bims-myxlip 2021-02-28 papers

bims-myxlip

Biomed News

on Myxoid liposarcoma

Issue of 2021–02–28
seven papers selected by
Laura Mannarino, Mario Negri Institute

Prospective evaluation of doxorubicin cardiotoxicity in advanced soft tissue sarcoma patients treated in the ANNOUNCE Phase 3 randomized trial.
Establishment and characterization of NCC-SS4-C1: a novel patient-derived cell line of synovial sarcoma.
Immunotherapy for sarcomas.
Frequent amplification of HDAC genes and efficacy of HDAC inhibitor chidamide and PD-1 blockade combination in soft tissue sarcoma.
Lipid and glucose metabolism in white adipocytes: pathways, dysfunction and therapeutics.
Associations of PD-L1, PD-L2, and HLA class I expression with responses to immunotherapy in patients with advanced sarcoma: post hoc analysis of a phase 1/2 trial.
Establishment of a patient-derived xenograft mouse model of pleomorphic leiomyosarcoma.

Clin Cancer Res. 2021 Feb 25. pii: clincanres.4592.2020. [Epub ahead of print]

Prospective evaluation of doxorubicin cardiotoxicity in advanced soft tissue sarcoma patients treated in the ANNOUNCE Phase 3 randomized trial.

Robin L Jones, Andrew J Wagner, Akira Kawai, Kazuo Tamura, Ashwin Shahir, Brian A Van Tine, Javier Martín-Broto, Patrick M Peterson, Jennifer Wright, William D Tap.

PURPOSE: Few prospective studies have assessed anthracycline-associated cardiotoxicity in sarcoma patients. We evaluated cardiotoxicity in patients with soft tissue sarcomas administered doxorubicin in the Phase 3 ANNOUNCE trial (NCT02451943).
PATIENTS &METHODS: Patients were anthracycline-naïve adults with locally advanced or metastatic disease and left ventricular ejection fraction (LVEF) {greater than or equal to}50%. Patients could receive 8 cycles of doxorubicin at 75 mg/m2. The cardioprotectant dexrazoxane was allowed at investigator discretion. Symptomatic cardiac adverse events (AEs) were recorded using MedDRA and graded using CTCAE 4.0. LVEF deterioration was measured by echocardiogram or multigated acquisition scan, defined as a decrease to <50%, or decrease from baseline value >10%.
RESULTS: 504 patients received {greater than or equal to}1 cycles of doxorubicin (median cumulative dose, 450.3 mg/m2 [range, 72.3-634.0]). Median follow-up of cardiac AEs was 28 weeks. Dexrazoxane was co-administered more frequently to patients receiving higher cumulative doxorubicin doses (38.6% receiving <450 mg/m2, 88.5% receiving 450 - <600 mg/m2, 90% receiving {greater than or equal to}600 mg/m2) and did not affect treatment efficacy. LVEF deterioration was seen in 62/153 (40.5%) who received a cumulative dose <450 mg/m2, 82/159 (51.6%) who received 450 - <600 mg/m2, and 50/89 (56.2%) who received {greater than or equal to}600 mg/m2. Grade {greater than or equal to}3 cardiac dysfunction occurred in 2% of patients at <450 mg/m2, 3% at 450 - <600 mg/m2, and 1.1% at {greater than or equal to}600 mg/m2. Incidence of treatment-related cardiac AEs were low across all dose ranges.
CONCLUSIONS: Although follow-up was short, these results suggest doxorubicin can be administered at high cumulative doses (>450 mg/m2), with a low rate of cardiotoxicities, in the context of dexrazoxane co-administration.

DOI: https://doi.org/10.1158/1078-0432.CCR-20-4592
Hum Cell. 2021 Feb 20.

Establishment and characterization of NCC-SS4-C1: a novel patient-derived cell line of synovial sarcoma.

Ryuto Tsuchiya, Yuki Yoshimatsu, Rei Noguchi, Takuya Ono, Akane Sei, Fumitaka Takeshita, Jun Sugaya, Shintaro Iwata, Akihiko Yoshida, Seiji Ohtori, Akira Kawai, Tadashi Kondo.

