Targeting Cancer Stem Cells in Triple-Negative Breast Cancer
Abstract
:1. Introduction
2. Approaches for Targeting the Self-Renewal Process in TNBC Cells
2.1. STAT3
2.1.1. STAT3 Signaling in BCSCs
2.1.2. STAT3 Signaling Dysregulation in TNBC Cells
2.1.3. STAT3 Signaling Inhibitors in Clinical Trials
2.2. Proto-Oncogene Tyrosine-Protein Kinase Src (SRC)Signaling
2.2.1. SRC Kinase Signaling in BCSCs
2.2.2. SRC Kinase Signaling Dysregulation in TNBC Cells
2.2.3. SRC Kinase Inhibitors in Clinical Trials
2.3. Wnt/β-Catenin Signaling
2.3.1. Wnt/β-Catenin Signaling in BCSCs
2.3.2. Dysregulation of Wnt/β-Catenin Signaling in TNBC Cells
2.3.3. Wnt/β-Catenin Signaling Inhibitors in Clinical Trials
2.4. Other Molecules Linked to TNBC Self-Renewal
2.4.1. Connexin (CX)
2.4.2. Ubiquitin-Specific Protease (USP)
2.4.3. Polo-Like Kinase (PLK)
3. Attempts to Target Metabolic Reprogramming in Triple Negative Breast Cancer (TNBC)
3.1. Anaerobic Glycolysis
3.1.1. Glycolysis in Breast Cancer Stem Cells (BCSCs)
3.1.2. Glycolysis in TNBC Cells
3.1.3. Glycolysis Inhibitors in Clinical Trials
3.2. OXPHOS
3.2.1. OXPHOS in BCSCs
3.2.2. OXPHOS in TNBC Cells
3.2.3. OXPHOS Inhibitors
3.3. FAO
3.3.1. FAO in BCSCs
3.3.2. FAO in TNBC Cells
3.3.3. FAO Inhibitors in Clinical Trials
3.4. Other Molecules Linked to TNBC Metabolism
Glutathione S-Transferase Pi 1 (GSTP1)
4. Conclusions and Future Perspectives
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
List of Abbreviations
2DG | 2-Deoxyglucose |
ACADM | Acyl-coenzyme A dehydrogenase medium chain |
acetyl-CoA | Acetyl-coenzyme A |
ALDH | Aldehyde dehydrogenase |
APC | Adenomatous polyposis coli |
ATP | Adenosine triphosphate |
BCSC | Breast cancer stem cells |
CBP | cAMP response element-binding protein (CREB)-binding protein |
CD24 | Cluster of differentiation 24 |
CDCP1 | CUB domain-containing protein 1 |
CK1 | Casein kinase 1 |
CPT1 | Carnitine palmitoyltransferase 1 |
CREB | cAMP response element-binding protein |
CSC | Cancer stem cell |
CX | Connexin |
CXCL | Chemokine (C-X-C motif) ligand |
DCA | Dichloroacetate |
ECAR | Extracellular acidification rate |
ECM | Extracellular matrix |
EGF | Epidermal growth factor |
EGFR | Epidermal growth factor receptor |
EMT | Epithelial to mesenchymal transition |
ER | Estrogen receptor |
FAK | Focal adhesion kinase |
FAO | Fatty acid oxidation |
FBP1 | Fructose-1,6-biphosphatase 1 |
FDR | False discovery rate |
FGFR | Fibroblast growth factor receptor |
FZD | Frizzled |
G-6-P | Glucose-6-phosphate |
GEO | Gene expression omnibus |
GF/R | Growth factor and receptor |
GJ | Gap junction |
GSE | Gene set enrichment |
GSEA | Gene set enrichment analysis |
GSK3β | Glycogen synthase kinase 3 beta |
GSTO1 | Glutathione S-transferase omega 1 |
GSTP1 | Glutathione S-transferase pi 1 |
HAS1 | Hyaluronan synthase 1 |
HER2 | Human epidermal growth factor receptor 2 |
HIF1α | Hypoxia-inducible factor 1 alpha |
HK | Hexokinase |
HN1L | Hematological and neurological expressed 1-like |
IL | Interleukin |
IL6RA | Interleukin 6 receptor, alpha |
JAG1 | Jagged canonical Notch ligand 1 |
JAK | Janus kinase |
KLF4 | Kruppel-like factor 4 |
LACS | Long-chain acyl-CoA synthetase |
LEF | Lymphoid enhancer-binding factor |
LEPR | Leptin receptor |
LIF | Leukemia inhibitory factor |
LRP | Low-density lipoprotein receptor-related protein |
MMTV-PyMT | Mouse mammary tumor virus-polyoma middle tumor-antigen |
MSI1 | Musashi RNA binding protein 1 |
mTOR | Mammalian target of rapamycin |
mTORC1 | Mammalian target of rapamycin complex 1 |
NES | Normalized enrichment score |
NICD | Notch1 intracellular domain |
