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New Strategies in Therapeutic Targets of Soft Tissue Sarcoma: Translational Implications

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 23561

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Dr. Cecilia Garofalo

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Advanced Translational Research Laboratory, Veneto Institute of Oncology IOV—IRCCS, 35127 Padua, Italy
Interests: sarcoma; prognostic and predictive cancer biomarkers; pharmacogenomics; chemoresistance; targeted therapy; anticancer drugs; signal transduction; IGF system in cancer
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Special Issue Information

Dear Colleagues,

Sarcomas are an uncommon and heterogeneous group of mesenchymal malignant tumors originating from bone, cartilage as well as other mesenchymal tissues, such as muscle, fat, peripheral nerves, fibrous, or related tissues. The two main types of sarcoma are soft tissue and bone sarcomas, but there are more than 70 different entities within these two categories. Even if the incidence is low, sarcoma presents a high mortality rate due to high metastatic potential, late diagnosis, and relapse. Survival for treated patients with metastatic disease is only 14-17 months, and the 2-years survival rate is about 30%.

Over the last two decades, the increased knowledge of the new primary molecular and genomic mechanisms of different sarcoma histotypes allowed reclassification of these tumors and consequently to the discovery of innovative chemotherapeutic agents. However, although the raised progress in discovering genetic aberrations and their functions in these tumors, the main therapeutic option for the majority of local recurrence and metastatic sarcomas remains cytotoxic chemotherapy. Moreover, the response rates to novel molecular-targeting drugs are not very extraordinary, and new treatment strategies are required. Thus, there is an urgent need to develop novel treatments and find biomarkers that can help physicians to identify patients who are possible good responders or resistant to specific therapies and predict individual predisposition to toxicity reactions associated with therapies.

This Special Issue aims to summarize the recent advance of new therapeutic options and biomarkers in Soft Tissue Sarcoma (STS). We welcome original research articles and reviews covering clinical, translational, and basic studies, focusing on but not limited to:

(1) In vitro, in vivo, or ex vivo-validated studies on emerging therapeutic targets for Soft Tissue Sarcoma, including immune checkpoints, oncogenes, tumor suppressor genes, non-coding RNAs (miRNA, lncRNA, circRNA), and exosomes;
(2) Innovative therapeutics including small molecules, antibodies (such as PD-1/PD-L1 antibodies), as well as cell therapy (CAR-T and other gene-engineered cells);
(3) Prognostic and predictive biomarkers;
(4) Clinical evaluation of novel treatments efficacy with biomolecular experiments;
(5) New drug delivery systems to achieve precise control of drug release at specific tissue sites and time points, including nanoparticles, micelles, and other natural or artificial materials.

Dr. Cecilia Garofalo
Guest Editor

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Keywords

Soft Tissue Sarcoma
GIST
Prognostic and Predictive cancer biomarkers
Resistance to chemotherapy
Precision Medicine
Targeted Therapy
Pharmacogenomics

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Published Papers (8 papers)

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Research

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15 pages, 2348 KiB

Open AccessArticle

Integrated Antitumor Activities of Cellular Immunotherapy with CIK Lymphocytes and Interferons against KIT/PDGFRA Wild Type GIST

by Erika Fiorino, Alessandra Merlini, Lorenzo D’Ambrosio, Ilaria Cerviere, Enrico Berrino, Caterina Marchiò, Lidia Giraudo, Marco Basiricò, Annamaria Massa, Chiara Donini, Valeria Leuci, Ramona Rotolo, Federica Galvagno, Letizia Vitali, Alessia Proment, Soldano Ferrone, Alberto Pisacane, Ymera Pignochino, Massimo Aglietta, Giovanni Grignani, Giulia Mesiano and Dario Sangiolo Show full author list Hide full author list

Int. J. Mol. Sci. 2022, 23(18), 10368; https://doi.org/10.3390/ijms231810368 - 8 Sep 2022

