Background
Unsupervised omics and single cell-based analyses highlight metabolic signatures in cancer
Cell processes | Biomarkers (genes or metabolites) | STS subtype | Prognosis significance | References | |
---|---|---|---|---|---|
Signaling | RAS signaling | GLUT, HK, PFK | UPS, MFS | Poor prognosis | |
PI3K-AKT signaling | LMS, EWS | Poor prognosis | |||
miR-181b | STLMS, ULMS | RFS | [8] | ||
MDM2 amplification | DDLPS | Poor prognosis | |||
GFR signaling | IGFR1 overexpression | STLMS, EWS, MLS, ARMS, SS | Poor RFS/DSS | ||
Her4/Erbb4 | OS, EWS | Poor prognosis | [38] | ||
Serum bFGF, VEGF | STS | Poor prognosis | [39] | ||
JUN signaling | DDLPS | Poor prognosis | [8] | ||
HIPPO pathway | Nuclear YAP/TAZ, VGLL3 | UPS, MFS, MLS, RMS | Poor prognosis | ||
WNT pathway | Nuclear β-catenin/LEF1; MEG3 (lncRNA) downregulation | EWS, OS | Poor prognosis | ||
Cell cycle/death | Cell cycle | CINSARC—67 genes | STS | Poor prognosis | [48] |
TP53, RB1, CDKN2A deficiency | LMS, UPS, MFS | Poor prognosis | |||
TP53, IGAR, GLUT | LMS, UPS, MFS, EWS | Poor prognosis | |||
CDCA2, KIF14, IGBP7 | SS | Metastasis | [52] | ||
CDK4 amplification | DDLPS | Poor prognosis | [8] | ||
DNA replication | TOP2A | MPNST | Poor prognosis | [8] | |
RRM1 | OS, EWS | Good prognosis | [8] | ||
ATRX deletion | DDLPS | Poor prognosis | [8] | ||
Transcriptional regulation | DNA hypermethylation, | DDLPS, STLMS | poor RFS/DSS | [8] | |
HMGA2 amplification | DDLPS | Poor prognosis | [8] | ||
Energetic pathways | Glycolysis | GLUT, ENO1, TPI1, PKG1, LDHC, lactate, pyruvate | STS | Poor prognosis | |
FBP2 loss | LPS, LMS, FS, UPS | Poor DSS | [55] | ||
Serum LDH | ULMS, EWS | Poor prognosis | |||
PKM1/2 isoenzymes | OS | Poor prognosis | [56] | ||
Pentose and glucoronate interconversions | UGT | STS | Prognosis | [20] | |
Citrate cycle/OXPHOS | Downregulated metabolites | OS | Poor prognosis | [27] | |
Decreased ATP Synthase subunits | OS | Poor prognosis | [56] | ||
SDH, FH mutations (succinate accumulation) | GIST | Poor prognosis | [57] | ||
Others | AMPKa, CHK1, S6, ARID1A, RBM15, MSH6, AcetylTubulin | STS | Combined survival related signature | [58] | |
Nucleotide metabolism | STS | Poor prognosis | [57] | ||
Amino acids | Alanine, aspartate, glutamate | GLS | OS, KS, EWS | High risk | |
Arginine, ornithine | ASS1 deficiency, ODC | OS, MFS, KS | DSS, MFS | ||
Proline | PYCR2 | OS, KS | DSS, MFS | ||
Serine, glycine | PHGDH, PSAT1, PSPH, SHMT2, SLC1A5, MTHFD2, MTHFD1L | EWS | DSS, MFS | ||
Tryptophane | TDO2 (low) | EWS | DSS, MFS | [65] | |
5 methylthioadenosine | OS | DSS, MFS | [27] | ||
Redox, vitamins | Pantothenate metabolism | VNN1 (low) | FS | Poor prognosis | [66] |
Redox metabolism | TXR, MIF1, GAL1, AcCoaBP | LMS (high), MFS (low) | Poor prognosis | [67] | |
Hypoxia | HIF1α, hypoxia gene signatures | EWS, OS, GIST, KS | Poor prognosis |
Oncogenic drivers upstream of growth pathways rewire metabolism in sarcomas
Overactivated MAP and PI3 kinase pathways drive a Warburg effect
Biomarker target | Therapeutic agent | Tumor type | Biomarker relevance/clinical trial phase | N° Clinical trial | References | |
---|---|---|---|---|---|---|
MAPK pathways | RAF | Dabrafenib | Advanced solid tumors with BRAF mutations | Phase II | NCT02465060 | [75] [A] [B] |
Vemurafenib | Relapsed or refractory advanced solid tumors with BRAF V600 mutations | Phase II | NCT03220035 | |||
