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16 pages, 2980 KiB

Open AccessArticle

Predictive Biomarkers of Pathological Response to Neoadjuvant Chemoradiotherapy for Locally Advanced Soft Tissue Sarcomas

by Anna Szumera-Ciećkiewicz, Klaudia Bobak, Mateusz J. Spałek, Kamil Sokół, Michał Wągrodzki, Daria Owczarek, Monika Kawecka, Beata Puton, Hanna Koseła-Paterczyk, Piotr Rutkowski and Anna M. Czarnecka

Cancers 2023, 15(11), 2960; https://doi.org/10.3390/cancers15112960 - 29 May 2023

Cited by 4 | Viewed by 1881

Abstract

Background: Marginally resectable and unresectable soft tissue sarcomas (STS) remain a therapy challenge due to the lack of highly active treatment. The aim of the study was to identify a biomarker to predict the pathological response (PR) to preplanned treatment of these STSs. [...] Read more.

Background: Marginally resectable and unresectable soft tissue sarcomas (STS) remain a therapy challenge due to the lack of highly active treatment. The aim of the study was to identify a biomarker to predict the pathological response (PR) to preplanned treatment of these STSs. Methods: In the phase II clinical trial (NCT03651375), locally advanced STS patients received preoperative treatment with a combination of doxorubicin-ifosfamide chemotherapy and 5 × 5 Gy radiotherapy. PR to the treatment was classified using the European Organization for Research and Treatment of Cancer–Soft Tissue and Bone Sarcoma Group recommendations. We have chosen HIF-1α, CD163, CD68, CD34, CD105, and γH2AFX proteins, rendering different biological phenomena, for biomarker study. Results: Nineteen patients were enrolled and in four cases a good PR was reported. The high expression of HIF-1α before surgery showed a negative correlation with PR, which means a poor response to therapy. Furthermore, the samples after surgery had decreased expression of HIF-1α, which confirmed the correlation with PR. However, high expression of γH2AFX positively correlated with PR, which provides better PR. The high number of positive-staining TAMs and the high IMVD did not correlate with PR. Conclusions: HIF1α and γH2AFX could be potential biomarkers for PR prediction after neoadjuvant treatment in STS. Full article

(This article belongs to the Special Issue Targeted Treatment for Soft Tissue Sarcoma and Bone Sarcoma)

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19 pages, 4449 KiB

Open AccessArticle

The MYC-YBX1 Circuit in Maintaining Stem-like Vincristine-Resistant Cells in Rhabdomyosarcoma

by Madeline Fritzke, Kenian Chen, Weiliang Tang, Spencer Stinson, Thao Pham, Yadong Wang, Lin Xu and Eleanor Y. Chen

Cancers 2023, 15(10), 2788; https://doi.org/10.3390/cancers15102788 - 17 May 2023

Cited by 2 | Viewed by 2118

Abstract

Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma that causes significant devastation, with no effective therapy for relapsed disease. The mechanisms behind treatment failures are poorly understood. Our study showed that treatment of RMS cells with vincristine led to an increase in CD133-positive [...] Read more.

Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma that causes significant devastation, with no effective therapy for relapsed disease. The mechanisms behind treatment failures are poorly understood. Our study showed that treatment of RMS cells with vincristine led to an increase in CD133-positive stem-like resistant cells. Single cell RNAseq analysis revealed that MYC and YBX1 were among the top-scoring transcription factors in CD133-high expressing cells. Targeting MYC and YBX1 using CRISPR/Cas9 reduced stem-like characteristics and viability of the vincristine-resistant cells. MYC and YBX1 showed mutual regulation, with MYC binding to the YBX1 promoter and YBX1 binding to MYC mRNA. The MYC inhibitor MYC361i synergized with vincristine to reduce tumor growth and stem-like cells in a zebrafish model of RMS. MYC and YBX expression showed a positive correlation in RMS patients, and high MYC expression correlated with poor survival. Targeting the MYC-YBX1 axis holds promise for improving survival in RMS patients. Full article

(This article belongs to the Special Issue Targeted Treatment for Soft Tissue Sarcoma and Bone Sarcoma)

