Genomics and Therapeutic Vulnerabilities of Primary Bone Tumors
Abstract
:1. Introduction
2. Osteosarcoma
2.1. Low-Grade Osteosarcomas
2.2. High-Grade Osteosarcomas
2.2.1. Germline Genetics
2.2.2. Somatic Genetics
2.2.3. Candidate Predictive and Prognostic Biomarkers
2.2.4. Epigenetics
2.2.5. Immunotherapy and Tumor Mutational Burden
3. Chondrosarcoma
3.1. Central Chondrosarcomas
3.2. Secondary Peripheral Chondrosarcomas
3.3. Rare Variants of Chondrosarcoma
4. Ewing Sarcoma
5. Critical Open Issues and Perspectives
6. Concluding Remarks
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ACT/CS1 | atypical cartilaginous tumour/chondrosarcoma grade 1 |
ACVR2A-FN | activin receptor 2A- fibronectin |
AKT | Serine/Threonine Kinase+ |
APC | APC regulator of WNT signaling pathway |
APCDD1 | APC down-regulated 1 |
Bcl-2 | Apoptosis Regulator |
BET | the bromodomain and extra terminal domain |
BRCA1 | breast related cancer antigen 1 |
BRCA2 | breast related cancer antigen 2 |
CD99 | CD99 Molecule (XgBloodGroup) |
CDK4 | cyclin-dependent kinase 4 |
CDK4/6 | cyclin-dependent kinase 4/6 |
CDKN2A | cyclin-dependent kinase Inhibitor 2A |
CR | complete response |
DAPK1 | death-associated protein kinase 1 |
DNA/RNA | DeoxyriboNucleic Acid/RiboNucleic Acid |
DNMTs | DNA methyltransferases |
EGFR | epidermal growth factor receptor |
ERCC1 | excision repair cross-complementation group 1 |
ERCC2 | excision repair cross-complementation group 2 |
ERG | ETS transcription factor ERG |
ETS | proto-oncogene 1, transcription factor 1 |
ETV1 | ETS Variant Transcription Factor 1 |
ETV4 | ETS Variant Transcription Factor 4 |
EWS-FLI | Ewing Sarcoma-Friend Leukemia Insertion |
EWS | Ewing Sarcoma |
EWSR1 | Ewing sarcoma breakpoint region 1, EWS RNA Binding Protein 1 |
EWSR1–FLI1 | Ewing sarcoma breakpoint region 1 (EWS RNA Binding Protein 1) - Friend Leukemia Insertion |
EXT | exostosin glycosyltransferase |
EZH2 | enhancer of zeste homolog 2 |
FEV | FEV Transcription Factor, ETS Family Member |
FUS | FUS RNA Binding Protein |
GD2 | disialoganglioside 2 |
HDAC | histone deacetylase |
HEY1 | Hes Related Family BHLH Transcription Factor With YRPW Motif 1 |
HGOS | High-grade osteosarcoma |
HIC1 | HIC ZBTB transcriptional repressor 1 |
HSPGs | heparan sulphate proteoglycans |
ICB | immune checkpoint blockade |
IDH | isocitrate dehydrogenase genes |
IGF-1 | Insulin-like growth factor 1 |
IGF-1R | Insulin-like growth factor 1 receptor |
IGF-2 | Insulin-like growth factor 2 |
IGF | Insulin-like growth factor |
IGF-2BP3 | Insulin-like growth factor 2 - mRNA-binding protein 3 |
IHH | Indian Hedgehog Signaling Molecule |
INFORM | individualized therapy for relapsed malignancies in childhood |
IRF2BP2-CDX1 | Interferon Regulatory Factor 2 Binding Protein 2-Caudal Type Homeobox 1 |
ISG | Italian Sarcoma Group |
KDR | kinase insert domain receptor |
KIT | Proto-Oncogene, Receptor Tyrosine Kinase |
lncRNA | Long non-coding RNA |
lncRNAs | long non-coding RNAs |
LSAMP | Limbic System-Associated Membrane Protein |
LSD1 | Lysine Demethylase 1° |
MDM2 | MDM2 Proto-Oncogene |
MGMT | O-6-methylguanine DNA methyltransferase |
miRNA | microRNA |
miRNAs | microRNAs |
MSH2 | mut S homolog 2 |
MTHFR | 5,10-methylenetetrahydrofolate reductase |
mTOR | mammalian target of rapamycin |
NADPH | reduced nicotinamide adenine dinucleotide phosphate |
NCOA2 | Nuclear Receptor Coactivator 2 |
NER | Nucleotide excision repair |
NGS | Next-generation sequencing |
NRAS | NRAS Proto-Oncogene |
p16 | also known as p16INK4a, cyclin-dependent kinase inhibitor 2A or CDKN2A, multiple tumor suppressor 1 |
PALB2 | partner and localizer of BRCA2 |
PARP | poly (ADP-ribose) polymerase |
