Epigenetics of Most Aggressive Solid Tumors: Pathways, Targets and Treatments
Abstract
:Simple Summary
Abstract
1. Introduction
1.1. DNA Methylation
1.2. Histone Modification
1.3. Non-Coding RNA
2. Epigenetic Modulation in Highly Aggressive Solid Tumors
2.1. Epigenetic Modulation in Small-Cell Lung Cancer
2.2. Epigenetic Modulation in Triple-Negative Breast Cancer
2.3. Epigenetic Modulation in Pancreatic Ductal Adenocarcinoma
2.4. Epigenetic Modulation in Glioblastoma
2.5. Epigenetic Modulation in Metastatic Melanoma
2.6. Epigenetic Modulation in Ovarian Cancer
3. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Identifier | Disease | Stage | Design | Drugs | Administration of ET | Epigenetic Target | Brief | Status |
---|---|---|---|---|---|---|---|---|
NCT02847000 | Pancreatic cancer | Advanced | Early phase 1, single-arm, open-label, proof-of-concept clinical trial | Decitabine/tetra-hydrouridine | Orally | DNMT | Drug combination of decitabine and tetrahydrouridine in patients that have progressed through one or more lines of therapy. The most frequent adverse event was anemia and decitabine exhibited a limited systemic effect. | C |
NCT01845805 | Pancreatic cancer | Resected | Phase II trial, randomized, single group assignment, open label. | Oral azacitidine (CC-486)/nanoparticle albumin-bound paclitaxel or gemcitabine | Orally | DNMT | Azacitidine (CC-486) until recurrence, then first-line treatment: Abraxane or gemcitabine. | R |
NCT04257448 | Pancreatic cancer | Advanced | Open-label phase I/II study, non-randomized, sequential assignment, open label | Romidepsin, azacitidine, nab-paclitaxel, gemcitabine, durvalumab, lenalidomide | Subcutaneous | HDAC and DNMT | Azacitidine and/or romidepsin in combination with nab-paclitaxel/gemcitabine followed by sequential immune targeting with programmed death ligand (PD-L)1 blockade in combination with low-dose lenalidomide. | R |
NCT02489903 | SCLC, NSCLC, neuroendocrine tumors and ovarian epithelial cancer | Platinum refractory/resistant | Phase II study, randomized, parallel assignment, open label | RRx-001, cisplatin, etoposide, carboplatin, irinotecan, vinorelbine, Doxil, gemcitabine, taxane, Paclitaxel, nab-Paclitaxel, pemetrexed | Intravenously | DNMT | Participants with SCLC will receive one of the following: RRx-001 followed by platinum-doublet chemotherapy or platinum-based chemotherapy alone. Neuroendocrine, RRx-001 followed by platinum-doublet chemotherapy. NSCLC, RRx-001 followed by platinum-doublet chemotherapy. Participants with platinum refractory/resistant ovarian will receive one of the following: RRx-001 followed by platinum-doublet chemotherapy or chemotherapy alone. | A |
NCT03901469 | Triple-negative breast cancer | Without germline mutations of BRCA1 or BRCA2 | Phase 2 study, non-randomized, single group assignment, open label | ZEN-3694, talazoparib | Orally | BET | Triple-negative breast cancer without germline mutations of BRCA1 or BRCA2 | R |
NCT01194908 | Triple-negative breast cancer | Metastatic | Phase I/II trial, single group assignment, open label | Decitabine, panobinostat, tamoxifen | Intravenously | DNMT and HDAC | ER is silenced by methyl and histone groups. Reactivation of ER by demethylating inhibitors (such as decitabine) and histone deacetylase inhibitors (such as panobinostat) can remove these methyl and histone groups and reactivate ER with tamoxifen. | T |
NCT01700569 | Grade IV astrocytoma/glioblastoma | Complete or near-complete resection with unmethylated MGMT gene | A phase-1 dose-escalation study, single group assignment, open label, | Folinic acid concomitantly with temozolomide and radiation | Orally | DNMT | Temozolomide in combination with radiation therapy induces MGMT. Then, folinic Acid is able to lead MGMT methylation. | R |
NCT00925132 | Metastatic melanoma | Refractory/resistant to any prior treatment | Phase Ib/II trial with dose escalation, single group assignment, open label | Combination of temozolomide, decitabine, panobinostat | Orally | DNMT and HDAC | The treatment combination is proposed to unlock genes (Apaf-1) that may contribute to mechanisms that cause tumor growth. The triple agent was well tolerated. | T |