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15 pages, 31845 KiB

Open AccessArticle

Therapeutic Implications of TGF-β Pathway in Desmoid Tumor Based on Comprehensive Molecular Profiling and Clinicopathological Properties

by Kum-Hee Yun, Changhee Park, Hyang Joo Ryu, Chan-Young Ock, Young Han Lee, Wooyeol Baek, Hong In Yoon, Yoon Dae Han, Sang Kyum Kim, JooHee Lee, Seong-Jin Kim, Kyung-Min Yang, Seung Hyun Kim and Hyo Song Kim

Cancers 2022, 14(23), 5975; https://doi.org/10.3390/cancers14235975 - 2 Dec 2022

Cited by 4 | Viewed by 2064

Abstract

(1) Background: Desmoid tumors have a relatively high local failure rate after primary treatment using surgery and/or radiotherapy. Moreover, desmoid tumors recur at the primary site for many patients. An effective therapeutic strategy for the desmoid tumor is needed to maintain quality of [...] Read more.

(1) Background: Desmoid tumors have a relatively high local failure rate after primary treatment using surgery and/or radiotherapy. Moreover, desmoid tumors recur at the primary site for many patients. An effective therapeutic strategy for the desmoid tumor is needed to maintain quality of life and prolong survival. (2) Method: First of all, we collected desmoid tumor tissues and investigated the status of protein expression for beta-catenin and alpha-SMA through immunohistochemistry. Then, we performed targeted sequencing and whole RNA sequencing. To compare the data with other cancer types, we used NGS data from sarcoma patients at Yonsei Cancer Center (YCC-sarcoma cohort, n = 48) and The Cancer Genome Atlas (TCGA, n = 9235). Secondly, we established the novel patient-derived preclinical models (n = 2) for the validation of treatment strategy. The same gene alteration of primary tissue was demonstrated. (3) Results: We discovered specific gene sets related to the TGF-β signaling pathway. Moreover, we selected the combination treatment comprising TGF-β inhibitor, vactosertib, and imatinib. In screening for the anti-proliferation effect, the combination treatment of TGF-β inhibitor was more effective for tumor suppression than monotherapy. (4) Conclusion: We found preclinical indications that TGF-β inhibitors could prove useful as a potential treatment for patients with desmoid tumors. Moreover, we could find some examples in clinical trials. Full article

(This article belongs to the Special Issue Targeted Treatment for Soft Tissue Sarcoma and Bone Sarcoma)

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29 pages, 9819 KiB

Open AccessArticle

Investigating the Potential of Isolating and Expanding Tumour-Infiltrating Lymphocytes from Adult Sarcoma

by Alice Ko, Victoria S. Coward, Nalan Gokgoz, Brendan C. Dickson, Kim Tsoi, Jay S. Wunder and Irene L. Andrulis

Cancers 2022, 14(3), 548; https://doi.org/10.3390/cancers14030548 - 21 Jan 2022

Cited by 4 | Viewed by 2970

Abstract

Sarcomas are a heterogeneous group of mesenchymal neoplasms, many of which are associated with a high risk of metastasis and poor prognosis. Conventional chemotherapy and targeted therapies have varying effects across individuals and tumour subtypes. The current therapies frequently provide limited clinical benefit; [...] Read more.

Sarcomas are a heterogeneous group of mesenchymal neoplasms, many of which are associated with a high risk of metastasis and poor prognosis. Conventional chemotherapy and targeted therapies have varying effects across individuals and tumour subtypes. The current therapies frequently provide limited clinical benefit; hence, more effective treatments are urgently needed. Recent advances in immunotherapy, such as checkpoint inhibition or adoptive cell therapy (ACT), show potential in increasing efficacy by providing a more personalized treatment. Therapy with tumour-infiltrating lymphocytes (TILs) is an emerging field in immunotherapy. Here, we collected 190 sarcoma tumour specimens from patients without pre-operative adjuvant treatment in order to isolate TILs. We compared different methods of TIL expansion and optimized a protocol specifically for efficacy in culturing TILs from sarcoma. The expanded TIL populations were characterized by flow cytometry analysis using CD3, CD4, CD8, CD14, CD19 and CD56 markers. The TIL populations were non-specifically stimulated to establish TIL reactivity. Through an optimized expansion protocol, TILs were isolated and cultured from 54 of 92 primary sarcoma specimens. The isolated TILs varied in CD4⁺ and CD8⁺ T-cell compositions and retained their ability to release IFNγ upon stimulation. Our results suggest that certain sarcoma subtypes have the potential to yield a sufficient number of TILs for TIL therapy. Full article