Cited by 11 | Viewed by 1928

Abstract

Gastrointestinal stromal tumors (GISTs) are rare, mesenchymal tumors of the gastrointestinal tract, characterized by either KIT or PDGFRA mutation in about 85% of cases. KIT/PDGFRA wild type gastrointestinal stromal tumors (wtGIST) account for the remaining 15% of GIST and represent an unmet medical need: their prevalence and potential medical vulnerabilities are not completely defined, and effective therapeutic strategies are still lacking. In this study we set a patient-derived preclinical model of wtGIST to investigate their phenotypic features, along with their susceptibility to cellular immunotherapy with cytokine-induced killer lymphocytes (CIK) and interferons (IFN). We generated 11 wtGIST primary cell lines (wtGISTc). The main CIK ligands (MIC A/B; ULBPs), along with PD-L1/2, were expressed by wtGISTc and the expression of HLA-I molecules was preserved. Patient-derived CIK were capable of intense killing in vitro against wtGISTc resistant to both imatinib and sunitinib. We found that CIK produce a high level of granzyme B, IFNα and IFNγ. CIK-conditioned supernatant was responsible for part of the observed tumoricidal effect, along with positive bystander modulatory activities enhancing the expression of PD-L1/2 and HLA-I molecules. IFNα, but not In, had direct antitumor effects on 50% (4/8) of TKI-resistant wtGISTc, positively correlated with the tumor expression of IFN receptors. wtGIST cells that survived IFNα were still sensitive to CIK immunotherapy. Our data support the exploration of CIK immunotherapy in clinical studies for TKI-resistant wtGIST, proposing reevaluation for IFNα within this challenging setting. Full article

(This article belongs to the Special Issue New Strategies in Therapeutic Targets of Soft Tissue Sarcoma: Translational Implications)

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19 pages, 7236 KiB

Open AccessArticle

Endoglin and MMP14 Contribute to Ewing Sarcoma Spreading by Modulation of Cell–Matrix Interactions

by Pilar Puerto-Camacho, Juan Díaz-Martín, Joaquín Olmedo-Pelayo, Alfonso Bolado-Carrancio, Carmen Salguero-Aranda, Carmen Jordán-Pérez, Marina Esteban-Medina, Inmaculada Álamo-Álvarez, Daniel Delgado-Bellido, Laura Lobo-Selma, Joaquín Dopazo, Ana Sastre, Javier Alonso, Thomas G. P. Grünewald, Carmelo Bernabeu, Adam Byron, Valerie G. Brunton, Ana Teresa Amaral and Enrique De Álava

Int. J. Mol. Sci. 2022, 23(15), 8657; https://doi.org/10.3390/ijms23158657 - 4 Aug 2022

Cited by 3 | Viewed by 2771

Abstract

Endoglin (ENG) is a mesenchymal stem cell (MSC) marker typically expressed by active endothelium. This transmembrane glycoprotein is shed by matrix metalloproteinase 14 (MMP14). Our previous work demonstrated potent preclinical activity of first-in-class anti-ENG antibody-drug conjugates as a nascent strategy to eradicate Ewing sarcoma (ES), a devastating rare bone/soft tissue cancer with a putative MSC origin. We also defined a correlation between ENG and MMP14 expression in ES. Herein, we show that ENG expression is significantly associated with a dismal prognosis in a large cohort of ES patients. Moreover, both ENG/MMP14 are frequently expressed in primary ES tumors and metastasis. To deepen in their functional relevance in ES, we conducted transcriptomic and proteomic profiling of in vitro ES models that unveiled a key role of ENG and MMP14 in cell mechano-transduction. Migration and adhesion assays confirmed that loss of ENG disrupts actin filament assembly and filopodia formation, with a concomitant effect on cell spreading. Furthermore, we observed that ENG regulates cell–matrix interaction through activation of focal adhesion signaling and protein kinase C expression. In turn, loss of MMP14 contributed to a more adhesive phenotype of ES cells by modulating the transcriptional extracellular matrix dynamics. Overall, these results suggest that ENG and MMP14 exert a significant role in mediating correct spreading machinery of ES cells, impacting the aggressiveness of the disease. Full article

(This article belongs to the Special Issue New Strategies in Therapeutic Targets of Soft Tissue Sarcoma: Translational Implications)

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12 pages, 3712 KiB

Open AccessArticle

Enapotamab Vedotin, an AXL-Specific Antibody-Drug Conjugate, Demonstrates Antitumor Efficacy in Patient-Derived Xenograft Models of Soft Tissue Sarcoma

by Britt Van Renterghem, Agnieszka Wozniak, Patricia Garrido Castro, Patrick Franken, Nora Pencheva, Raf Sciot and Patrick Schöffski

