Molecular and clinicopathological analysis revealed an immuno-checkpoint inhibitor as a potential therapeutic target in a subset of high-grade myxofibrosarcoma

Yamashita, Atsushi; Suehara, Yoshiyuki; Hayashi, Takuo; Takagi, Tatsuya; Kubota, Daisuke; Sasa, Keita; Hasegawa, Naoto; Ishijima, Muneaki; Yao, Takashi; Saito, Tsuyoshi

doi:10.1007/s00428-022-03358-9

Cited by 5 publications

(8 citation statements)

References 53 publications

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“…Genetic analysis of the newly established cell lines revealed signi cant alterations in key tumor suppressor genes, including TP53, CDKN2A, and CDKN2B. These ndings align with those of previous studies highlighting the prevalence of such mutations in MFS, underscoring the relevance of these cell lines as models with representative genetic mutations in the disease [21][22][23]. However, the absence of CNA in genes such as RB1, ATRX, and HDLBP, which has been reported in other MFS studies, points to the genetic diversity inherent in MFS, further emphasizing the need for a broad range of patient-derived cancer models [9,24].…”

Section: Discussionsupporting

confidence: 88%

Establishment and characterization of two novel patient-derived cell lines from myxofibrosarcoma: NCC-MFS7-C1 and NCC-MFS8-C1

Adachi,

Noguchi,

Osaki

et al. 2024

Preprint

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Myxofibrosarcoma (MFS), an aggressive soft tissue sarcoma, presents a significant challenge because of its high recurrence rate, distal metastasis, and complex genetic background. Although surgical resection is the standard treatment for MFS, the outcomes are unsatisfactory, and effective non-surgical treatment strategies, including drug therapy, are urgently warranted. MFS is a rare tumor that requires comprehensive preclinical research to develop promising drug therapies; however, only two MFS cell lines are publicly available worldwide. The present study reports two novel patient-derived MFS cell lines, NCC-MFS7-C1 and NCC-MFS8-C1. These cell lines have been extensively characterized for their genetic profile, proliferation, spheroid-forming capacity, and invasive behavior, confirming that they retain MFS hallmarks. Furthermore, we conducted comprehensive drug screening against these cell lines and six others previously established in our laboratory to identify potential therapeutic candidates for MFS. Among the screened agents, actinomycin D, bortezomib, and romidepsin demonstrated considerable antiproliferative effects that were superior to those of doxorubicin, a standard drug, highlighting their potential as novel drugs. In conclusion, NCC-MFS7-C1 and NCC-MFS8-C1 are valuable research resources that contribute to the understanding of the pathogenesis and development of novel therapies for MFS.

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Section: Discussionsupporting

confidence: 88%

Establishment and characterization of two novel patient-derived cell lines from myxofibrosarcoma: NCC-MFS7-C1 and NCC-MFS8-C1

Adachi,

Noguchi,

Osaki

et al. 2024

Preprint

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“…To visualize in situ protein expression on biological sections, we used the relationship between antibodies and antigens to perform immunohistochemistry staining as described [48] for tumors obtained from five patients with in-frame tyrosine kinase fusions identified by the TruSight Tumor 170 assay and validated via RT-PCR using antibodies (Supplemental Table 3; http://links.lww.com/CORR/B254). Of the 82 patients, seven had in-frame tyrosine kinase fusions.…”

Section: Methodsmentioning

confidence: 99%

Detection of Novel Tyrosine Kinase Fusion Genes as Potential Therapeutic Targets in Bone and Soft Tissue Sarcomas Using DNA/RNA-based Clinical Sequencing