OCR | Oxygen consumption rate |
OCT4 | Octamer-binding transcription factor 4 |
OXPHOS | Oxidative phosphorylation |
PCR | Polymerase chain reaction |
PDH | Pyruvate dehydrogenase |
PDX | Patient-derived tumor xenograft |
p-FAK | Activated form of focal adhesion kinase |
PFKFB | 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase |
PI3K | Phosphoinositide 3-kinase |
PK | Pyruvate kinase |
PKM | M isoform of PK |
PLK | Polo-like kinase |
PR | Progesterone receptor |
PTGIS | Prostaglandin I2 (prostacyclin) synthase |
PTK7 | Tyrosine-protein kinase-like 7 |
PYK2 | Pyruvate kinase 2 |
ROS | Reactive oxygen species |
RYR1 | Type 1 ryanodine receptor |
SOX | SRY (sex determining region Y)-box |
SPSP | Self-renewal signaling pathway |
STAT | Signal transducer and activator of transcription |
TCF | T cell factor |
TNBC | Triple-negative breast cancer |
TRAIL | Tumor necrosis factor-related apoptosis-inducing ligand |
USP | Ubiquitin-specific protease |
VEGF | Vascular endothelial growth factor |
VEGFR | Vascular endothelial growth factor receptor |
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Target | Drug | Preclinical Results | Clinical Trial Status and Results |
---|---|---|---|
STAT3 signaling pathway inhibitors | |||
JAK | Merck-5 (JAK inhibitor I) | It reduces the growth of basal-like tumor cells through the inhibition of STAT3 activity in vitro [39]. | Preclinical |
Ruxolitinib | It reduces the proliferation, invasion, and mammosphere formation in HCC38 cells and increases apoptosis [98]. | Phase II -NCT01562873: The trial was terminated because of the limited responses to continue treatment despite on-target activity in refractory, metastatic TNBC patients [99]. -NCT02876302: The trial is currently recruiting patients to test the combinatory effect of ruxolitinib with paclitaxel on triple-negative inflammatory breast cancer patients. | |
STAT3 | OPB-51602 | It reduces mammosphere formation and CD44+/CD24− BCSC populations in MDA-MB-231 cells [100]. | Phase I -NCT01184807: The trial has been completed in patients with malignant solid cancer, and OPB-51602 demonstrated promising antitumor activity, particularly in non-small-cell lung cancer. It has a long half-life and poor tolerability to continuous dosing compared with intermittent dosing [101]. |
AZD9150 | It shows anti-proliferative efficacy as a single-agent in lymphoma and lung cancer preclinical mouse models. Its clinical trial is currently recruiting patients with advanced solid tumors [102]. | Phase I and II -NCT03421353: The trial is currently recruiting patients with advanced cancer. Phase I/Ib -NCT01839604: The trial has been completed in patients with advanced/metastatic hepatocellular carcinoma. | |
TTI-101 (STAT3 inhibitor XIII) | It reduces the in vitro cell proliferation more potently in TNBC cells (MDA-MB-468 and MDA-MB-231) than in non-TNBC cells (MDA-MB-435 and MCF7). This clinical trial is currently recruiting patients with advanced cancers, including breast cancer [103]. | Phase I -NCT03195699: The trial is currently recruiting advanced cancer patients. | |
SRC kinase signaling pathway inhibitors | |||
SRC | Dasatinib | It reduces the proliferation of TNBC cells in vitro and their tumorigenic potential in vivo. It sensitizes TNBC cells to paclitaxel [41,61]. | Phase II -NCT02720185: The trial was planned for the study of TNBC patients with nuclear translocation of EGFR; however, the trial has been suspended for protocol modifications. |