Int. J. Mol. Sci. 2022, 23(14), 7493; https://doi.org/10.3390/ijms23147493 - 6 Jul 2022

Cited by 5 | Viewed by 2731

Abstract

Doxorubicin (doxo) remains the standard of care for patients with advanced soft tissue sarcoma (STS), even though response rates to doxo are only around 14% to 18%. We evaluated enapotamab vedotin (EnaV), an AXL-specific antibody-drug conjugate (ADC), in a panel of STS patient-derived xenografts (PDX). Eight models representing multiple STS subtypes were selected from our STS PDX platform (n = 45) by AXL immunostaining on archived passages. Models were expanded by unilateral transplantation of tumor tissue into the left flank of 20 NMRI nu/nu mice. Once tumors were established, mice were randomized into an EnaV treatment group, or a group treated with isotype control ADC. Treatment efficacy was assessed by tumor volume evaluation, survival analysis, and histological evaluation of tumors, and associated with AXL expression. EnaV demonstrated significant tumor growth delay, regression, and/or prolonged survival compared to isotype control ADC in 5/8 STS PDX models investigated. Experimental passages of responding models were all found positive for AXL at varying levels, but no linear relationship could be identified between the level of expression and level of response to EnaV. One model was found negative for AXL on experimental passage and did not respond to EnaV. This study provides a preclinical rationale for the evaluation of AXL-targeting ADCs in the treatment of AXL-expressing sarcomas. Full article

(This article belongs to the Special Issue New Strategies in Therapeutic Targets of Soft Tissue Sarcoma: Translational Implications)

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15 pages, 6437 KiB

Open AccessArticle

Plocabulin, a Novel Tubulin Inhibitor, Has Potent Antitumour Activity in Patient-Derived Xenograft Models of Soft Tissue Sarcoma

by Yannick Wang, Agnieszka Wozniak, Jasmien Cornillie, Pablo Avilés, Maria Debiec-Rychter, Raf Sciot and Patrick Schöffski

Int. J. Mol. Sci. 2022, 23(13), 7454; https://doi.org/10.3390/ijms23137454 - 5 Jul 2022

Cited by 2 | Viewed by 2234

Abstract

A clinically relevant subset of patients with soft tissue sarcoma presents with either locally advanced or upfront metastatic disease, or will develop distant metastases over time, despite successful treatment of their primary tumour. The currently available systemic agents to treat such advanced cases only provide modest disease control and are not active in all histological subtypes. Thus, there is an unmet need for novel and more efficacious agents to improve the outcome of this rare disease. In the current preclinical in vivo study, we evaluated plocabulin, a novel tubulin inhibitor, in five distinct histological subtypes of soft tissue sarcoma: dedifferentiated liposarcoma, leiomyosarcoma, undifferentiated sarcoma, intimal sarcoma and CIC-rearranged sarcoma. The efficacy was tested in seven patient-derived xenograft models, which were generated by the engraftment of tumour fragments from patients directly into nude mice. The treatment lasted 22 days, and the efficacy of the drug was assessed and compared to the doxorubicin and vehicle groups by volumetric analysis, histopathology and immunohistochemistry. We observed tumour volume control in all the tested histological subtypes. Additionally, in three sarcoma subtypes, extensive central necrosis, associated with significant tumour regression, was seen. This histological response is explained by the drug’s vascular-disruptive properties, reflected by a decreased total vascular area in the xenografts. Our results demonstrate the in vivo efficacy of plocabulin in the preclinical models of soft tissue sarcoma and corroborate the findings of our previous study, which demonstrated similar vascular-disruptive effects in gastrointestinal stromal tumours—another subtype of soft tissue sarcoma. Our data provide a convincing rationale for further clinical exploration of plocabulin in soft tissue sarcomas. Full article

(This article belongs to the Special Issue New Strategies in Therapeutic Targets of Soft Tissue Sarcoma: Translational Implications)

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19 pages, 2679 KiB

Open AccessArticle

Correlation of Immunological and Molecular Profiles with Response to Crizotinib in Alveolar Soft Part Sarcoma: An Exploratory Study Related to the EORTC 90101 “CREATE” Trial

by Che-Jui Lee, Elodie Modave, Bram Boeckx, Bernd Kasper, Steinar Aamdal, Michael G. Leahy, Piotr Rutkowski, Sebastian Bauer, Maria Debiec-Rychter, Raf Sciot, Diether Lambrechts, Agnieszka Wozniak and Patrick Schöffski

