bims-myxlip 2022-01-02 papers

Issue of 2022‒01‒02
five papers selected by
Laura Mannarino
Humanitas Research

Am J Transl Res. 2021 ;13(11): 12181-12194

Challenges in modeling EWS-FLI1-driven transgenic mouse model for Ewing sarcoma.

Balaji Ramachandran, Thangarajan Rajkumar, Gopal Gopisetty.

EWS-FLI1 is a master regulator of Ewing sarcoma (ES) oncogenesis. Although EWS-FLI1 represents a clear therapeutic target, targeted therapeutic inhibitors are lacking. Scientific literature has indicated accumulating information pertaining to EWS-FLI1 translocation, pathogenesis, function, oncogenic partnerships, and potential clinical relevance. However, attempts to develop EWS-FLI1-driven human-like ES mouse models or in vivo systems ended up with limited success. Establishing such models as preclinical screening tools may accelerate the development of EWS-FLI1 targeted therapeutic inhibitors. This review summarizes the current scenario, which focuses on the limitations, challenges, and possible reasons for past failures in model development and also plausible interim alternatives.

Keywords: EWS-FLI1; Ewing sarcoma; fusion protein; mouse models; progenitor cells; tumor cell of origin

Genes Cancer. 2021 ;12 96-105

EZH2 suppresses endogenous retroviruses and an interferon response in cancers.

Panneerselvam Jayabal, Xiuye Ma, Yuzuru Shiio.

Ewing sarcoma is an aggressive cancer of bone and soft tissue in children. It is characterized by the chromosomal translocation between EWS and an Ets family transcription factor, most commonly FLI1. We recently reported that Ewing sarcoma depends on the autocrine signaling mediated by a cytokine, NELL2. NELL2 signaling stimulates the transcriptional output of EWS-FLI1 through the BAF chromatin remodeling complexes. While studying the impact of NELL2 silencing on Ewing sarcoma, we found that suppression of NELL2 signaling induces the expression of endogenous retroviruses (ERVs) and LINE-1 retrotransposons, an interferon response, and growth arrest. We determined that a histone methyltransferase, EZH2, is the critical downstream target of NELL2 signaling in suppressing ERVs, LINE-1, an interferon response, and growth arrest. We show that EZH2 inhibitors induce ERVs, LINE-1, and an interferon response in a variety of cancer types. These results uncover the role for NELL2-EZH2 signaling in suppressing endogenous virus-like agents and an antiviral response, and suggest the potential utility of EZH2 inhibitors in enhancing anti-tumor immunity.

Keywords: EZH2; Ewing sarcoma; NELL2; endogenous retroviruses; interferon response

DOI: https://doi.org/10.18632/genesandcancer.218

Cancer Sci. 2021 Dec 31.

High prevalence of TERT aberrations in myxoid liposarcoma: TERT reactivation may play a crucial role in tumorigenesis.

Junko Kunieda, Kyoko Yamashita, Yuki Togashi, Satoko Baba, Seiji Sakata, Kentaro Inamura, Keisuke Ae, Seiichi Matsumoto, Rikuo Machinami, Masanobu Kitagawa, Kengo Takeuchi.

Myxoid liposarcoma (MLPS) is genetically characterized by FUS-DDIT3 or EWSR1-DDIT3 gene fusion and high frequency of hotspot mutations (C228T or C250T) in the promoter region of TERT which encodes telomerase reverse transcriptase (TERT). The latter leads to telomerase reactivation, a mechanism of telomere maintenance. Although TERT promoter hotspot mutation is a poor prognostic factor in various tumors, its effect on MLPS has not been reported in detail. In the present study, we examined the clinicopathological characteristics, prognosis, and telomere maintenance mechanisms in 83 primary tumor samples of MLPS, which was resected surgically at Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan, from 2008 to 2020. TERT promoter hotspot mutations were observed in 77% (63/82) cases, and alternative lengthening of telomeres (ALT) was absent in all cases. Among the cases without TERT promoter hotspot mutations, TERT rearrangements and minor point mutations in the TERT promoter region were found in three and two cases, respectively. TERT mRNA expression was consistently observed even in cases where no genomic TERT aberrations were detected, and the presence of TERT promoter hotspot mutation did not correlate significantly with either overall and metastasis-free survival (p = 0.56, p = 0.83, respectively) or clinicopathological features. Thus, MLPS characteristically shows TERT expression and high prevalence of TERT aberrations. Our findings suggest that TERT aberration is not prognostic factor, but might occur at an early stage and play a key role in tumorigenesis.