PD-1 | programmedcelldeath 1 |
PD-L1 | programmed death-ligand 1 |
PI3K/mTOR | phosphatidylinositol 3-kinase/mammalian target of rapamycin |
PR | partial response |
RASSF1A | Ras association domain family 1A |
RB1 | RB TranscriptionalCorepressor 1 |
RECQL | RecQ-like helicase |
RHA | RNA helicase A |
SAHA | suberoylanilide hydroxamic acid |
SNP | Single nucleotide polymorphism |
SQSTM1 | Sequestosome 1 |
SRC | SRC Proto-Oncogene, Non-Receptor Tyrosine Kinase |
STAG2 | Stromal Antigen 2 |
SV | structural variations |
TAF15 | TATA-Box Binding Protein Associated Factor 15 |
TARGET | Generate Effective Treatments Osteosarcoma project |
TET | Tet Methylcytosine Dioxygenase |
TGFβ | transforming growth factor β |
TIMP3 | TIMP metallopeptidase inhibitor 3 |
TMB | tumor mutational burden |
TP53 | Tumor Protein P53 |
WWOX | WW Domain ContainingOxidoreductase |
α-KG | α-ketoglutarate |
2-HG | 2-hydroxyglutarate |
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Treatment | Mechanism of Action | Bone Sarcoma Histotypes | ClinicalTrials.gov NCT Identifier (Protocol Acronym) | Participating Countries | Stage of Development (Time Period) |
---|---|---|---|---|---|
Losartan + Sunitinib | Sunitinib: multi-target inhibition of RTK | HGOS | NCT03900793 | USA | phase I (08/2019–02/2025) |
Famitinib plus Camrelizumab (SHR-1210) or Famitinib alone or Famitinib plus Ifosfamide | Famitinib: multi-target inhibition of RTK, including SCFR (c-Kit), VEGFR2 and 3, PDGFR, Flt1 and Flt3 Camrelizumab: inhibition of PD-1 immune checkpoint | advanced HGOS | NCT04044378 | China | phase I/II (08/2019–09/2022) |
Pazopanib hydrochloride (Votrient®) with oral Topotecan hydrochloride | Inhibition of VEGFR-1, -2, -3, PDGFR-α and -β, and KIT (Pazopanib) | recurrent or metastatic HGOS | NCT02357810 | USA | phase II (02/2015–06/2022) |
Apatinib (YN968D1) in combination with chemotherapy | Inhibition of VEGFR2 | HGOS with pulmonary metastasis | NCT03742193 | China | phase II (03/2019–09/2022) |
Regorafenib (BAY 73-4506, commercial name Stivarga) | Multi-kinase inhibitor targeting VEGFR2, TIE2, PDGFR-beta, FGFR, KIT, RET, and RAF | HGOS, Ewing sarcoma | NCT02048371 (SARC024) | USA | phase II (07/2014–12/2020) |
Regorafenib (BAY 73-4506, commercial name Stivarga) | Multi-kinase inhibitor targeting VEGFR2, TIE2, PDGFR-beta, FGFR, KIT, RET, and RAF | metastatic bone sarcomas (HGOS, Ewing sarcoma, chondrosarcoma) | NCT02389244 (REGOBONE) | France | phase II (09/2014–03/2023) |
Cabozantinib-S-Malate (Cabometyx; Cometriq) | Inhibition of MET, VEGFR2, AXL and RET | recurrent, refractory, or newly diagnosed sarcomas, including HGOS | NCT02867592 | USA | phase II (05/2017–06/2020) |
Erdafitinib (JNJ-42756493) | FGFR inhibitor with negative effects on angiogenesis | relapsed or refractory advanced solid tumors, including HGOS | NCT03210714 (The Pediatric MATCH Screening Trial) | USA | phase II (11/2017–12/2024) |
Palbociclib (PD-0332991, trade name Ibrance) | Selective inhibition of the cyclin-dependent kinases CDK4 and CDK6 | relapsed or refractory advanced solid tumors, including refractory HGOS | NCT03526250 (The Pediatric MATCH Screening Trial) | USA | phase II (06/2018–06/2025) |
Abemaciclib (Verzenios) | Selective inhibition of the cyclin-dependent kinases CDK4 and CDK6 | recurrent or refractory solid tumors, including HGOS and Ewing sarcoma | NCT02644460 | USA | phase I (02/2016–12/2020) |
Abemaciclib (Verzenios) | Selective inhibition of the cyclin-dependent kinases CDK4 and CDK6 | advanced HGOS and chondrosarcoma | NCT04040205 | USA | phase II (10/2019–09/2024) |