SKI-606 (Bosutinib) | It reduces tumor growth, invasion, and metastasis in MDA-MB-231 xenografts [62]. | Phase I -NCT03854093: The trial is currently recruiting breast cancer patients. -NCT03023319: The trial is currently recruiting patients with metastatic solid cancers to assess SKI-606 in combination with pemetrexed. -NCT02810990: The trial is currently recruiting elderly chronic myeloid leukemia patients. | |
Wnt/β-catenin signaling inhibitors | |||
CBP | ICG-001 | It reduces mammosphere formation and sensitizes TNBC cells to paclitaxel [75]. | Preclinical |
PRI-724 | It is an ICG-001 derivative for clinical trials in patients with pancreatic cancer and myeloid leukemia [104]. | Phase I and II -NCT01606579: The trial has been completed in subjects with advanced myeloid malignancies, but the results have not yet been reported. Phase I -NCT01764477: The trial examined patients with advanced or metastatic pancreatic adenocarcinoma to assess PRI-724 in combination with gemcitabine (GEM), and the results show that this combination is safe and demonstrates modest clinical activity [105]. | |
Porcupine | LGK-974 | It reduces tumor growth in metastatic MDA-MB-231 cell (TMD-231) xenografts. It sensitizes TMD-231 cells to buparlisib [106]. | Phase I -NCT01351103: The trial is currently recruiting patients with malignancies dependent on Wnt ligands. |
FZD7 | SRI37892 | It reduces tumor growth and tumor-initiating potential in TNBC patient tissue- and cell line-derived xenografts [107]. | Preclinical |
scFvs | It inhibits cell growth inhibition and promotes apoptosis in MDA-MB-231 cells without affecting SK-BR3 cells [108,109]. | Preclinical | |
OMP-18R5 (vantictumab) | It promotes tumor growth regression by Taxol and prevents recurrent growth after Taxol treatment in breast cancer patient tissue-derived xenografts [89]. | Phase Ib -NCT01973309: The trial has been completed in patients with recurrent or metastatic breast cancer to evaluate OMP-18R5 in combination with paclitaxel. This combination was demonstrated to be well tolerated. Bone toxicity was encountered early in the study [110]. | |
PTK7 | PTK7-ADC | It reduces tumor growth and tumor-initiating potential in TNBC patient tissue- and cell line-derived xenografts [86]. | Phase I -NCT03243331: The trial is currently recruiting metastatic TNBC patients to assess a combination drug regimen with gedatolisib. |
Other molecules linked to the self-renewal process in TNBC | |||
CX26 | - | The specific inhibitors have not been developed yet. | - |
USP2 | ML364 | It reduces tumorsphere formation in vitro and tumor growth in vivo. It sensitizes TNBC cells to doxorubicin and paclitaxel [93]. | Preclinical |
PLK1 | BI-2536 | It reduces tumor growth in TNBC xenografts [97]. | Phase II -NCT00526149: The trial has been completed in patients with recurrent or metastatic solid cancer, and BI-2536 showed limited antitumor activity [111]. |
Target | Drug | Preclinical Results | Clinical Trial Status and Results |
---|---|---|---|
Glycolysis inhibitors | |||
HK2 | Metformin | A systemic glycolysis inhibitor; it suppresses TNBC stem cells and reduces the tumor-initiating potential in TNBC xenografts [137,153]. | Phase III -NCT02201381: The trial is currently recruiting cancer patients; overall survival is the primary outcome measure. |
HL010183 | A metformin derivative; it inhibits proliferation and invasion of TNBC cells and reduces tumor growth in MDA-MB-231 xenografts [139]. | Preclinical | |
Benserazide | FDA-approved drug for Parkinson’s disease. It reduces anaerobic glycolysis in breast cancer cells and inhibits tumor growth [140]. | Preclinical | |