Int. J. Mol. Sci. 2022, 23(10), 5689; https://doi.org/10.3390/ijms23105689 - 19 May 2022

Cited by 4 | Viewed by 2872

Abstract

Alveolar soft part sarcoma (ASPS) is a rare subtype of soft tissue sarcoma characterized by an unbalanced translocation, resulting in ASPSCR1-TFE3 fusion that transcriptionally upregulates MET expression. The European Organization for Research and Treatment of Cancer (EORTC) 90101 “CREATE” phase II trial evaluated the MET inhibitor crizotinib in ASPS patients, achieving only limited antitumor activity. We performed a comprehensive molecular analysis of ASPS tissue samples collected in this trial to identify potential biomarkers correlating with treatment outcome. A tissue microarray containing 47 ASPS cases was used for the characterization of the tumor microenvironment using multiplex immunofluorescence. DNA isolated from 34 available tumor samples was analyzed to detect recurrent gene copy number alterations (CNAs) and mutations by low-coverage whole-genome sequencing and whole-exome sequencing. Pathway enrichment analysis was used to identify diseased-associated pathways in ASPS sarcomagenesis. Kaplan–Meier estimates, Cox regression, and the Fisher’s exact test were used to correlate histopathological and molecular findings with clinical data related to crizotinib treatment, aiming to identify potential factors associated with patient outcome. Tumor microenvironment characterization showed the presence of PD-L1 and CTLA-4 in 10 and 2 tumors, respectively, and the absence of PD-1 in all specimens. Apart from CD68, other immunological markers were rarely expressed, suggesting a low level of tumor-infiltrating lymphocytes in ASPS. By CNA analysis, we detected a number of broad and focal alterations. The most common alteration was the loss of chromosomal region 1p36.32 in 44% of cases. The loss of chromosomal regions 1p36.32, 1p33, 1p22.2, and 8p was associated with shorter progression-free survival. Using whole-exome sequencing, 13 cancer-associated genes were found to be mutated in at least three cases. Pathway enrichment analysis identified genetic alterations in NOTCH signaling, chromatin organization, and SUMOylation pathways. NOTCH4 intracellular domain dysregulation was associated with poor outcome, while inactivation of the beta-catenin/TCF complex correlated with improved outcome in patients receiving crizotinib. ASPS is characterized by molecular heterogeneity. We identify genetic aberrations potentially predictive of treatment outcome during crizotinib therapy and provide additional insights into the biology of ASPS, paving the way to improve treatment approaches for this extremely rare malignancy. Full article

(This article belongs to the Special Issue New Strategies in Therapeutic Targets of Soft Tissue Sarcoma: Translational Implications)

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21 pages, 8661 KiB

Open AccessArticle

Deciphering the Genomic Landscape and Pharmacological Profile of Uncommon Entities of Adult Rhabdomyosarcomas

by Alessandro De Vita, Silvia Vanni, Valentina Fausti, Claudia Cocchi, Federica Recine, Giacomo Miserocchi, Chiara Liverani, Chiara Spadazzi, Massimo Bassi, Manlio Gessaroli, Angelo Campobassi, Giovanni De Luca, Federica Pieri, Anna Farnedi, Eugenia Franchini, Anna Ferrari, Chiara Domizio, Enrico Cavagna, Lorena Gurrieri, Alberto Bongiovanni, Nada Riva, Sebastiano Calpona, Giandomenico Di Menna, Silvia Angela Debonis, Toni Ibrahim and Laura Mercatali Show full author list Hide full author list

Int. J. Mol. Sci. 2021, 22(21), 11564; https://doi.org/10.3390/ijms222111564 - 26 Oct 2021

