Research

Jump to: Review

25 pages, 4706 KiB

Open AccessArticle

Selective Targeting of Class I Histone Deacetylases in a Model of Human Osteosarcoma

by Haydee M. Torres, Ashley M. VanCleave, Mykayla Vollmer, Dakota L. Callahan, Austyn Smithback, Josephine M. Conn, Tania Rodezno-Antunes, Zili Gao, Yuxia Cao, Yohannes Afeworki and Jianning Tao

Cancers 2021, 13(16), 4199; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164199 - 20 Aug 2021

Cited by 7 | Viewed by 3789

Abstract

Dysregulation of histone deacetylases (HDACs) is associated with the pathogenesis of human osteosarcoma, which may present an epigenetic vulnerability as well as a therapeutic target. Domatinostat (4SC-202) is a next-generation class I HDAC inhibitor that is currently being used in clinical research for [...] Read more.

Dysregulation of histone deacetylases (HDACs) is associated with the pathogenesis of human osteosarcoma, which may present an epigenetic vulnerability as well as a therapeutic target. Domatinostat (4SC-202) is a next-generation class I HDAC inhibitor that is currently being used in clinical research for certain cancers, but its impact on human osteosarcoma has yet to be explored. In this study, we report that 4SC-202 inhibits osteosarcoma cell growth in vitro and in vivo. By analyzing cell function in vitro, we show that the anti-tumor effect of 4SC-202 involves the combined induction of cell-cycle arrest at the G2/M phase and apoptotic program, as well as a reduction in cell invasion and migration capabilities. We also found that 4SC-202 has little capacity to promote osteogenic differentiation. Remarkably, 4SC-202 revised the global transcriptome and induced distinct signatures of gene expression in vitro. Moreover, 4SC-202 decreased tumor growth of established human tumor xenografts in immunodeficient mice in vivo. We further reveal key targets regulated by 4SC-202 that contribute to tumor cell growth and survival, and canonical signaling pathways associated with progression and metastasis of osteosarcoma. Our study suggests that 4SC-202 may be exploited as a valuable drug to promote more effective treatment of patients with osteosarcoma and provide molecular insights into the mechanism of action of class I HDAC inhibitors. Full article

(This article belongs to the Special Issue Research Advances and Therapeutic Strategies of Human Osteosarcoma)

► Show Figures

Figure 1

16 pages, 2743 KiB

Open AccessArticle

The YAP/TEAD Axis as a New Therapeutic Target in Osteosarcoma: Effect of Verteporfin and CA3 on Primary Tumor Growth

by Sarah Morice, Mathilde Mullard, Regis Brion, Maryne Dupuy, Sarah Renault, Robel Tesfaye, Bénédicte Brounais-Le Royer, Benjamin Ory, Françoise Redini and Franck Verrecchia

Cancers 2020, 12(12), 3847; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123847 - 20 Dec 2020

Cited by 25 | Viewed by 3934

Abstract

Although some studies suggested that disruption of the Hippo signaling pathway is associated with osteosarcoma progression, the molecular mechanisms by which YAP regulates primary tumor growth is not fully clarified. In addition, the validation of YAP as a therapeutic target through the use [...] Read more.

Although some studies suggested that disruption of the Hippo signaling pathway is associated with osteosarcoma progression, the molecular mechanisms by which YAP regulates primary tumor growth is not fully clarified. In addition, the validation of YAP as a therapeutic target through the use of inhibitors in a preclinical model must be demonstrated. RNA-seq analysis and Kaplan–Meier assays identified a YAP signature in osteosarcoma patients and a correlation with patients’ outcomes. Molecular and cellular analysis (RNAseq, PLA, immunoprecipitation, promoter/specific gene, proliferation, cell cycle assays) using overexpression of mutated forms of YAP able or unable to interact with TEAD, indicate that TEAD is crucial for YAP-driven cell proliferation and in vivo tumor growth. In addition, in vivo experiments using an orthotopic mice model of osteosarcoma show that two YAP/TEAD inhibitors, verteporfin and CA3, reduce primary tumor growth. In this context, in vitro experiments demonstrate that these inhibitors decrease YAP expression, YAP/TEAD transcriptional activity and cell viability mainly by their ability to induce cell apoptosis. We thus demonstrate that the YAP/TEAD signaling axis is a central actor in mediating primary tumor growth of osteosarcoma, and that the use of YAP inhibitors may be a promising therapeutic strategy against osteosarcoma tumor growth. Full article

(This article belongs to the Special Issue Research Advances and Therapeutic Strategies of Human Osteosarcoma)

► Show Figures

Graphical abstract

12 pages, 3715 KiB

Open AccessArticle

Head and Neck Osteosarcoma—The Ongoing Challenge about Reconstruction and Dental Rehabilitation

by Andrea Cassoni, Edoardo Brauner, Resi Pucci, Valentina Terenzi, Nicolò Mangini, Andrea Battisti, Marco Della Monaca, Alessandro Ciolfi, Federico Laudoni, Stefano Di Carlo and Valentino Valentini

Cancers 2020, 12(7), 1948; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071948 - 18 Jul 2020

Cited by 9 | Viewed by 5349

Abstract

Head and Neck osteosarcoma is an uncommon disease. Hitherto, the treatment is surgical resection and survival is influenced by the presence of free margins. However, the dimension of the resection may represent a hurdle for an adequate Quality of Life (QOL). Maxillofacial district [...] Read more.

