumors from Ewing sarcoma family tumors (ESFT) is critical because of the clinical impact but is still challenging due to the overlapped histological and immunohistochemical phenotypes of each subtype. The present study investigated small round cell sarcoma to identify CIC-DUX4 fusion positive sarcoma, examined clinical, histopathologic and immunohistochemical characteristics of CIC-DUX4 sarcoma, and evaluated parameters to differentiate Ewing sarcoma family tumors. Seventy patients with undifferentiated round cell sarcoma or Ewing-like sarcoma were retrieved. Molecular tests including EWSR1, CIC break apart FISH, and RT-PCR for CIC-DUX4 gene fusion were performed and immunohistochemistry was performed. Six cases (8.6%) of CIC-DUX4 sarcomas were detected. Histologically, CIC-DUX4 sarcomas composed of heterogeneous round, plasmacytoid, and spindle cells and more commonly showed cytologic pleomorphism with bizarre nuclei and multinucleated cells and myxoid stoma unlike ESFT. CIC-DUX4 sarcomas didn't show overall survival differences (p = 0.325) compared to ESFT but they demonstrated short disease-free survival (p = 0.034) and poor response to treatment (p = 0.007). Therefore, molecular analysis to detect the distinctive genetic alteration is mandatory in tumors with atypical histologic, immunohistochemical and/or clinical presentation for accurate diagnosis and treatment.

Keywords: CIC-DUX4 sarcoma; Ewing-like sarcoma; Small round cell sarcoma

DOI: https://doi.org/10.1016/j.prp.2022.153779

Cancers (Basel). 2022 Jan 31. pii: 736. [Epub ahead of print]14(3):

A Proposed Trial Design for the Treatment of Widely Metastatic Ewing Sarcoma Inspired by Evolutionary Dynamics.

Jonathan Metts, Thomas Russell, Damon Reed, Matteo Trucco.

Metastatic Ewing sarcoma has dismal long-term survival despite multiple attempts to intensify standard therapy through the addition of new agents to the existing chemotherapy backbone. Here, based on the application of evolutionary dynamics to pediatric sarcoma, we propose an alternative treatment strategy that varies exposure to agents and dosing intensities, termed sequential second-strike therapy (SSST). We announce an upcoming clinical trial to apply these principles to patients with widely metastatic Ewing sarcoma, those with metastatic disease beyond the lungs.

Keywords: Ewing sarcoma; clinical trial; evolutionary dynamics

DOI: https://doi.org/10.3390/cancers14030736

Curr Treat Options Oncol. 2022 Feb 15.

Preoperative Radiation for Soft Tissue Sarcomas: How Much Is Needed?

Safia K Ahmed, Ivy A Petersen.

OPINION STATEMENT: Preoperative radiation therapy is an important component of curative treatment for extremity and superficial trunk soft tissue sarcomas. It has traditionally been delivered to a dose of 50 Gy in 2 Gy fractions over 5 weeks. With significant advances in the multidisciplinary approach to soft tissue sarcomas, preoperative radiation therapy may be omitted for certain cases, delivered over a shortened period of time (1-3 weeks), deintensified for myxoid liposarcomas, or combined with systemic therapy to improve the therapeutic ratio. This article reviews the innovative preoperative radiation therapy strategies currently used to treat extremity and superficial trunk soft tissue sarcomas.

Keywords: Combination therapy; Dose deintensification; Hypofractionation; Omission of radiation therapy; Preoperative radiation therapy; Soft tissue sarcoma

DOI: https://doi.org/10.1007/s11864-022-00943-7

Biochem Pharmacol. 2022 Feb 07. pii: S0006-2952(22)00038-7. [Epub ahead of print]198 114944

Combinatorial strategies to potentiate the efficacy of HDAC inhibitors in fusion-positive sarcomas.

Cinzia Lanzi, Giuliana Cassinelli.

Fusion positive (FP) sarcomas are characterized by chromosomal rearrangements generating pathognomonic fusion transcripts and oncoproteins. In Ewing's sarcoma family of tumors (ESFTs), FP-rhabdomyosarcomas (FP-RMS) and synovial sarcomas (SS), the most common and aggressive forms of sarcomas in childhood and adolescence, the oncogenic rearrangements involve transcription cofactors causing widespread epigenetic rewiring and aberrant gene expression. Through the cooperation with histone deacetylases (HDACs) in transcription regulatory complexes, the fusion oncoproteins affect histone acetylation and chromatin remodeling. The participation of HDACs in core mechanisms of sarcoma cell transformation has paved the way to the investigation of HDAC inhibitors (HDACis) for therapeutic intervention. Preclinical studies have provided convincing evidence that HDAC activity abrogation can revert malignant cell features driven by FET-ETS, PAX3/7-FOXO1 or SS18-SSX fusion oncogenes in ESFTs, FP-RMS, or SS models, respectively, resulting in in vitro and in vivo growth inhibition. While clinical trials of HDACi monotherapies led to drug approval in some hematologic malignancies, no significant therapeutic benefit has been reported in solid tumors, including sarcomas. HDACi-based combination therapies with targeted or conventional anticancer agents have shown limited efficacy in early studies recruiting sarcoma patients, although partial responses and disease stabilization have been reported. In these trials, sarcomas were represented, however, as unclassified group in most cases. We summarize, here, studies addressing the role of HDACs in FP-sarcoma pathobiology and HDACi-based rational drug combinations. Finally, we discuss the opportunity of exploiting drug inhibitory profile and expression/function of specific HDAC isoenzymes to harness the full therapeutic potential of HDACis in these sarcoma histotypes.

Keywords: Drug combination; Ewing’s family of tumors; Fusion positive-rhabdomyosarcoma; Fusion-positive sarcomas; HAT; HDAC; HDAC inhibitor; Synovial sarcoma

DOI: https://doi.org/10.1016/j.bcp.2022.114944

Curr Treat Options Oncol. 2022 Feb 16.

Proteomic and Metabolomic Profiling in Soft Tissue Sarcomas.

Madhumeeta Chadha, Paul H Huang.

OPINION STATEMENT: Advances in proteomic and metabolomic technologies have accelerated our understanding of multiple aspects of cancer biology across distinct tumour types. Here we review the current state-of-the-art in the use of proteomics and metabolomics in soft tissue sarcomas. We highlight the utility of these Omics-based methodologies to identify new drug targets, synthetic lethal interactions, candidate therapeutics and novel biomarkers to facilitate patient stratification. Due to the unbiased and global nature of these profiling methods to assess the levels of protein expression, post-translational modifications such as phosphorylation and glycosylation as well as key metabolites, many of these findings have broad applications not just in specific histotypes but across multiple STS subtypes. Specific examples of proteomic and metabolomic findings that have led to the development of early phase clinical trials of investigational agents will be discussed. While promising, the use of these technologies in the study of sarcoma is still limited, and there is a need for further research in this area. In particular, it would be important to integrate these approaches with other Omics strategies such as genomics and epigenomics as well as implement these tools alongside clinical trials in order to maximize the impact of these tools on our biological understanding and treatment of this group of rare diseases of unmet need.

Keywords: Biomarkers; Drug discovery; Metabolomics; Proteomics; Sarcoma

DOI: https://doi.org/10.1007/s11864-022-00947-3