(This article belongs to the Special Issue Targeted Treatment for Soft Tissue Sarcoma and Bone Sarcoma)

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9 pages, 597 KiB

Open AccessArticle

Pre-Treatment Neutrophil-to-Lymphocyte Ratio (NLR) as a Predictive Marker of Pazopanib Treatment for Soft-Tissue Sarcoma

by Yasuyoshi Sato, Kenji Nakano, Xiaofei Wang, Naoki Fukuda, Tetsuya Urasaki, Akihiro Ohmoto, Naomi Hayashi, Mayu Yunokawa, Makiko Ono, Junichi Tomomatsu, Masanori Saito, Yusuke Minami, Keiko Hayakawa, Yuki Funauchi, Taisuke Tanizawa, Keisuke Ae, Seiichi Matsumoto and Shunji Takahashi

Cancers 2021, 13(24), 6266; https://doi.org/10.3390/cancers13246266 - 14 Dec 2021

Cited by 11 | Viewed by 2547

Abstract

Pazopanib with trabectedin and eribulin is widely used to treat soft-tissue sarcoma (STS). We have shown that baseline neutrophil-to-lymphocyte ratio (NLR) may predict the efficacy and patient prognosis of eribulin. Changes in NLR, but not baseline NLR, can predict patient prognosis of trabectedin. [...] Read more.

Pazopanib with trabectedin and eribulin is widely used to treat soft-tissue sarcoma (STS). We have shown that baseline neutrophil-to-lymphocyte ratio (NLR) may predict the efficacy and patient prognosis of eribulin. Changes in NLR, but not baseline NLR, can predict patient prognosis of trabectedin. However, prognostic factors of pazopanib for STS have not been identified. We present a retrospective analysis of 141 patients treated with pazopanib for recurrent or metastatic non-round cell STS. Univariate and multivariate analyses were performed to determine the predictive factors of durable clinical benefit (DCB), overall survival (OS), and progression-free survival. L-sarcoma histology (odds ratio [OR] = 0.31, 95% CI = 0.12–0.79; p = 0.014) and pre-treatment NLR < 3.0 (OR = 2.03, 95% CI = 1.02–6.67; p = 0.045) were independent predictive factors of DCB. Pre-treatment NLR < 3.0 (hazard ratio [HR] = 0.55, 95% CI = 0.36–0.84; p = 0.0057), liposarcoma histology (HR = 1.78, 95% CI = 1.09–2.91; p = 0.022), primary extremity site (HR = 0.48, 95% CI = 0.31–0.75; p = 0.0010), ECOG PS ≥ 1 (HR = 1.62, 95% CI = 1.08–2.42; p = 0.019), and CRP < 0.3 (HR = 0.52, 95% CI = 0.33–0.82; p = 0.0050) were independent predictive factors of OS. These findings indicate that baseline NLR predicts the efficacy and patient prognosis of pazopanib for STS. Full article

(This article belongs to the Special Issue Targeted Treatment for Soft Tissue Sarcoma and Bone Sarcoma)

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Review

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20 pages, 1181 KiB

Open AccessReview

Innovative Breakthroughs for the Treatment of Advanced and Metastatic Synovial Sarcoma

by Lorena Landuzzi, Maria Cristina Manara, Laura Pazzaglia, Pier-Luigi Lollini and Katia Scotlandi

Cancers 2023, 15(15), 3887; https://doi.org/10.3390/cancers15153887 - 30 Jul 2023

Cited by 5 | Viewed by 2482

Abstract

Synovial sarcoma (SyS) is a rare aggressive soft tissue sarcoma carrying the chromosomal translocation t(X;18), encoding the fusion transcript SS18::SSX. The fusion oncoprotein interacts with both BAF enhancer complexes and polycomb repressor complexes, resulting in genome-wide epigenetic perturbations and a unique altered genetic [...] Read more.