  Synovial sarcoma (SS) is defined as a monomorphic blue spindle cell sarcoma showing variable epithelial differentiation, and is characterized by a specific fusion gene, SS18-SSX. Although SS is rare, it accounts for approximately 8% of all soft tissue sarcomas, which occupies a significant proportion of soft tissue tumors. The prognosis of SS is unfavorable, with 5-year survival rate of 50-60%, and only a few anti-cancer agents are recommended for its treatment. Thus, we need to urgently establish novel treatment methods. Patient-derived cell lines are essential tools in basic research and pre-clinical studies. However, there are only 4 publicly available SS cell lines. Therefore, we established a novel SS cell line, NCC-SS4-C1, using surgically resected tumor tissues of a patient with SS. The cell line maintained the characteristic fusion gene, SS18-SSX1, and copy number alteration, in concordance with the original tumor. The cells also exhibited moderate cell proliferation, invasion ability, and spheroid formation ability. Moreover, a drug-screening test using 4 SS cell lines, including NCC-SS4-C1, demonstrated the significant anti-proliferative effects of ALK and HDAC inhibitors. Thus, we concluded that the NCC-SS4-C1 cell line is a useful tool for basic and pre-clinical studies of SS.

Keywords:  Drug screening; Patient-derived cancer model; Patient-derived cell line; Sarcoma; Synovial sarcoma

DOI:  https://doi.org/10.1007/s13577-021-00509-z
Jpn J Clin Oncol. 2021 Feb 22. pii: hyab005. [Epub ahead of print]

Immunotherapy for sarcomas.

Eiji Nakata, Tomohiro Fujiwara, Toshiyuki Kunisada, Tastuo Ito, Shota Takihira, Toshifumi Ozaki.

  Sarcomas are a heterogeneous group of malignancies of mesenchymal origin; their molecular and genomic mechanisms differ with regard to histology. These characteristics lead to the presentation of varied immunological profiles based on the tumor microenvironment. Various immunotherapies are considered for the treatment of sarcoma. These treatments are performed either in isolation or in combination with other methods such as cytotoxic chemotherapy or the use of molecular target agents. Among these, two recently emerging immunotherapies include T-cell receptor gene therapy and immune checkpoint inhibitor therapy, which are expected to be effective for many types of sarcoma. A sarcoma with a disease-specific translocation and a limited number of mutations, such as synovial sarcoma, expresses high levels of self-antigens, like the New York esophageal squamous cell carcinoma 1, which has been targeted in T-cell receptor gene therapy. On the other hand, sarcomas with a greater number of mutations, such as undifferentiated pleomorphic sarcomas, myxofibrosarcoma and dedifferentiated liposarcomas, can be good candidates for immune checkpoint inhibitors. Among immune checkpoint inhibitor therapies, programmed cell death-1 blockade (nivolumab and pembrolizumab) and cytotoxic T-lymphocyte-associated antigen 4 blockade (ipilimumab) have been investigated most often in sarcoma. Although the sole use of immune checkpoint inhibitors provides limited efficacy, combined immunotherapy with immune checkpoint inhibitors or molecular target agents, especially antiangiogenic agents, has shown moderate results against some types of sarcoma, such as the alveolar soft part sarcoma. Several clinical trials utilizing immunotherapy, including T-cell receptor gene therapy and immune checkpoint inhibitors, in sarcomas are under progress. By clarifying the tumor microenvironment and biomarker-predictive capacity of immunotherapy in sarcomas, better clinical trials can be designed; this could lead to improved outcomes for immunotherapy in sarcoma.

Keywords:  immune checkpoint inhibitor; immunotherapy; sarcoma

DOI:  https://doi.org/10.1093/jjco/hyab005
J Immunother Cancer. 2021 Feb;pii: e001696. [Epub ahead of print]9(2):

Frequent amplification of HDAC genes and efficacy of HDAC inhibitor chidamide and PD-1 blockade combination in soft tissue sarcoma.

