Targeting Autophagy in Breast Cancer
Abstract
:1. Introduction
2. Main Mechanisms Inducing Autophagy
3. Role of Autophagy in Cancer Diseases
Targeting Autophagy as a Cancer Treatment
4. Targeting Autophagy in Breast Cancer
4.1. ER+, PgR+, HER2-Subtype
4.2. HER2-Positive Subtype
4.3. TNBC Subtype
4.4. Clinical Trials
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
3-MA | 3-methyladenine |
AI | Aromatase Inhibitor |
ALDH | Aldehyde Dehydrogenase |
AMPK | 5’ AMP-activated protein kinase |
ATG | Autophagy related genes |
ACD | Autophagic cell death |
BC | Breast Cancer |
CQ | Chloroquine |
CSCs | Cancer Stem Cells |
DNA | Deoxyribonucleic Acid |
ECM | Extracellular matrix |
EGFR | Epidermal Growth Factor Receptor |
EMT | Epithelial Mesenchymal Transition |
ER | Estrogen Receptor |
EXE | Exemestane |
HCQ | Hidroxychloroquine |
HER2 | Human Epidermal Growth Factor Receptor 2 |
HIF-1 | Hipoxia-inducible factor 1 |
YAP | Yes-associated protein |
LC3 | Light chain 3 |
MAPK | Mitogen-activated protein kinase |
MSL | Mesenchymal Stem-Like |
mTOR | Mammalian Target Of Rapamycin |
mTORC1 | mTOR complex 1 |
NFKB | Nuclear factor kappa-light-chain-enhancer of activated B cells |
PAS | Phagophore assembly site |
PDL1 | Programmed Cell Death Ligand-1 |
PDX | Patient-Derived-Xenograft |
PE | Phosphatidylethanolamine |
PI3K | Phosphatidylinositol 3-kinase |
PIK3CA | Phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit, alpha |
PIP3 | Phosphatidylinositol (3,4,5)-trisphosphate |
PTEN | Phosphatase and Tensin Homolog |
PgR | Progesteron Receptor |
RB | Retinoblastoma protein |
ROS | Reactive Oxygen Species |
T-DM1 | Trastuzumab emtansine |
TFEB | Transcription factor EB |
TNBC | Triple-Negative Breast Cancer |
ULK1 | Unc-51 like autophagy activating kinase |
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Breast Cancer Stage/Subtype/Setting | Intervention | Study Design | Dosage | Clinicaltrial.gov |
---|---|---|---|---|
Invasive Breast Cancer/Neoadjuvant | Drug: Chloroquine Drug: Placebo | Phase 2 Randomized, Double-blind, placebo-controlled | chloroquine 500 mg daily as an oral capsule during the wait time to surgery. | * NCT02333890 |
Advanced or Metastatic Breast Cancer | Chloroquine in Combination with taxane or taxane-like Chemo Agents | Phase II Non-Randomized, open label | chloroquine 250 mg daily as an oral capsule | NCT01446016 |
Carcinoma, Intraductal, Noninfiltrating DCIS Ductal Carcinoma In Situ Neoadjuvant | Chloroquine | Phase 1 Phase 2 Non-Randomized open label | chloroquine standard dose (500mg/week) or chloroquine low dose (250mg/week) for 1 month prior to surgical removal of the tumor. | NCT01023477 |
Metastatic Breast Cancer | Hydroxychloroquine + Ixabepilone | Phase 1 Phase 2 Non-Randomized, open label | Dose escalation from 200 mg po qd to 200 mg po bid. | # NCT00765765 |
Estrogen Receptor-Positive Metastatic Breast Cancer | Hydroxychloroquine in combination with the current hormonal therapy | Phase Ib/II Study Non-Randomized, open label | Not available | NCT02414776 |
Invasive breast cancer | Arm A: Abemaciclib Arm B: Abemaciclib + Hydroxychloroquine | Phase II Pilot Trial, Randomized, open lable | Hydroxychloroquine 600 mg BID | NCT04523857 |
Recurrent Breast Cancer | Phase II Arm A: Hydroxychloroquine for 24 weeks Arm B: Hydroxychloroquine for 24 weeks + Gedatolisib and × 2 weeks administered weekly Arm C: Hydroxychloroquine for 24 weeks + Gedatolisib and × 6 weeks administered weekly Arm D: Hydroxychloroquine for 24 weeks + Gedatolisib and × 12 weeks administered weekly Phase Ib: Hydroxychloroquine for 24 weeks + Gedatolisib and × 6 weeks administered weekly | Phase 1 Phase 2 Randomized open label | Hydroxychloroquine 600 mg BID | NCT03400254 |
Breast Cancer Stage IIB | Arm A: Hydroxychloroquine Arm B: Everolimus Arm C: Hydroxychloroquine + Everolimus Arm D: Observation | Phase 2 Pilot Randomized | Not available | NCT03032406 |
HR+/Her 2- Advanced Breast Cancer | Arm A: Abemaciclib + Hydroxychloroquine 200 mg b.i.d. Arm B. Abemaciclib + Hydroxychloroquine 400 mg b.i.d. Arm C: Abemaciclib + Hydroxychloroquine 600 mg b.i.d. Arm D: Abemaciclib + Hydroxychloroquine + endocrine therapy. | Phase 1 Non-Randomized Sequential Assignment Open Label | Hydroxychloroquine 200 mg Hydroxychloroquine 400 mg Hydroxychloroquine 600 mg | NCT04316169 |
Participants with advanced, metastatic (stage IV) breast cancer (phase I) Participants with early stage (stage I-III) breast cancer (phase II) | Hydroxychloroquine, Palbociclib, and Letrozole | Phase 1 Phase 2 Open label | Hydroxychloroquine 400 mg | NCT03774472 |
Breast Cancer Neoadijuvant | Hydrochloroquine | Phase II Pilot Open Label | Hydrochloroquine 800 mg per os once, and then 400 mg per day | NCT01292408 |
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Cocco, S.; Leone, A.; Piezzo, M.; Caputo, R.; Di Lauro, V.; Di Rella, F.; Fusco, G.; Capozzi, M.; Gioia, G.d.; Budillon, A.; et al. Targeting Autophagy in Breast Cancer. Int. J. Mol. Sci. 2020, 21, 7836. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217836
Cocco S, Leone A, Piezzo M, Caputo R, Di Lauro V, Di Rella F, Fusco G, Capozzi M, Gioia Gd, Budillon A, et al. Targeting Autophagy in Breast Cancer. International Journal of Molecular Sciences. 2020; 21(21):7836. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217836
Chicago/Turabian StyleCocco, Stefania, Alessandra Leone, Michela Piezzo, Roberta Caputo, Vincenzo Di Lauro, Francesca Di Rella, Giuseppina Fusco, Monica Capozzi, Germira di Gioia, Alfredo Budillon, and et al. 2020. "Targeting Autophagy in Breast Cancer" International Journal of Molecular Sciences 21, no. 21: 7836. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217836