Activation of the IGF Axis in Thyroid Cancer: Implications for Tumorigenesis and Treatment
Abstract
:1. Introduction
2. IGF Signaling in Thyroid Cancer
3. Targeting IGF Signaling in Thyroid Cancer
3.1. IGF-IR Direct Inhibitors
3.1.1. IGF-IRmAbs
AVE1642
Cixutumumab (IMAC-A12)
Ganitumab (AMG-479)
3.1.2. IGF-IRTKIs
Linsitinib
NVP-ADW742
NVP-AEW541
3.2. Inhibitors Targeting Downstream Signaling Mediators Shared by IGF-IR/RTKs (IGF-IR/RTKs Downstream Inhibitors)
3.2.1. PI3Ki/AKTi/mTORi
Buparlisib (PI3Ki)
Ipatasertib (AKTi)
Everolimus (mTORi)
Sirolimus (mTORi)
Temsirolimus (mTORi)
3.2.2. MEKi
Binimetinib and Pimasertib
Selumetinib
Trametinib
3.2.3. FAKi
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ATC | Anaplastic Thyroid Cancer |
AKT | V-Akt Murine Thymoma Viral Oncogene Homolog |
AKTi | V-Akt Murine Thymoma Viral Oncogene Homolog inihibitors |
ALK | Anaplastic Lymphoma Kinase |
DDR1 | Discoidin Domain Receptor Tyrosine Kinase 1 |
DTC | Differentiated Thyroid Cancer |
FAK | Focal Adhesion Kinase |
FAKi | Focal Adhesion Kinase inhibitors |
FTC | Follicular Thyroid Cancer |
EGFR | Epidermal Growth Factor Receptor |
ERK | Extracellular Signal-Regulated Kinase |
IGF-1 | Insulin-like growth ligand 1 |
IGF-2 | Insulin-like growth ligand 2 |
IGF-IR | Insulin-like growth factor receptor I |
IGF-IIR | Insulin-like growth factor receptor II |
IGFBP | Insulin-like growth factor binding protein |
IRA | Insulin receptor isoform A |
IRB | Insulin receptor isoform B |
IRS | Insulin receptor substrate |
IGF- | Insulin-like growth factor receptor monoclonal antibodies |
IRmAbs | Insulin-like growth factor receptor tyrosine kinase inhibitors |
IGF-IRTKIs | Mitogen-Activated Protein Kinase |
MEK | Mammalian Target of Rapamycin inhibitors |
MEKi | Mitogen-Activated Protein Kinase inhibitors |
MET | MET Proto-Oncogene, Receptor Tyrosine Kinase |
mTOR | Mammalian Target of Rapamycin |
MTC | Neural Precursor Cell Expressed, Developmentally Down-Regulated 4 |
NEDD4 | Sodium Iodide Symporter |
NIS | Platelet Derived Growth Factor Receptor |
PDGFR | Poorly Differentiated Thyroid Cancer |
PDTC | Phosphatidylinositol kinase |
PI3K | Phosphatidylinositol kinase inhibitors |
PI3Ki | Papillary Thyroid Cancer |
PTC | Proto-Oncogene Serine/Threonine-Protein Kinase |
RECIST | Response Evaluation Criteria in Solid Tumors |
RTK | Receptor tyrosine kinase |
SHC | Src Homology 2 Domain Containing) Transforming Protein 1 |
TSH | Thyroid Stimulating Hormone |
TKI | Tyrosine Kinase Inhibitors |
VEGF | Vascular Endothelial Growth Factor |
VEGFR | Vascular Endothelial Growth Factor Receptor |
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Class of Drugs | Drug Name | Published Data | Phase | Tumor Type | N°* | Regimen |
---|---|---|---|---|---|---|
IGF-IRi | AVE1642 | [61] | I | Advanced Solid | 1 | AVE1642+Docetaxel |
Cixutumumab | [62] | I | Advanced Solid | 4 | Cixutumumab + Selumetinib | |
Ganitumab | [63] | I | Advanced Solid | 2 | Ganitumab + Sorafenib or Panitumumab | |
PI3Ki | Buparlisib | [64] | I | Advanced Solid | 1 | Monotherapy |
[65] | II | FTC + PDTC | 43 | Monotherapy | ||
AKTi | Ipatasertib | [66] | I | Advanced Solid | 1 | Monotherapy |
FAKi | VS-6063 | [67] | I | Advanced Solid | 1 | Monotherapy |
GSK2256098 | [68] | I | Advanced Solid | 2 | Monotherapy | |