Samotolisib (LY3023414) | Inhibition of PI3K/AKT/mTOR pathway | relapsed or refractory advanced solid tumors, including HGOS | NCT03213678 (The Pediatric MATCH Screening Trial) | USA | phase II (07/2017–09/2024) |
Berzosertib (M6620; VX-970; Captisol®) | Selective inhibitor of ATR | HGOS | NCT03718091 | USA | phase II (01/2019–04/2025) |
Olaparib (AZD-2281, MK-7339 trade name Lynparza®) | Inhibition of PARP1, opposing DNA repair, in patients with hereditary BRCA1 or BRCA2 mutations | relapsed or refractory advanced solid tumors, including HGOS | NCT03233204 (The Pediatric MATCH Screening Trial) | USA | phase II (07/2017–09/2024) |
Ulixertinib (BVD-523; VRT752271) | Inhibition of ERK1/2 kinases, belonging to the MAPK pathway | relapsed or refractory advanced solid tumors, including recurrent HGOS | NCT03698994 (The Pediatric MATCH Screening Trial) | USA | phase II (10/2018–12/2025) |
Vemurafenib (PLX40321; Zelboraf®) | Inhibition of the mutated B-Raf protein, interrupting its stimulation of cell growth | relapsed or refractory advanced solid tumors, including HGOS | NCT03220035 (The Pediatric MATCH Screening Trial) | USA | phase II (07/2017–12/2023) |
Larotrectinib (ARRY-470; LOXO-101; Vitrakvi®) | Inhibition of tropomyosin kinase receptors TrkA, TrkB, and TrkC | relapsed or refractory advanced solid tumors, including HGOS | NCT03213704 | USA | phase II (07/2017–09/2024) |
9-ING-41 with Gemcitabine, Doxorubicin, Lomustine, Carboplatin, Nab paclitaxel, Paclitaxel | 9-ING-41: inhibition of GSK-3 | advanced cancers, including HGOS | NCT03678883 | USA | phase I/II (01/2019–11/2022) |
Tazemetostat (EPZ-6438) | Inhibition of the activity of human polycomb repressive complex 2 -containing wild-type histone-lysine N-methyltransferases EZH1 and EZH2 | advanced cancers, including HGOS and Ewing sarcoma | NCT03213665 (The Pediatric MATCH Screening Trial) | USA | phase II (07/2017–09/2024) |
Avelumab (Bavencio®) | Targeting PD-L1 | recurrent or progressive HGOS | NCT03006848 | USA | phase II (02/2017–01/2023) |
ZKAB001 (STI-1014; STI-A1014) | Targeting PD-L1 | recurrent or refractory HGOS | NCT03676985 | China | phase I/II (10/2018–06/2023) |
Nivolumab (Opdivo®) with or without Azacitidine | Targeting PD-1 (Nivolumab) | recurrent HGOS | NCT03628209 | USA | phase I/II (07/2019–07/2022) |
Pembrolizumab (MK3475) combined with metronomic Cyclophosphamide | Targeting PD-1 in association with metronomic chemotherapy | advanced sarcomas | NCT02406781 | France | phase II (06/2015–06/2023) |
Pepinemab (VX15/2503) | Targeting Semaphorin-4D (SEMA4D), also known as Cluster of Differentiation 100 (CD100), which binds to CD72 to activate B cells and dendritic cells | recurrent and refractory HGOS | NCT03320330 | USA | phase I/II (01/2018–09/2021) |
4th generation safety-engineered CAR T cells targeting sarcomas | 4th generation safety-engineered CAR T cells targeting sarcoma surface antigens | sarcomas including HGOS and Ewing sarcoma | NCT03356782 | China | phase I (12/2017–12/2020) |
EGFR806 CAR T cell immunotherapy | second generation EGFR-specific CAR T cells, which have been genetically modified to express either the EGFR receptor alone (EGFR806CAR(2G)-EGFRt) or in addition also the CD19 receptor (CD19CAR(2G)-T2A-HER2tG) | recurrent or refractory solid tumors, including HGOS and Ewing sarcoma | NCT03618381 | USA | phase I (06/2019–06/2036) |
C7R-GD2.CAR T cell immunotherapy | relapsed or refractory GD2-positive tumors, including HGOS and Ewing sarcoma | NCT03635632 | USA | phase I (04/2019–12/2037) | |
Humanized Monoclonal Antibody 3F8 (Hu3F8) combined with GM-CSF | Targeting GD2 with the humanized antibody Hu3F8 | recurrent HGOS | NCT02502786 | USA | phase II (07/2015–07/2021) |
