Endometrial Cancer Stem Cells: Role, Characterization and Therapeutic Implications
Abstract
:1. Introduction
2. CSCs in Endometrial Cancer: Role and Biomarkers
3. Activated Pathways in Endometrial CSCs
- Hedgehog signaling pathway, with its downstream effectors SMO and Gli1; its inhibitors are sonidegib and cyclopamine.
- PI3K/AKT/mTOR Complex (mTORC)pathway, inhibited by everolimus and metformin.
- Wnt/β-catenin pathway, inhibited by salinomycin and ETC-159.
- NOTCH pathway whose inhibitors are DAPT ((N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester))), Enoticumab and NOV1501 (also ALB001).
4. Agents Targeting CSCs in EC: Preclinical Development
5. Agents Targeting CSCs in EC: Clinical Trials and New Perspectives
6. Discussion
- Which is the best biomarker to detect CSCs?
- Is there a dependency on a specific pathway?
- Which is the most promising strategy to target CSCs?
- Probably CSCs heterogeneity justifies the presence of multiple biomarkers [85]. Indeed, CD133 and ALDH1 are the most studied and their expression correlates with prognosis and aggressiveness [63,83]. On the other hand markers of EMT [60] and expression of efflux pumps of ABCs family are certain markers of CSCs suggesting that the definition of a cluster of biomarkers could be the best strategy to detect CSCs in EC.
- CSCs related pathways are multiple and crosstalking, suggesting that there is no strict dependency on a specific pathway. Wnt-βcatenin [76], Notch [89] and Hedgehog [90] are the most important but also other signaling cascades implied in multiple biological mechanism like ER [113] and PI3K/AKT pathways [94] are involved in maintaining endometrial CSCs with a main role played also by epigenetic modulators.
- Nowadays we have few clinical data on drugs targeting CSCs. Certainly, most early phase studies showed that these drugs are safe but data on activity are lacking. Crosstalk and redundant pathways maintaining stemness are probably intrinsic mechanisms of resistance in several cancers and next therapeutic strategies could consider combination of drugs. The addition of drugs against CSC pathways to chemotherapy could be a tool to overcome resistance in ECs. An even more promising combination is the one of checkpoint inhibitors with drugs targeting CSCs above all in inflamed tumors among which MSI-high EC is one of the most interesting example [15,130]. Another powerful strategy could be treatment with chimeric antigen receptor-modified T (CART) cells, that recognize specific antigens, inducing T cell activation and survival, thus resulting in antitumor activity [44]. Preclinical works suggest that CSC-targeted CART cells against CD133 are effective in peritoneal carcinomatosis from gynecological cancers PDXs [131] but there is no ongoing study with CART133 including patients with ECs.
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Description | Condition | Line of Therapy | Primary Endpoint | Phase | Status | Trial Identifier |
---|---|---|---|---|---|---|
Targeted Therapy Directed by Genetic Testing (Pi3k inhibitors, AKT inhibitors, Hedgehog Antagonist) | Advanced solid tumors | ≥2 line | ORR | II | Recruiting | NCT02465060 |
DKN-01 +/− Paclitaxel | EC, OC or Carcinosarcoma | ≥2 line | ORR, toxicity, pharmacokinetic | II | Recruiting | NCT03395080 |
ETC-159 +/− Pembrolizumab | EC, OC or colorectal cancer | ≥2 line | % AE | I | Active not recruiting | NCT02521844 |
COTI-2 (Against p53) +/− cisplatin | EC or Other solid tumors | na | DLT, MTD, RP2D | I | Recruiting | NCT02433626 |
Everolimus, Letrozole, and Metformin | EC | ≤3 line | CBR | II | Active not recruiting | NCT01797523 |
Ribociclib+ Everolimus + Letrozole | EC | ≤ 3 line | DLT/CBR | I/II | Recruiting | NCT03008408 |
Gedatolisib + Palbociclib | Solid tumors | NA | MTD, RP2D, %AE | I | Recruiting | NCT03065062 |
Cyclophosphamide + Metformin + Olaparib | EC | ≥2 line | RP2D | I/II | Notyetrecruiting | NCT02755844 |
AZD2014(MTOR inhibitor) + anastrozole | ER+ EC | ≥2 line | % AE, 8weeks PFS | I/II | Recruiting | NCT02730923 |
NOV1501 (anti DLL-4) | Solid tumors | NA | DLT | I | Recruiting | NCT03292783 |
Itacitinib (anti Jak 3) (INCB039110) and/or Pembrolizumab | Solid tumors | NA | Toxicity | I | Active not recruiting | NCT02646748 |
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Giannone, G.; Attademo, L.; Scotto, G.; Genta, S.; Ghisoni, E.; Tuninetti, V.; Aglietta, M.; Pignata, S.; Valabrega, G. Endometrial Cancer Stem Cells: Role, Characterization and Therapeutic Implications. Cancers 2019, 11, 1820. https://doi.org/10.3390/cancers11111820
Giannone G, Attademo L, Scotto G, Genta S, Ghisoni E, Tuninetti V, Aglietta M, Pignata S, Valabrega G. Endometrial Cancer Stem Cells: Role, Characterization and Therapeutic Implications. Cancers. 2019; 11(11):1820. https://doi.org/10.3390/cancers11111820
Chicago/Turabian StyleGiannone, Gaia, Laura Attademo, Giulia Scotto, Sofia Genta, Eleonora Ghisoni, Valentina Tuninetti, Massimo Aglietta, Sandro Pignata, and Giorgio Valabrega. 2019. "Endometrial Cancer Stem Cells: Role, Characterization and Therapeutic Implications" Cancers 11, no. 11: 1820. https://doi.org/10.3390/cancers11111820