Hasegawa,

Hayashi,

Niizuma

et al. 2023

Clin Orthop Relat Res

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Background Approximately 1% of clinically treatable tyrosine kinase fusions, including anaplastic lymphoma kinase, neurotrophic tyrosine receptor kinase, RET proto-oncogene, and ROS proto-oncogene 1, have been identified in soft tissue sarcomas via comprehensive genome profiling based on DNA sequencing. Histologic tumor-specific fusion genes have been reported in approximately 20% of soft tissue sarcomas; however, unlike tyrosine kinase fusion genes, these fusions cannot be directly targeted in therapy. Approximately 80% of tumor-specific fusion-negative sarcomas, including myxofibrosarcoma and leiomyosarcoma, that are defined in complex karyotype sarcomas remain genetically uncharacterized; this mutually exclusive pattern of mutations suggests that other mutually exclusive driver oncogenes are yet to be discovered. Tumor-specific, fusion-negative sarcomas may be associated with unique translocations, and oncogenic fusion genes, including tyrosine kinase fusions, may have been overlooked in these sarcomas. Questions/purposes (1) Can DNA- or RNA-based analysis reveal any characteristic gene alterations in bone and soft tissue sarcomas? (2) Can useful and potential tyrosine kinase fusions in tumors from tumor-specific, fusion-negative sarcomas be detected using an RNA-based screening system? (3) Do the identified potential fusion tumors, especially in neurotrophic tyrosine receptor kinase gene fusions in bone sarcoma, transform cells and respond to targeted drug treatment in in vitro assays? (4) Can the identified tyrosine kinase fusion genes in sarcomas be useful therapeutic targets? Methods Between 2017 and 2020, we treated 100 patients for bone and soft tissue sarcomas at five institutions. Any biopsy or surgery from which a specimen could be obtained was included as potentially eligible. Ninety percent (90 patients) of patients were eligible; a further 8% (8 patients) were excluded because they were either lost to follow-up or their diagnosis was changed, leaving 82% (82 patients) for analysis here. To answer our first and second questions regarding gene alterations and potential tyrosine kinase fusions in eight bone and 74 soft tissue sarcomas, we used the TruSight Tumor 170 assay to detect mutations, copy number variations, and gene fusions in the samples. To answer our third question, we performed functional analyses involving in vitro assays to determine whether the identified tyrosine kinase fusions were associated with oncogenic abilities and drug responses. Finally, to determine usefulness as therapeutic targets, two pediatric patients harboring an NTRK fusion and an ALK fusion were treated with tyrosine kinase inhibitors in clinical trials. Results DNA/RNA-based analysis demonstrated characteristic alterations in bone and soft tissue sarcomas; DNA-based analyses detected TP53 and copy number alterations of MDM2 and CDK4. These single-nucleotide variants and copy number variations were enriched in specific fusion-negative sarcomas. RNA-based screening detected fusion genes in 24% (20 of 82) of patients. Useful potential fusions were detected in 19% (11 of 58) of tumor-specific fusion-negative sarcomas, with nine of these patients harboring tyrosine kinase fusion genes; five of these patients had in-frame tyrosine kinase fusion genes (STRN3-NTRK3, VWC2-EGFR, ICK-KDR, FOXP2-MET, and CEP290-MET) with unknown pathologic significance. The functional analysis revealed that STRN3-NTRK3 rearrangement that was identified in bone had a strong transforming potential in 3T3 cells, and that STRN3-NTRK3–positive cells were sensitive to larotrectinib in vitro. To confirm the usefulness of identified tyrosine kinase fusion genes as therapeutic targets, patients with well-characterized LMNA-NTRK1 and CLTC-ALK fusions were treated with tyrosine kinase inhibitors in clinical trials, and a complete response was achieved. Conclusion We identified useful potential therapeutic targets for tyrosine kinase fusions in bone and soft tissue sarcomas using RNA-based analysis. We successfully identified STRN3-NTRK3 fusion in a patient with leiomyosarcoma of bone and determined the malignant potential of this fusion gene via functional analyses and drug effects. In light of these discoveries, comprehensive genome profiling should be considered even if the sarcoma is a bone sarcoma. There seem to be some limitations regarding current DNA-based comprehensive genome profiling tests, and it is important to use RNA testing for proper diagnosis and accurate identification of fusion genes. Studies on more patients, validation of results, and further functional analysis of unknown tyrosine kinase fusion genes are required to establish future treatments. Clinical Relevance DNA- and RNA-based screening systems may be useful for detecting tyrosine kinase fusion genes in specific fusion-negative sarcomas and identifying key therapeutic targets, leading to possible breakthroughs in the treatment of bone and soft tissue sarcomas. Given that current DNA sequencing misses fusion genes, RNA-based screening systems should be widely considered as a worldwide test for sarcoma. If standard treatments such as chemotherapy are not effective, or even if the sarcoma is of bone, RNA sequencing should be considered to identify as many therapeutic targets as possible.