Humanized anti-GD2 bispecific antibody Hu3F8-BsAb | Targeting GD2 with the bispecific antibody Hu3F8-BsAb | HGOS | NCT03860207 | USA | phase I/II (02/2019–02/2022) |
Treatment | Mechanism of Action | Bone Sarcoma Histotypes | ClinicalTrials.gov NCT Identifier (Protocol Acronym) | Participating Countries | Stage of Development (Time Period) |
---|---|---|---|---|---|
Sirolimus and Cyclophosphamide | Inhibition of mTOR signalling | Conventional, Mesenchymal and Dedifferentiated Chondrosarcomas | NCT02821507 (COSYMO) | Netherlands Spain | phase II (06/2014–06/2021) |
FT 2102 (Olutasidenib) | Inhibitor of mutant IDH1 | Chondrosarcoma | NCT03684811 | USA | phase II (11/2018–04/2022) |
Treatment | Mechanism of Action | Bone Sarcoma Histotypes | ClinicalTrials.gov NCT Identifier (Protocol Acronym) | Participating Countries | Stage of Development (Time Period) |
---|---|---|---|---|---|
SP-2577 (Seclidemstat) | Inhibition of the LSD1 epigenetic enzyme | Ewing Sarcoma | NCT03600649 | USA | phase I (06/2018–12/2021) |
INCB059872 | Inhibition of the LSD1 epigenetic enzyme | relapsed or refractory Ewing sarcoma | NCT03514407 | USA Italy Spain UK | phase I (06/2018–06/2021) |
Niraparib and Temozolomide and/or Irinotecan | Niraparib: inhibition of PARP | previously treated, incurable Ewing sarcoma | NCT02044120 | USA UK | phase I (05/2014–04/2021) |
Pbi-shRNA™ EWS/FLI1 Type 1 LPX | Targeting EWS/FLI1 type 1 fusion transcript | advanced Ewing sarcoma | NCT02736565 | USA | phase I (10/2016–02/2022) |
TK216 | Inhibition of the between EWS-FLI1 and RNA helicase A through binding to EWS-FLI1 | relapsed or refractory Ewing sarcoma | NCT02657005 | USA | phase I (08/2016–06/2021) |
Vorinostat (Zolinza) in combination with chemotherapy | Inhibition of HDAC | Ewing Sarcoma | NCT04308330 | USA | phase I (03/2017–12/2022) |
Olaparib and Temozolomide | Inhibition of PARP | Ewing Sarcoma | NCT01858168 | USA | phase I (07/2013–07/2024) |
Anlotinib and Irinotecan | Multi-target inhibition of RTK, including VEGFR2 and VEGFR3 | metastatic Ewing Sarcoma | NCT03416517 | China | phase I (01/2018–12/2020) |
Palbociclib combined with chemotherapy | Inhibition of CDK4/6 | Ewing Sarcoma | NCT03709680 | USA | phase I (05/2019–04/2024) |
Palbociclib plus Ganitumab | Palbociclib: inhibition of CDK4/6 Ganitumab: inhibition of IGF-1R | Ewing Sarcoma | NCT04129151 | USA | phase II (12/2019–08/2022) |
Eribulin Mesylate | Inhibition polymerization of tubulin subunits impairing the EWS-FLI1 mediated microtubule stabilization | Ewing Sarcoma | NCT03441360 | USA | phase II (04/2018–06/2020) |
Eribulin Mesylate | Inhibition polymerization of tubulin subunits impairing the EWS-FLI1 mediated microtubule stabilization | Ewing Sarcoma | NCT03245450 | France Germany Greece Italy Spain UK | phase II (08/2017–09/2021) |
Nivolumab (Opdivo®) plus ABI-009 (Nab-rapamycin; Nab-sirolimus) | Targeting PD-1 (Nivolumab) and mTOR (ABI-009) | Ewing sarcoma | NCT03190174 | USA | phase I/II (08/2017–04/2021) |
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Scotlandi, K.; Hattinger, C.M.; Pellegrini, E.; Gambarotti, M.; Serra, M. Genomics and Therapeutic Vulnerabilities of Primary Bone Tumors. Cells 2020, 9, 968. https://doi.org/10.3390/cells9040968
Scotlandi K, Hattinger CM, Pellegrini E, Gambarotti M, Serra M. Genomics and Therapeutic Vulnerabilities of Primary Bone Tumors. Cells. 2020; 9(4):968. https://doi.org/10.3390/cells9040968
Chicago/Turabian StyleScotlandi, Katia, Claudia Maria Hattinger, Evelin Pellegrini, Marco Gambarotti, and Massimo Serra. 2020. "Genomics and Therapeutic Vulnerabilities of Primary Bone Tumors" Cells 9, no. 4: 968. https://doi.org/10.3390/cells9040968