Keywords: TERT ; TERT promoter; myxoid liposarcoma; telomerase; telomere

DOI: https://doi.org/10.1111/cas.15256

Front Cell Dev Biol. 2021 ;9 763640

The Extracellular Matrix in Soft Tissue Sarcomas: Pathobiology and Cellular Signalling.

Valeriya Pankova, Khin Thway, Robin L Jones, Paul H Huang.

Soft tissue sarcomas are rare cancers of mesenchymal origin or differentiation comprising over 70 different histological subtypes. Due to their mesenchymal differentiation, sarcomas are thought to produce and deposit large quantities of extracellular matrix (ECM) components. Interactions between ECM ligands and their corresponding adhesion receptors such as the integrins and the discoidin domain receptors play key roles in driving many fundamental oncogenic processes including uncontrolled proliferation, cellular invasion and altered metabolism. In this review, we focus on emerging studies that describe the key ECM components commonly found in soft tissue sarcomas and discuss preclinical and clinical evidence outlining the important role that these proteins and their cognate adhesion receptors play in sarcomagenesis. We conclude by providing a perspective on the need for more comprehensive in-depth analyses of both the ECM and adhesion receptor biology in multiple histological subtypes in order to identify new drug targets and prognostic biomarkers for this group of rare diseases of unmet need.

Keywords: collagen; discoidin domain receptors; extracellular matrix; integrins; sarcoma

DOI: https://doi.org/10.3389/fcell.2021.763640

Clin Cancer Res. 2021 Dec 29. pii: clincanres.2258.2021. [Epub ahead of print]

Trabectedin plus durvalumab in patients with advanced pretreated soft tissue sarcoma and ovarian carcinoma (TRAMUNE): an open-label, multicenter phase Ib study.

Maud Toulmonde, Mehdi Brahmi, Antoine Giraud, Camille Chakiba, Alban Bessede, Michèle Kind, Emilie Toulza, Marina Pulido, Sabrina Albert, Jean-Philippe Guégan, Sophie Cousin, Simone Mathoulin-Pélissier, Raul Perret, Sabrina Croce, Jean-Yves Blay, Isabelle Ray-Coquard, Anne Floquet, Antoine Italiano.

PURPOSE: Trabectedin has shown pre-clinical synergy with immune-checkpoint inhibitors in pre-clinical models.EXPERIMENTAL DESIGN: TRAMUNE is a phase Ib study investigating trabectedin combined with durvalumab trough a dose-escalation phase and two expansion cohorts (soft tissue sarcoma and ovarian carcinoma). Trabectedin was given at three dose levels (1 mg/m2, 1.2 mg/m2 and 1.5 mg/m2) on day 1, in combination with durvalumab, 1120 mg on day 2, every 3 weeks. The primary endpoints were the recommended phase II dose (RP2D) of trabectedin combined with durvalumab and the objective response rate (ORR) as per RECIST 1.1. The secondary endpoints included safety, 6-month progression-free rate (PFR), progression-free survival (PFS), overall survival, and biomarker analyses.
RESULTS: 40 patients were included (dose escalation: n=9; STS cohort: n=16; ovarian cohort: n=15, 80% platinum resistant/refractory). The most frequent toxicities were grade 1-2 fatigue, nausea, neutropenia, and alanine/aspartate aminotransferase increase. One patient experienced a dose-limiting toxicity at dose level 2. Trabectedin at 1.2 mg/m2 was selected as the RP2D. In the STS cohort, 43% of patients experienced tumor shrinkage, the ORR was 7% (95% CI 0.2 - 33.9) and the 6-month PFR 28.6% (95% CI 8.4-58.1). In the ovarian carcinoma cohort, 43% of patients experienced tumor shrinkage, the ORR was 21.4% (95% CI 4.7 - 50.8) and the 6-month PFR 42.9% (95% CI 17.7 - 71.1). Baseline levels of PD-L1 expression and CD8-positive T-cell infiltrates were associated with PFS in ovarian carcinoma patients.
CONCLUSIONS: Combining trabectedin and durvalumab is manageable. Promising activity is observed in platinum-refractory ovarian carcinoma patients.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-2258