Head and Neck osteosarcoma is an uncommon disease. Hitherto, the treatment is surgical resection and survival is influenced by the presence of free margins. However, the dimension of the resection may represent a hurdle for an adequate Quality of Life (QOL). Maxillofacial district is a narrow space where the function, esthetics and patient’s relational skills fit together like the gears of a clock. The functional results depend on the type of reconstruction and prosthetic rehabilitation that are both important to guarantee a good aesthetic result and finally increase the patient’s self-esteem. This study aims to report our experience about head and neck (HN) osteosarcoma focusing the attention on reconstructive and dental-rehabilitative problems. It is a retrospective study all patients were surgically treated in our department. Subjects with histological diagnosis of HN osteosarcoma, treated between 2005 and 2017 were included. The demographic characteristics, surgical treatment, eventually secondary reconstruction and prosthetic rehabilitation, performed in the same department, have been collected. The QOL was assessed through the EORTC QLQ-H&N35 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck 35) questionnaire. Fifteen patients were enrolled, eight received a free flap microsurgical reconstruction. Dental rehabilitation was performed in five cases and a mobile prosthesis was always delivered. Eighteen implants were inserted in fibula bones for three patients; highly porous implants were used. Full article

(This article belongs to the Special Issue Research Advances and Therapeutic Strategies of Human Osteosarcoma)

► Show Figures

Figure 1

13 pages, 1832 KiB

Open AccessArticle

Combinatorial Nanomedicine Made of Squalenoyl-Gemcitabine and Edelfosine for the Treatment of Osteosarcoma

by Carlos Rodríguez-Nogales, Haritz Moreno, Carolina Zandueta, Didier Desmaële, Fernando Lecanda, Patrick Couvreur and María J. Blanco-Prieto

Cancers 2020, 12(7), 1895; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071895 - 14 Jul 2020

Cited by 7 | Viewed by 2571

Abstract

Due to chemoresistance and a high propensity to form lung metastasis, survival rates in pediatric osteosarcoma (OS) are poor. With the aim to improve anticancer activity in pediatric OS, a multidrug nanomedicine was designed using the alkyl-lysophospholipid edelfosine (EF) co-assembled with squalenoyl–gemcitabine (SQ–Gem) [...] Read more.

Due to chemoresistance and a high propensity to form lung metastasis, survival rates in pediatric osteosarcoma (OS) are poor. With the aim to improve anticancer activity in pediatric OS, a multidrug nanomedicine was designed using the alkyl-lysophospholipid edelfosine (EF) co-assembled with squalenoyl–gemcitabine (SQ–Gem) to form nanoassemblies (NAs) of 50 nm. SQ–Gem/EF NAs modified the total Gem pool exposure in the blood stream in comparison with SQ–Gem NAs, which correlated with a better tolerability and a lower toxicity profile after multiple intravenous administrations in mice. For in vivo preclinical assessment in an orthotopic OS tumor model, P1.15 OS cells were intratibially injected in athymic nude mice. SQ–Gem/EF NAs considerably decreased the primary tumor growth kinetics and reduced the number of lung metastases. Our findings support the candidature of this anticancer nanomedicine as a potential pediatric OS therapy. Full article

(This article belongs to the Special Issue Research Advances and Therapeutic Strategies of Human Osteosarcoma)

► Show Figures

Graphical abstract

21 pages, 4004 KiB

Open AccessArticle

Pazopanib and Trametinib as a Synergistic Strategy against Osteosarcoma: Preclinical Activity and Molecular Insights

by Giulia Chiabotto, Giovanni Grignani, Maja Todorovic, Valentina Martin, Maria Laura Centomo, Elisa Prola, Giorgia Giordano, Alessandra Merlini, Umberto Miglio, Enrico Berrino, Lucia Napione, Claudio Isella, Federica Capozzi, Marco Basiricò, Cristina Marsero, Ilaria Gerardi, Tiziana Venesio, Dario Sangiolo, Massimo Aglietta, Lorenzo D’Ambrosio and Ymera Pignochino Show full author list Hide full author list

Cancers 2020, 12(6), 1519; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061519 - 10 Jun 2020

Cited by 14 | Viewed by 4003

Abstract

Receptor tyrosine kinases (RTKs) inhibitors’ activity in advanced osteosarcoma is significant but short-lived. To prevent or at least delay drug resistance, we explored a vertical inhibition by combining drugs acting at different levels of the RTK pathways (pazopanib + trametinib). We studied pazopanib [...] Read more.