MEKi | Binimetinib | [69] | II | Advanced Solid | 2 | Monotherapy |
Pimasertib | [70] | I | Advanced Solid | 1 | Pimasertib+Temsirolimus | |
Selumetinib | [71] | I | Advanced Solid | 2 | Selumetinib + Temsirolimus | |
[72] | I | PTC | 39 | Monotherapy | ||
Trametinib | [73] | I | Advanced Solid | 5 | Monotherapy | |
[74] | I | Advanced Solid | 1 | Trametinib + Everolimus | ||
mToRi | Everolimus | [75] | II | ATC | 5 | Monotherapy |
[76] | I | Advanced Solid | 7 | Everolimus + Cisplatin | ||
[77] | II | DTC+ATC+MTC | 40 | Monotherapy | ||
[78] | II | MTC | 7 | Monotherapy | ||
[79] | II | DTC+MTC | 41 | Everolimus + Sorafenib | ||
[80] | II | DTC+ATC | 28 | Monotherapy | ||
Temsirolimus | [81] | I | Advanced Solid | 1 | Temsirolimus + Trebananib | |
[79] | II | DTC+ATC | 36 | Temsirolimus + Sorafenib |
Intervention | Population | Design | Pts (n) | Primary End Point | Status | Identifier |
---|---|---|---|---|---|---|
CixutumumabIGF-IRmAb EverolimusmTORi Octreotide somatostatin analogue | Advanced low- or intermediate-grade neuroendocrine cancers | Nonrandomized, Open label, phase I | 27 actual | DLTs, PD, PK, SP | Completed | NCT01204476 |
Binimetinib MEKi Capivasertib Akt Copanlisib PI3Ki TaselisibPI3Ki GSK2636771PI3Ki Trametinib MEKi | Genetic testing-directed targeted therapy in patients with advanced refractory solid tumors, lymphomas, or multiple myeloma | Nonrandomized, Open label, phase II (molecular analysis for therapy choice) | 6452 estimated | ORR | Recruiting | NCT02465060 |
Everolimus mTORi Sorafenib MKi | Metastatic differentiated thyroid cancer progressed on Sorafenib | Nonrandomized, Open label, phase II | 40 estimated | ORR, PFS | Active, not Recruiting | NCT01263951 |
Everolimus mTORi Sorafenib MKi | Advanced thyroid cancer naive to m-TOR inhibitors or Sorafenib | Nonrandomized, Open label, phase II | 41 actual | ORR | Active, not Recruiting | NCT01141309 |
Everolimus mTORi Pasireotide somatostatin analogue | Radioiodine-refractory differentiated and medullary thyroid cancer | Randomized, Open label, phase II | 42 actual | ORR | Completed | NCT01270321 |
Everolimus mTORi | Radioiodine-refractory thyroid cancer | Nonrandomized, Open label, phase II | 33 estimated | PFS | Active, not Recruiting | NCT00936858 |
Everolimus mTORi Sorafenib MKi | Advanced radioiodine-refractory Hurthle cell thyroid cancer | Randomized, Open label, phase II | 34 estimated | PFS | Recruiting | NCT02143726 |
Everolimus mTORi Lenvatinib MKi | Metastatic differentiated thyroid cancer progressed on Lenvatinib | Nonrandomized, Open label, phase II | 40 estimated | PFS | Recruiting | NCT03139747 |
Everolimus mTORi Pasireotide somatostatin analogue | Advanced medullary thyroid cancer | Nonrandomized, Open label, phase II | 19 actual | PFS | Completed | NCT01625520 |
Everolimus mTORi | Locally advanced or metastatic thyroid cancer | Nonrandomized, Open label, phase II | 40 actual | ORR | Completed | NCT01164176 |
Everolimus mTORi Neratinib EGFRi or Neratinib EGFRi Trametinib MEKi | Advanced cancer with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation or KRAS mutation | Nonrandomized, Open label, phase I | 120 estimated | DLTs | Recruiting | NCT03065387 |
Everolimus mTORi Vatalanib VEGFi | Advanced solid tumors | Nonrandomized, Open label, phase I | 96 estimated | DLTs, SP | Completed | NCT00655655 |