Synovial sarcoma (SyS) is a rare aggressive soft tissue sarcoma carrying the chromosomal translocation t(X;18), encoding the fusion transcript SS18::SSX. The fusion oncoprotein interacts with both BAF enhancer complexes and polycomb repressor complexes, resulting in genome-wide epigenetic perturbations and a unique altered genetic signature. Over 80% of the patients are initially diagnosed with localized disease and have a 5-year survival rate of 70–80%, but metastatic relapse occurs in 50% of the cases. Advanced, unresectable, or metastatic disease has a 5-year survival rate below 10%, representing a critical issue. This review summarizes the molecular mechanisms behind SyS and illustrates current treatments in front line, second line, and beyond settings. We analyze the use of immune check point inhibitors (ICI) in SyS that do not behave as an ICI-sensitive tumor, claiming the need for predictive genetic signatures and tumor immune microenvironment biomarkers. We highlight the clinical translation of innovative technologies, such as proteolysis targeting chimera (PROTAC) protein degraders or adoptive transfer of engineered immune cells. Adoptive cell transfer of engineered T-cell receptor cells targeting selected cancer/testis antigens has shown promising results against metastatic SyS in early clinical trials and further improvements are awaited from refinements involving immune cell engineering and tumor immune microenvironment enhancement. Full article

(This article belongs to the Special Issue Targeted Treatment for Soft Tissue Sarcoma and Bone Sarcoma)

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12 pages, 616 KiB

Open AccessReview

Targetable Pathways in the Treatment of Retroperitoneal Liposarcoma

by Lucia Casadei, Fernanda Costas Casal de Faria, Alexandra Lopez-Aguiar, Raphael E. Pollock and Valerie Grignol

Cancers 2022, 14(6), 1362; https://doi.org/10.3390/cancers14061362 - 8 Mar 2022

Cited by 15 | Viewed by 3933

Abstract

Liposarcoma (LPS) is the most prevalent soft tissue sarcoma histological subtype. When it occurs in the abdomen the overall survival rate is as low as 10% at 10 years and is fraught with high rates of recurrence, particularly for the more aggressive dedifferentiated [...] Read more.

Liposarcoma (LPS) is the most prevalent soft tissue sarcoma histological subtype. When it occurs in the abdomen the overall survival rate is as low as 10% at 10 years and is fraught with high rates of recurrence, particularly for the more aggressive dedifferentiated subtype. Surgery remains the mainstay of treatment. Systemic therapies for the treatment of metastatic or unresectable disease have low response rates. Deep understanding of well-differentiated and de-differentiated LPS (WDLPS and DDLPS, respectively) oncologic drivers is necessary for the development of new efficacious targeted therapies for the management of this disease. This review discusses the current treatments under evaluation for retroperitoneal DDLPS and the potential targetable pathways in DDLPS. Full article

(This article belongs to the Special Issue Targeted Treatment for Soft Tissue Sarcoma and Bone Sarcoma)

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23 pages, 3780 KiB

Open AccessReview

TP53 in Biology and Treatment of Osteosarcoma

by Kamil Jozef Synoradzki, Ewa Bartnik, Anna M. Czarnecka, Michał Fiedorowicz, Wiktoria Firlej, Anna Brodziak, Agnieszka Stasinska, Piotr Rutkowski and Paweł Grieb

Cancers 2021, 13(17), 4284; https://doi.org/10.3390/cancers13174284 - 25 Aug 2021

Cited by 34 | Viewed by 5029

Abstract

The TP53 gene is mutated in 50% of human tumors. Oncogenic functions of mutant TP53 maintain tumor cell proliferation and tumor growth also in osteosarcomas. We collected data on TP53 mutations in patients to indicate which are more common and describe their role [...] Read more.

The TP53 gene is mutated in 50% of human tumors. Oncogenic functions of mutant TP53 maintain tumor cell proliferation and tumor growth also in osteosarcomas. We collected data on TP53 mutations in patients to indicate which are more common and describe their role in in vitro and animal models. We also describe animal models with TP53 dysfunction, which provide a good platform for testing the potential therapeutic approaches. Finally, we have indicated a whole range of pharmacological compounds that modulate the action of p53, stabilize its mutated versions or lead to its degradation, cause silencing or, on the contrary, induce the expression of its functional version in genetic therapy. Although many of the described therapies are at the preclinical testing stage, they offer hope for a change in the approach to osteosarcoma treatment based on TP53 targeting in the future. Full article

(This article belongs to the Special Issue Targeted Treatment for Soft Tissue Sarcoma and Bone Sarcoma)

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