Yi Que, Xiao-Long Zhang, Ze-Xian Liu, Jing-Jing Zhao, Qiu-Zhong Pan, Xi-Zhi Wen, Wei Xiao, Bu-Shu Xu, Dong-Chun Hong, Tian-Hui Guo, Lu-Jun Shen, Wei-Jun Fan, Huo-Ying Chen, De-Sheng Weng, Hai-Rong Xu, Peng-Hui Zhou, Yi-Zhuo Zhang, Xiao-Hui Niu, Xing Zhang.

   BACKGROUND: The advent of immune checkpoint therapy has been a tremendous advance in cancer treatment. However, the responses are still insufficient in patients with soft tissue sarcoma (STS). We aimed to identify rational combinations to increase the response to immune checkpoint therapy and improve survival.
METHODS: Whole-exome sequencing (WES) was performed in 11 patients with liposarcoma. Somatic copy number alterations (SCNAs) were analyzed at the gene level to identify obvious amplification patterns in drug-target genes. The expression and prognostic value of class I histone deacetylases (HDACs) was evaluated in 49 patients with sarcoma in our center and confirmed in 263 sarcoma samples from The Tumor Cancer Genome Atlas (TCGA) database. Q-PCR, flow cytometry and RNA-seq were performed to determine the correlations between class I HDACs, chidamide and PD-L1 in vitro and in vivo. The efficacy of combining chidamide with PD-1 blockade was explored in an immunocompetent murine model and a small cohort of patients with advanced sarcoma. Western blot, ChIP assay and dual luciferase assessment were applied in the mechanistic study.
RESULTS: The HDAC gene family was frequently amplified in STS. SCNAs in the HDAC gene family were extensively amplified in 8 of 11 (73%) patients with liposarcoma, based on a drug-target gene set, and we verified amplification in 76.65% (197/257) of cases by analyzing TCGA sarcoma cohort. Class I HDAC expression is associated with a poor prognosis for patients with STS, and its inhibition is responsible for promoting apoptosis and upregulating of programmed cell death ligand 1 (PD-L1). The HDAC class I inhibitor chidamide significantly increases PD-L1 expression, increased the infiltration of CD8+ T cells and reduced the number of MDSCs in the tumor microenvironment. The combination of chidamide with an anti-PD-1 antibody significantly promotes tumor regression and improves survival in a murine model. Moreover, chidamide combined with the anti-PD-1 antibody toripalimab is effective in patients with advanced and metastatic sarcoma, and the side effects are tolerable. Mechanistically, chidamide increases histone acetylation at the PD-L1 gene through the activation of the transcriptional factor STAT1.
CONCLUSIONS: The combination of chidamide and anti-programmed cell death 1 (PD-1) therapy represents a potentially important strategy for STS.

Keywords:  programmed cell death 1 receptor; sarcoma

DOI:  https://doi.org/10.1136/jitc-2020-001696
Nat Rev Endocrinol. 2021 Feb 24.

Lipid and glucose metabolism in white adipocytes: pathways, dysfunction and therapeutics.

Pauline Morigny, Jeremie Boucher, Peter Arner, Dominique Langin.

In mammals, the white adipocyte is a cell type that is specialized for storage of energy (in the form of triacylglycerols) and for energy mobilization (as fatty acids). White adipocyte metabolism confers an essential role to adipose tissue in whole-body homeostasis. Dysfunction in white adipocyte metabolism is a cardinal event in the development of insulin resistance and associated disorders. This Review focuses on our current understanding of lipid and glucose metabolic pathways in the white adipocyte. We survey recent advances in humans on the importance of adipocyte hypertrophy and on the in vivo turnover of adipocytes and stored lipids. At the molecular level, the identification of novel regulators and of the interplay between metabolic pathways explains the fine-tuning between the anabolic and catabolic fates of fatty acids and glucose in different physiological states. We also examine the metabolic alterations involved in the genesis of obesity-associated metabolic disorders, lipodystrophic states, cancers and cancer-associated cachexia. New challenges include defining the heterogeneity of white adipocytes in different anatomical locations throughout the lifespan and investigating the importance of rhythmic processes. Targeting white fat metabolism offers opportunities for improved patient stratification and a wide, yet unexploited, range of therapeutic opportunities.