Receptor tyrosine kinases (RTKs) inhibitors’ activity in advanced osteosarcoma is significant but short-lived. To prevent or at least delay drug resistance, we explored a vertical inhibition by combining drugs acting at different levels of the RTK pathways (pazopanib + trametinib). We studied pazopanib + trametinib antitumor activity both in vitro and in vivo (MNNG-HOS and KHOS xenografts in NOD/SCID mice) investigating the molecular mechanisms and potential escapes. The involvement of MAPK-PI3K pathways was validated by Nanostring technology, western blot and by silencing/overexpression experiments. Pazopanib targets were expressed on seven osteosarcoma cell lines and their pathways were activated. Pazopanib + trametinib exhibited synergistic antitumor activity by inducing apoptosis and inhibiting ERK1/2 and Akt. In vivo antitumor activity was shown in osteosarcoma-bearing mice. The drug combination significantly down-modulated RTK Ephrin Type-A Receptor 2 (EphA2) and Interleukin-7 Receptor (IL-7R), whereas induced mitogen-activated protein-kinase kinase (MAPKK) MEK6. EphA2 silencing significantly reduced osteosarcoma cell proliferation and migration, while impeding MEK6 up-regulation in the treated cells significantly increased the antitumor effect of the studied drugs. Moreover, the up-regulation of MEK6 reduced combination activity. Pazopanib + trametinib demonstrated synergistic antitumor effects in osteosarcoma models through ERK and Akt inhibition and EphA2 and IL-7R down-modulation. MEK6 up-regulation might evoke escaping mechanism. Full article

(This article belongs to the Special Issue Research Advances and Therapeutic Strategies of Human Osteosarcoma)

► Show Figures

Figure 1

15 pages, 2328 KiB

Open AccessArticle

Safety and Activity of the Combination of Ceritinib and Dasatinib in Osteosarcoma

by Olaf Beck, Claudia Paret, Alexandra Russo, Jürgen Burhenne, Margaux Fresnais, Kevin Steimel, Larissa Seidmann, Daniel-Christoph Wagner, Nadine Vewinger, Nadine Lehmann, Maximilian Sprang, Nora Backes, Lea Roth, Marie Astrid Neu, Arthur Wingerter, Nicole Henninger, Khalifa El Malki, Henrike Otto, Francesca Alt, Alexander Desuki, Thomas Kindler and Joerg Faber Show full author list Hide full author list

Cancers 2020, 12(4), 793; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12040793 - 26 Mar 2020

Cited by 15 | Viewed by 3658

Abstract

Osteosarcoma (OS) is the second most common cause of cancer-related death in pediatric patients. The insulin-like growth factor (IGF) pathway plays a relevant role in the biology of OS but no IGF targeted therapies have been successful as monotherapy so far. Here, we [...] Read more.

Osteosarcoma (OS) is the second most common cause of cancer-related death in pediatric patients. The insulin-like growth factor (IGF) pathway plays a relevant role in the biology of OS but no IGF targeted therapies have been successful as monotherapy so far. Here, we tested the effect of three IGF specific inhibitors and tested ceritinib as an off-target inhibitor, alone or in combination with dasatinib, on the proliferation of seven primary OS cells. Picropodophyllin, particularly in combination with dasatinib and the combination ceritinib/dasatinib were effective in abrogating the proliferation. The ceritinib/dasatinib combination was applied to the primary cells of a 16-year-old girl with a long history of lung metastases, and was more effective than cabozantinib and olaparib. Therefore, the combination was used to treat the patient. The treatment was well tolerated, with toxicity limited to skin rush and diarrhea. A histopathological evaluation of the tumor after three months of therapy indicated regions of high necrosis and extensive infiltration of macrophages. The extension of the necrosis was proportional to the concentration of dasatinib and ceritinib in the area, as analysed by an ultra performance liquid chromatography–tandem mass spectrometer (UPLC-MS/MS). After the cessation of the therapy, radiological analysis indicated a massive growth of the patient’s liver metastases. In conclusion, these data indicate that the combination of ceritinib/dasatinib is safe and may be used to develop new therapy protocols. Full article

(This article belongs to the Special Issue Research Advances and Therapeutic Strategies of Human Osteosarcoma)

► Show Figures

Figure 1

Review

Jump to: Research

24 pages, 1625 KiB

Open AccessEditor’s ChoiceReview

Mechanisms of Resistance to Conventional Therapies for Osteosarcoma

by Louise Marchandet, Morgane Lallier, Céline Charrier, Marc Baud’huin, Benjamin Ory and François Lamoureux

Cancers 2021, 13(4), 683; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040683 - 08 Feb 2021

Cited by 68 | Viewed by 4182

Abstract

Osteosarcoma (OS) is the most common primary bone tumor, mainly occurring in children and adolescents. Current standard therapy includes tumor resection associated with multidrug chemotherapy. However, patient survival has not evolved for the past decades. Since the 1970s, the 5-year survival rate is [...] Read more.