PKM2 | TLN-232 | It has anti-proliferative effects on diverse cancer cells [154,155]. | Phase II -NCT00422786: The trial has been completed in patients with refractory metastatic renal cell carcinoma, but the results have not yet been reported. -NCT00735332): The trial was conducted in recurring metastatic melanoma patients, but it was stopped because of license termination. |
PDK1 | DCA | It inhibits metastatic breast cancer cell growth in vitro and in vivo [142]. | Phase II -NCT01029925: The trial was conducted in patients with metastatic breast cancer or with lung cancer, but it was terminated early due to higher than expected risk/safety concerns. |
AR-12 (OSU-03012) | It reduces proliferation and induces apoptosis of MDA-MB-231 cells in vitro and in vivo. Additionally, it sensitizes MDA-MB-231 cells to tamoxifen [156]. | Phase I -NCT00978523: The trial was conducted in patients with advanced or recurrent solid tumors or with lymphoma. | |
BX795/BX912 | It reduces the cell viability of MYC-expressing TNBC cells (MDA-MB-231, SUM159PT, Hs578T) but does not affect non-TNBC cells (BT474 and T47D). In addition, it attenuates the CD44+/CD24- population in MDA-MB-231 cells [95,157]. | Preclinical | |
OXPHOS inhibitors | |||
Mitochondrial complex I | IACS-010759 | It reduces cell growth and viability across a panel of cancer cell lines, including TNBC without affecting normal cells [147]. | Phase I -NCT03291938: The trial is currently recruiting patients with advanced cancer. -NCT02882321: The trial is currently recruiting subjects with relapsed or refractory acute myeloid leukemia. |
ME-344 | It sensitizes breast tumors to tyrosine kinase inhibitors in mouse mammary tumor virus-polyoma middle tumor-antigen (MMTV-PyMT) mouse model [158,159,160]. | Phase I -NCT02100007: The trial was terminated because of the lack of efficacy in solid tumor patients as a combinatory agent with Hycamtin® -NCT01544322: The trial was completed in patients with refractory solid cancer; however, the results have not yet been released. -NCT02806817: The trial was recruiting HER2-negative breast cancer patients with antiangiogenic-induced mitochondrial metabolism, but the trial status has not been verified in over two years. | |
FAO inhibitors | |||
CPT1 | Etomoxir | It reduces the ATP production in MYC-expressing TNBC cells, thus leads to tumor regression in vitro and in vivo. Moreover, it reduces the CSC proliferation and their self-renewing activity in TNBC cells [116,117]. | Preclinical |
Perhexiline | It reduces tumor growth, CSC population, and Sox2 expression in MMTV-PyMT tumors. Additionally, it restores the efficacy of paclitaxel in the paclitaxel-resistant MDA-MB-231 cells [117]. | Phase II and III -NCT00845364: The trial was conducted to assess whether an anti-anginal agent could protect the myocardium in patients undergoing coronary artery surgery (CASPER). The role of perhexiline in cardiac surgery is limited [161]. | |
Other molecules linked to TNBC metabolism | |||
GSTP1 | LAS17 | It reduces survival in TNBC cells and tumor growth in TNBC xenografts [152]. | Preclinical |
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Park, S.-Y.; Choi, J.-H.; Nam, J.-S. Targeting Cancer Stem Cells in Triple-Negative Breast Cancer. Cancers 2019, 11, 965. https://doi.org/10.3390/cancers11070965
Park S-Y, Choi J-H, Nam J-S. Targeting Cancer Stem Cells in Triple-Negative Breast Cancer. Cancers. 2019; 11(7):965. https://doi.org/10.3390/cancers11070965
Chicago/Turabian StylePark, So-Yeon, Jang-Hyun Choi, and Jeong-Seok Nam. 2019. "Targeting Cancer Stem Cells in Triple-Negative Breast Cancer" Cancers 11, no. 7: 965. https://doi.org/10.3390/cancers11070965