BevacizumabVEGFmAbs Temsirolimus mTORi | Advanced or metastatic malignancies or other benign diseases | Nonrandomized, Open label, phase I | 216 estimated | DLTs | Recruiting | NCT01552434 |
Temsirolimus mTORi Vinorelbine | Unresectable or metastatic solid tumors | Nonrandomized, Open label, phase I | 19 actual | DLTs, ORR | Completed | NCT01155258 |
Ciclophosfamide Sirolimus mTORi | Metastatic, RAI-refractory, differentiated thyroid cancer | Nonrandomized, Open label, phase II | 19 estimated | ORR | Recruiting | NCT03099356 |
Grapefruit juice Sirolimus mTORi | Advanced malignancies | Nonrandomized, Open label, phase Ib | 41 actual | PK | Completed | NCT00375245 |
Iodine I-131 Selumetinib MEKi | Recurrent or metastatic thyroid cancer | Randomized, Double blind, phase II | 60 estimated | ORR | Recruiting | NCT02393690 |
Olaparib PARPi Selumetinib MEKi | Endometrial, ovarian and other solid tumors with RAS pathway alterations and ovarian tumors with resistance to PARPis | Nonrandomized, Open label, phase I | 90 estimated | DLTs | Recruiting | NCT03162627 |
Paclitaxel Trametinib MEKi | Anaplastic thyroid cancer | Nonrandomized, Open label, early phase I | 12 estimated | PFS | Recruiting | NCT03085056 |
Dabrafenib BRAFi Trametinib MEKi | Recurrent thyroid cancer | Randomized, Open label, phase II | 53 actual | ORR | Active, not Recruiting | NCT01723202 |
Dabrafenib BRAFi Trametinib MEKi | Refractory metastatic differentiated thyroid cancer with RAS or BRAFV600E mutations | Nonrandomized, Open label, phase II | 87 estimated | ORR | Recruiting | NCT03244956 |
Pazopanib MKi Trametinib MEKi | Advanced solid tumors enriched for patients with differentiated thyroid cancer, soft tissue sarcoma, and cholangiocarcinoma | Nonrandomized, Open label, phase I | 89 actual | DLTs, SP | Completed | NCT01438554 |
RAI TrametinibMEKi | Mutant RAS or wild-type RAS/RAF, RAI-refractory recurrent and/or metastatic thyroid cancer | Nonrandomized, Open label, phase II | 35 estimated | PFS, ORR | Recruiting | NCT02152995 |
CobimetinibMEKi | Differentiated, poorly differentiated and anaplastic thyroid carcinomas | Nonrandomized, Open label, phase II | 50 estimated | OS | Recruiting | NCT03181100 |
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Manzella, L.; Massimino, M.; Stella, S.; Tirrò, E.; Pennisi, M.S.; Martorana, F.; Motta, G.; Vitale, S.R.; Puma, A.; Romano, C.; et al. Activation of the IGF Axis in Thyroid Cancer: Implications for Tumorigenesis and Treatment. Int. J. Mol. Sci. 2019, 20, 3258. https://doi.org/10.3390/ijms20133258
Manzella L, Massimino M, Stella S, Tirrò E, Pennisi MS, Martorana F, Motta G, Vitale SR, Puma A, Romano C, et al. Activation of the IGF Axis in Thyroid Cancer: Implications for Tumorigenesis and Treatment. International Journal of Molecular Sciences. 2019; 20(13):3258. https://doi.org/10.3390/ijms20133258
Chicago/Turabian StyleManzella, Livia, Michele Massimino, Stefania Stella, Elena Tirrò, Maria Stella Pennisi, Federica Martorana, Gianmarco Motta, Silvia Rita Vitale, Adriana Puma, Chiara Romano, and et al. 2019. "Activation of the IGF Axis in Thyroid Cancer: Implications for Tumorigenesis and Treatment" International Journal of Molecular Sciences 20, no. 13: 3258. https://doi.org/10.3390/ijms20133258