Osteosarcoma (OS) is the most common primary bone tumor, mainly occurring in children and adolescents. Current standard therapy includes tumor resection associated with multidrug chemotherapy. However, patient survival has not evolved for the past decades. Since the 1970s, the 5-year survival rate is around 75% for patients with localized OS but dramatically drops to 20% for bad responders to chemotherapy or patients with metastases. Resistance is one of the biological processes at the origin of therapeutic failure. Therefore, it is necessary to better understand and decipher molecular mechanisms of resistance to conventional chemotherapy in order to develop new strategies and to adapt treatments for patients, thus improving the survival rate. This review will describe most of the molecular mechanisms involved in OS chemoresistance, such as a decrease in intracellular accumulation of drugs, inactivation of drugs, improved DNA repair, modulations of signaling pathways, resistance linked to autophagy, disruption in genes expression linked to the cell cycle, or even implication of the micro-environment. We will also give an overview of potential therapeutic strategies to circumvent resistance development. Full article

(This article belongs to the Special Issue Research Advances and Therapeutic Strategies of Human Osteosarcoma)

► Show Figures

Figure 1

26 pages, 9882 KiB

Open AccessReview

Surgical Advances in Osteosarcoma

by Marcus J. Brookes, Corey D. Chan, Bence Baljer, Sachin Wimalagunaratna, Timothy P. Crowley, Maniram Ragbir, Alistair Irwin, Zakareya Gamie, Thomas Beckingsale, Kanishka M. Ghosh and Kenneth S. Rankin

Cancers 2021, 13(3), 388; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13030388 - 21 Jan 2021

Cited by 30 | Viewed by 4333

Abstract

Osteosarcoma (OS) is the most common primary bone cancer in children and, unfortunately, is associated with poor survival rates. OS most commonly arises around the knee joint, and was traditionally treated with amputation until surgeons began to favour limb-preserving surgery in the 1990s. [...] Read more.

Osteosarcoma (OS) is the most common primary bone cancer in children and, unfortunately, is associated with poor survival rates. OS most commonly arises around the knee joint, and was traditionally treated with amputation until surgeons began to favour limb-preserving surgery in the 1990s. Whilst improving functional outcomes, this was not without problems, such as implant failure and limb length discrepancies. OS can also arise in areas such as the pelvis, spine, head, and neck, which creates additional technical difficulty given the anatomical complexity of the areas. We reviewed the literature and summarised the recent advances in OS surgery. Improvements have been made in many areas; developments in pre-operative imaging technology have allowed improved planning, whilst the ongoing development of intraoperative imaging techniques, such as fluorescent dyes, offer the possibility of improved surgical margins. Technological developments, such as computer navigation, patient specific instruments, and improved implant design similarly provide the opportunity to improve patient outcomes. Going forward, there are a number of promising avenues currently being pursued, such as targeted fluorescent dyes, robotics, and augmented reality, which bring the prospect of improving these outcomes further. Full article

(This article belongs to the Special Issue Research Advances and Therapeutic Strategies of Human Osteosarcoma)

► Show Figures

Figure 1

18 pages, 3491 KiB

Open AccessReview

Recent Insights into Therapy Resistance in Osteosarcoma

by Zachary D. Prudowsky and Jason T. Yustein

Cancers 2021, 13(1), 83; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13010083 - 30 Dec 2020

Cited by 56 | Viewed by 4812

Abstract

Osteosarcoma, the most common bone malignancy of childhood, has been a challenge to treat and cure. Standard chemotherapy regimens work well for many patients, but there remain minimal options for patients with progressive or resistant disease, as clinical trials over recent decades have [...] Read more.

Osteosarcoma, the most common bone malignancy of childhood, has been a challenge to treat and cure. Standard chemotherapy regimens work well for many patients, but there remain minimal options for patients with progressive or resistant disease, as clinical trials over recent decades have failed to significantly improve survival. A better understanding of therapy resistance is necessary to improve current treatments and design new strategies for future treatment options. In this review, we discuss known mechanisms and recent scientific advancements regarding osteosarcoma and its patterns of resistance against chemotherapy, radiation, and other newly-introduced therapeutics. Full article

(This article belongs to the Special Issue Research Advances and Therapeutic Strategies of Human Osteosarcoma)

► Show Figures