Dabrafenib + trametinib | MULTISARC | Phase III | NCT03784014 | |||
Dabrafenib + trametinib | BRAF V600E- mutated rare cancers | Phase II | NCT02034110 | |||
MEK1/2 | Binimetinib + pexidartinib | Advanced GIST | Phase I completed | NCT03158103 | [A] [B] [C] | |
Trametinib | Advanced solid tumors with BRAF mutations | Phase II | NCT02465060 | |||
Cobimetinib + MPDL3280A | Locally advanced or metastatic solid tumors | Phase I | NCT01988896 | |||
GDC-0941 + GDC-0973 | Locally advanced or metastatic solid tumors | Phase II | NCT00996892 | |||
ERK1/2 | Ulixertinib | STS, OS, EWS | Phase I/II | NCT03520075 | [C] | |
PI3K/AKT/mTOR signaling | PIK3CA/mTOR | Samotolisib | STS GIST | Phase I/II | NCT02008019 | [C] [76] |
Pediatric sarcoma | Phase II MATCH trial | NCT03458728 NCI MATCH EAY131-Z1F | [77] [78] | |||
GDC-0941 | Locally advanced or metastatic solid tumors | Phase I | NCT00876109 | [A] | ||
GDC-0980 | Locally advanced or metastatic solid tumors Refractory solid tumors | Phase I | NCT00876122NCT00854152 NCT00854126 | [A] | ||
AKT/ERK | ONC201 | Desmoplastic small round cell tumor | In vitro | [C] | ||
GDC-0973 + GDC-0068 | Locally advanced or metastatic solid tumors | Phase I | NCT01562275 | [A] | ||
mTOR | Sirolimus + pexidartinib | STS MPNST | Phase I/II | NCT02584647 | [79] [80] [A] | |
Rapamycin + gemcitabine | OS | Phase II completed | NCT02429973 | |||
nanoparticle albumin-bound rapamycin + pazopanib | Advanced nonadipocytic soft tissue sarcomas | Phase I/II trial | NCT03660930 | |||
Lenvatinib + everolimus | Refractory pediatric solid tumors | Phase I/II | NCT03245151 | |||
CCI-779 | STS/GIST | Phase II | NCT00087074 | |||
Cixutumumab + temsirolimus | Locally advanced, metastatic, or recurrent STS or bone sarcoma | Phase II | NCT01016015 | |||
CP-751,871 + RAD001 | Advanced sarcomas and other malignant neoplasms | Phase I | NCT00927966 | |||
Everolimus | RAD001/progressive sarcoma | Phase II | NCT00767819 | |||
HIPPO | YAP/TAZ | Verteporfin | High histological grade | Reduced EWS metastatic potential | [81] [82] [83] [84] | |
TCA CYCLE | IDH 1 | IDH 1—AG-120 | Chondrosarcoma | Phase I | NCT02073994 | [85] [86] [87] |
IDH 1—FT-2102 | Advanced solid tumors | Active | NCT03684811 | |||
IDH 1—IDH305 | Advanced malignancies with IDH1R132 mutations | Phase I | NCT02381886 | |||
IDH 1—BAY1436032 | IDH1-mutant advanced solid tumors | Active | NCT02746081 | |||
AG-881 | Advanced solid tumors with an IDH1 and/or IDH2 mutation | Phase I | NCT02481154 | |||
AG-120 + nivolumab | IDH1 mutant tumors | Phase II | NCT04056910 | |||
IDH2 | IDH 2—AG-221 | Advanced solid tumors | Phase I/II | NCT02273739 | ||
TCA cycle enzymes | Devimistat | STS | FDA orphan drug designation | [D] | ||
Amino acids | ASS1 deficiency | ADI-PEG20 + gemcitabine + docetaxel | STS, OS, EWS | Phase II | NCT03449901 | [88] [89] |
PDK | DCA | FS | Mice | [90] | ||
GLS | CB-839—glutaminase inhibitor | GIST | Phase I completed | NCT02071862 | [59] | |
Telaglenastat | NF1 mutation positive MPNST | Phase II | NCT03872427 | |||
Telaglenastat + talazoparib | Solid tumors | Phase I + phase II | NCT03875313 | |||
Heparan sulfate proteoglycans | Sulfen | EWS | Zebrafish model | [91] | ||
NAMPT | FK866—MV87 inhibitors | FS | Mice | [92] | ||
Folate receptor α | Pemetrexed | STS | Phase II | NCT04605770 | [C] | |
Lipid metabolism | CPI-613 | CCS | Phase II | NCT01832857 | [A] [E] |