NCT02816021 | Metastatic melanoma | Unresectable stage III/IV metastatic melanoma | Phase II non-randomized, open label | Oral azacitidine (CC-486), pembrolizumab | Orally | DNMT | The goal of this clinical research study is to learn if oral azacitidine (CC-486) and pembrolizumab (MK-3475) can help to control melanoma progression. | R |
NCT01876641 | Metastatic melanoma | BRAF-mutated tumors regardless of prior treatment | Phase 1/2 trial, single group assignment, open label | Vemurafenib, cobimetinib, Decitabine | Subcutaneous | DNMT | Improve the low therapy response rate with the combination of vemurafenib with decitabine plus cobimetinib. | T |
NCT03765229 | Metastatic melanoma | In non-Inflamed stage III/IV | An exploratory, open-label, single-arm, phase II study | Entinostat, pembrolizumab or any other PD-1/PD-L1 inhibitor | Orally | HDAC | Induction of epigenetic changes in tumor biology by entinostat to enhance treatment response, progression-free survival and incidence of adverse events. | R |
NCT00715793 | Metastatic melanoma | Unresectable stage IIIB/IV despite prior therapies | Single-arm phase I/II trial, single group assignment, open label | Decitabine, temozolomide | Intravenously | DNMT | The combination of decitabine and temozolomide may induce changes in DNA to improve clinical response. Determine the efficacy, safety and tolerability of the combination decitabine and temozolomide. This study obtained 18% ORR and 61% clinical benefit rate (CR + PR + SD) | C |
NCT03903458 | Metastatic melanoma | Refractory, locally advanced or metastatic | Open label, non-randomized, phase IB, single group assignment | Tinostamustine, nivolumab | N/A | HDAC | To assess the safety, tolerability and recommended dose of tinostamustine in combination with nivolumab and characterize potential predictive biomarkers of the combination treatment. | R |
NCT00404508 | Ovarian cancer and other solid tumors | Persistent or progression to first-line platinum-based chemotherapy | Randomized, double-blind phase II trial. Parallel assignment | Topotecan, hydralazine, valproate | Orally | DNMT and HDAC | Inhibitors of DNA methylation and HDAC inhibition may synergize the cytotoxicity of chemotherapy to improve response, progression-free survival and overall survival. A clinical benefit was observed in 80% patients and the main toxicity was hematologic. | C |
NCT02159820 | Ovarian cancer | Previously untreated | Open label, randomized, phase II to III, intergroup trial. Parallel assignment | Decitabine, paclitaxel, carboplatin | Intravenously | DNMT | Decitabine may trigger epigenetic reprogramming of tumor cells and possible immune cells could induce pronounced long-term clinical effect by chemosensitization and immunopotentiation. | R |
NCT02900560 | Ovarian cancer | Platinum-resistant/refractory | Open-label, non-randomized, four-cohort phase II. Parallel assignment | Pembrolizumab and oral azacitidine (CC-486) | Orally | DNMT | Four cohorts of combined oral azacitidine (CC-486) and intravenous pembrolizumab to evaluate the safety and efficacy. Mandatory tumor biopsies for DNA methylation analysis. | A |
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Martinez-Useros, J.; Martin-Galan, M.; Florez-Cespedes, M.; Garcia-Foncillas, J. Epigenetics of Most Aggressive Solid Tumors: Pathways, Targets and Treatments. Cancers 2021, 13, 3209. https://doi.org/10.3390/cancers13133209
Martinez-Useros J, Martin-Galan M, Florez-Cespedes M, Garcia-Foncillas J. Epigenetics of Most Aggressive Solid Tumors: Pathways, Targets and Treatments. Cancers. 2021; 13(13):3209. https://doi.org/10.3390/cancers13133209
Chicago/Turabian StyleMartinez-Useros, Javier, Mario Martin-Galan, Maria Florez-Cespedes, and Jesus Garcia-Foncillas. 2021. "Epigenetics of Most Aggressive Solid Tumors: Pathways, Targets and Treatments" Cancers 13, no. 13: 3209. https://doi.org/10.3390/cancers13133209