DOI: https://doi.org/10.1038/s41574-021-00471-8
Clin Transl Oncol. 2021 Feb 26.

Associations of PD-L1, PD-L2, and HLA class I expression with responses to immunotherapy in patients with advanced sarcoma: post hoc analysis of a phase 1/2 trial.

S Miwa, T Nojima, A A Alomesen, H Ikeda, N Yamamoto, H Nishida, K Hayashi, A Takeuchi, K Igarashi, T Higuchi, H Yonezawa, Y Araki, S Morinaga, Y Asano, H Tsuchiya.

   BACKGROUND: Although immunotherapy is thought to be a promising cancer treatment, most patients do not respond to immunotherapy. In this post hoc analysis of a phase 1/2 study, associations of programmed death ligand 1 (PD-L1), PD-L2, and HLA class I expressions with responses to dendritic cells (DCs)-based immunotherapy were investigated in patients with advanced sarcoma.
METHODS: This study enrolled 35 patients with metastatic and/or recurrent sarcomas who underwent DC-based immunotherapy. The associations of PD-L1, PD-L2, and HLA class I expressions in tumor specimens, which were resected before immunotherapy, with immune responses (increases of IFN-γ and IL-12) and oncological outcomes were evaluated.
RESULTS: Patients who were PD-L2 (+) showed lower increases of IFN-γ and IL-12 after DC-based immunotherapy than patients who were PD-L2 (-). The disease control (partial response or stable disease) rates of patients who were PD-L1 (+) and PD-L1 (-) were 0% and 22%, respectively. Disease control rates of patients who were PD-L2 (+) and PD-L2 (-) were 13% and 22%, respectively. Patients who were PD-L1 (+) tumors had significantly poorer overall survival compared with patients who were PD-L1 (-). No associations of HLA class I expression with the immune response or oncological outcomes were observed.
CONCLUSIONS: This study suggests that PD-L1 and PD-L2 are promising biomarkers of DC-based immunotherapy, and that addition of immune checkpoint inhibitors to DC-based immunotherapy may improve the outcomes of DC-based immunotherapy.

Keywords:  Biomarker; Dendritic cells; Immunotherapy; PD-L1; PD-L2; Sarcoma

DOI:  https://doi.org/10.1007/s12094-021-02559-z
J Toxicol Pathol. 2021 Jan;34(1): 89-93

Establishment of a patient-derived xenograft mouse model of pleomorphic leiomyosarcoma.

Yasuhiro Shimada, Tomoharu Naito, Takuo Hayashi, Tsuyoshi Saito, Yoshiyuki Suehara, Chihaya Kakinuma, Yuji Nozaki, Hisayoshi Takagi, Takashi Yao.

  Soft tissue sarcomas are difficult to treat using chemotherapy owing to a current deficiency in candidate drugs for specific targets. Screening candidate compounds and analyzing therapeutic targets in sarcomas is insufficient, given the lack of an appropriate human sarcoma animal model to accurately evaluate their efficacy, as well as the lack of an adequate technical protocol for efficient transplantation and engraftment of sarcoma specimens in patient-derived xenograft (PDX) models. Accordingly, in this study, we sought to identify the optimal type of sarcoma and develop a protocol for generating a PDX model. We characterized a PDX mouse model using histopathological and immunohistochemical analyses to determine whether it would show pathological characteristics similar to those of human sarcomas. We achieved engraftment of one of the 10 transplanted sarcoma specimens, the xenografted tumor of which exhibited massive proliferation. Histologically, the engrafted sarcoma foci resembled a primary tumor of pleomorphic leiomyosarcoma and maintained their histological structure in all passages. Moreover, immunohistochemical analysis revealed the expression of specific markers of differentiation to smooth muscle, which is consistent with the features of leiomyosarcoma. We thus demonstrated that our pleomorphic leiomyosarcoma PDX mouse model mimics at least one aspect of human sarcomas, and we believe that this model will facilitate the development of novel therapies for sarcomas.

Keywords:  mouse model; patient-derived xenograft (PDX); pleomorphic leiomyosarcoma (PLMS)

DOI:  https://doi.org/10.1293/tox.2020-0061