Cited by 20 | Viewed by 3209

Abstract

Adult rhabdomyosarcoma (RMS) represents an uncommon entity with an incidence of less than 3% of all soft tissue sarcomas (STS). Consequently, the natural history and the clinical management of this disease are infrequently reported. In order to fill this gap, we investigated the molecular biology of an adult RMS case series. The expression of epithelial mesenchymal transition-related gene and chemoresistance-related gene panels were evaluated. Moreover, taking advantage of our STS translational model combining patient-derived primary culture and 3D-scaffold, the pharmacological profile of an adult head and neck sclerosing RMS was assessed. Furthermore, NGS, microsatellite instability, and in silico analyses were carried out. RT-PCR identified the upregulation of CDH1, SLUG, MMP9, RAB22a, S100P, and LAPTM4b, representing promising biomarkers for this disease. Pharmacological profiling showed the highest sensitivity with anthracycline-based regimen in both 2D and 3D culture systems. NGS analysis detected RAB3IP-HMGA2 in frame gene rearrangement and FGFR4 mutation; microsatellite instability analysis did not detect any alteration. In silico analysis confirmed the mutation of FGFR4 as a promising marker for poor prognosis and a potential therapeutic target. We report for the first time the molecular and pharmacological characterization of rare entities of adult head and neck and posterior trunk RMS. These preliminary data could shed light on this poorly understood disease. Full article

(This article belongs to the Special Issue New Strategies in Therapeutic Targets of Soft Tissue Sarcoma: Translational Implications)

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19 pages, 8641 KiB

Open AccessArticle

CHIR99021, trough GSK-3β Targeting, Reduces Epithelioid Sarcoma Cell Proliferation by Activating Mitotic Catastrophe and Autophagy

by Sabino Russi, Alessandro Sgambato, Anna Maria Bochicchio, Pietro Zoppoli, Michele Aieta, Alba Maria Lucia Capobianco, Vitalba Ruggieri, Emanuela Zifarone, Geppino Falco and Simona Laurino

Int. J. Mol. Sci. 2021, 22(20), 11147; https://doi.org/10.3390/ijms222011147 - 15 Oct 2021

Cited by 13 | Viewed by 3513

Abstract

Epithelioid sarcoma (ES) is a rare disease representing <1% of soft tissue sarcomas. Current therapies are based on anthracycline alone or in combination with ifosfamide or other cytotoxic drugs. ES is still characterized by a poor prognosis with high rates of recurrence. Indeed, for years, ES survival rates have remained stagnant, suggesting that conventional treatments should be revised and improved. New therapeutic approaches are focused to target the key regulators of signaling pathways, the causative markers of tumor pathophysiology. To this end, we selected, among the drugs to which an ES cell line is highly sensitive, those that target signaling pathways known to be dysregulated in ES. In particular, we found a key role for GSK-3β, which results in up-regulation in tumor versus normal tissue samples and associated to poor prognosis in sarcoma patients. Following this evidence, we evaluated CHIR99021, a GSK-3 inhibitor, as a potential drug for use in ES therapy. Our data highlight that, in ES cells, CHIR99021 induces cell cycle arrest, mitotic catastrophe (MC) and autophagic response, resulting in reduced cell proliferation. Our results support the potential efficacy of CHIR99021 in ES treatment and encourage further preclinical and clinical studies. Full article

(This article belongs to the Special Issue New Strategies in Therapeutic Targets of Soft Tissue Sarcoma: Translational Implications)

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Review

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14 pages, 783 KiB

Open AccessReview

Organoids: A New Chapter in Sarcoma Diagnosis and Treatment

by Iason Psilopatis, Stefania Kokkali, Kostas Palamaris, Antonia Digklia, Kleio Vrettou and Stamatios Theocharis

Int. J. Mol. Sci. 2022, 23(19), 11271; https://doi.org/10.3390/ijms231911271 - 24 Sep 2022

Cited by 11 | Viewed by 3017

Abstract

Sarcomas are malignant tumors of mesenchymal origin that can occur at any age. The rarity of these tumors in combination with the vast number of histological subtypes render the study of sarcomas challenging. Organoids represent complex three-dimensional cell culture systems, deriving from stem cells and preserving the capacity to differentiate into the cell types of their tissue of origin. The aim of the present review is to study the current status of patient-derived organoids, as well as their potential to model tumorigenesis and perform drug screenings for sarcomas. In order to identify relevant studies, a literature review was conducted and we were able to identify 16 studies published between 2019 and 2022. The current manuscript represents the first comprehensive review of the literature focusing on the use of organoids for disease modelling and drug sensitivity testing in diverse sarcoma subtypes. Full article

(This article belongs to the Special Issue New Strategies in Therapeutic Targets of Soft Tissue Sarcoma: Translational Implications)

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