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“…However, current scholarly attention predominantly centers on the imperative of achieving complete tumor resection, with limited insights into the underlying molecular mechanisms. Recent investigations have pointed towards a signi cant correlation between the RB1 gene and recurrence-free survival in MFS patients, as evidenced by both univariate and multivariate analyses [31] . Some scholars have also found changes in HDLBP driving genes in myxo brosarcoma [35] .…”

Section: Blay Et Al Established a Positive Correlation Between Surger...mentioning

confidence: 98%

Analysis of clinical factors impacting recurrence in myxofibrosarcoma

chen,

sun,

wei

2023

Preprint

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Background Myxofibrosarcoma (MFS) is a malignant fibroblastic/myofibroblastic neoplasm with the prominent myxoid area. It has the clinical features of frequent local recurrence (LR) and occasional distant metastasis. Robust epidemiological data of China on MFS are lacking. The aim of this retrospective analysis is to understand the natural history of MFS and aim to identify prognostic factors of recurrence and describe real-life outcomes of MFS. Methods We reviewed 52 patients with primary MFS from the first affiliated Hospital of Nanjing Medical University and diagnosed between 2016 and 2020. All tumors were retrospectively univariate analyzed for prognostic factors of the disease, including tumor size, grade, location and gender, patient age, planned operation, surgical margin and laboratory results. Then the significant factors of univariate analysis were analyzed by multivariate analysis. Overall survival (OS), post-treatment LR and metastatic-free survival were assessed as outcomes. Results Median age was 61 years (range, 13–93). Fourteen (26.92%) were low grade, 38 (73.08%) were high grade. 29 males, 23 females, 15 cases(28.85%) occurred in the trunk and 37 ༈71.15%༉cases in the extremities, 26 received planned surgery and 26 underwent an unexpected operation. The margin was negative in 39 ༈75%༉cases and positive in 13 cases༈25%༉. Serum creatine kinase (CK) was high level in 33(63.46%) cases and low level in 19(36.54%) cases. LR occurred in 25 cases༈48.08%༉ and metastasis in 4 cases. A worse LR rate was found in low CK level (84.21%) than in the high CK level (27.27%) at 5 years (p ༜0.05). The LR rate of patients undergoing planned surgery was lower than that of patients undergoing unplanned surgery (p ༜0.05). The patients with positive margin were significantly higher than that of patients with negative margin (92.30%,33.33%, respectively, p ༜0.05). And tumors recorded as superficial were also associated with higher recurrence rate of 2/20 (10%) when compared to deep tumors, at 23/32 (71.86%) (p ༜0.05). Conclusions The probability of LR of MFS was significantly higher in patients with unplanned operation, positive margin, low serum CK levels and superficial tumor depth. These data could help identify a high-risk patient group, thus selecting a more careful follow-up for higher-risk patients. Diagnosis and treatment in qualified regular medical centers can reduce the local recurrence rate of MFS.

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Molecular and clinicopathological analysis revealed an immuno-checkpoint inhibitor as a potential therapeutic target in a subset of high-grade myxofibrosarcoma

Cited by 5 publications

References 53 publications

Establishment and characterization of two novel patient-derived cell lines from myxofibrosarcoma: NCC-MFS7-C1 and NCC-MFS8-C1

Establishment and characterization of two novel patient-derived cell lines from myxofibrosarcoma: NCC-MFS7-C1 and NCC-MFS8-C1

Detection of Novel Tyrosine Kinase Fusion Genes as Potential Therapeutic Targets in Bone and Soft Tissue Sarcomas Using DNA/RNA-based Clinical Sequencing

Analysis of clinical factors impacting recurrence in myxofibrosarcoma

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