Targeting RTK-PI3K-mTOR Axis in Gliomas: An Update
Abstract
:1. Introduction
2. RTK Expression and Signaling in Glioma
3. PI3K/mTOR Axis in Glioma
4. RTK/PI3K/mTOR Axis and TMZ-Resistance
5. Targeting the RTK-PI3K-Akt-mTOR Axis
5.1. RTK Inhibitors
5.1.1. EGFR-Directed Therapies
5.1.2. PDGFR-Directed Therapies
5.1.3. VEGFR-Directed Therapies
5.1.4. Therapies Directed against Other RTKs
5.2. mTOR Inhibitors
5.3. PI3K Inhibitors
5.3.1. Pan-PI3K Inhibitors
5.3.2. Isoform-Specific PI3K Inhibitors
5.3.3. Dual PI3K/mTOR Inhibitors
6. Limitations of RTK/PI3K/mTOR-Targeting Therapies
6.1. Resistance to RTKs
6.2. Limitations of the mTOR-Inhibiting Approaches
7. Combination Strategies within the EGFR-PI3K-mTOR Pathways to Improve Therapeutic Efficacy
8. Conclusions and Future Directions
Funding
Acknowledgments
Conflicts of Interest
References
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RTK | Drug Name | Type of Glioma (Number of Patients Enrolled) | Adjuvant Therapy | Clinical Trial |
---|---|---|---|---|
EGFR | Gefitinib | Recurrent GBM (N = 22) | None | Phase II NCT00250887 |
GBM (N = 158) | Radiotherapy | Phase I/II NCT00052208 | ||
GBM (N = 36) | Radiotherapy | Phase II NCT00238797 | ||
Gliomas and meningiomas (N = 105) | None | Phase II NCT00025675 | ||
Erlotinib | GBM (N = 110) | None | Phase II NCT00337883 | |
GBM, gliosarcoma (N = 66) | TMZ, radiotherapy | Phase II NCT00187486 | ||
Afatinib | Refractory solid tumors (N = 60) | None | Phase II NCT00875433 | |
GBM (N = 36) | TMZ, radiotherapy | Phase I NCT00977431 | ||
GBM (N =151) | TMZ | Phase II NCT00727506 | ||
Lapatinib | GBM (N = 24) | None | Phase I/II NCT00099060 | |
Malignant brain tumors (N = 9) | None | Phase II NCT00107003 | ||
Nimotuzumab | GBM (N = 45) | None | Phase II NCT00561873 | |
GBM (N = 150) | TMZ, radiotherapy | Phase III NCT00753246 | ||
AMG 595 | GBM (N = 32) | None | Phase I NCT01475006 | |
Sym004 | Malignant glioma (N = 43) | None | Phase II NCT02540161 | |
Cetuximab | GBM (N = 46) | TMZ, radiotherapy | Phase I/II NCT00311857 | |
Osimertinib (AZD9291) | Metastatic brain tumors (N = 112) | None | Phase II NCT02971501 | |
PDGFR | Nilotinib | Glioma (N = 38) | None | Phase II NCT01140568 |
Imatinib | Brain and CNS tumors (N = 112) | None | Phase II NCT00039364 | |
GBM, Gliosarcoma (N = 64) | Hydroxyurea | Phase II NCT00615927 | ||
Dasatinib | GBM, gliosarcoma, reccurrent adult brain tumors (N = 64) | None | Phase II NCT00423735 | |
GBM (N = 28) | Lomustine (CCNU) | Phase I/II NCT00948389 | ||
Tandutinib | GBM, gliosarcoma, primary and recurrent brain tumor (N = 60) | None | Phase I/II NCT00379080 | |
VEGFR | Cediranib (AZD2171) | GBM and gliosarcoma (N = 46) | TMZ, radiotherapy | Phase I/II NCT00662506 |
Aflibercept | Anaplastic astrocytoma, anaplastic oligodendroglioma, GBM, gliosarcoma, mixed glioma, recurrent brain tumors (N = 61) | TMZ, radiotherapy | Phase I NCT00650923 | |
BIBF 1120 | Recurrent GBM (N = 25) | None | Phase II NCT01251484 | |
Pazopanib | GBM, gliosarcoma, recurrent brain tumor (N = 35) | None | Phase II NCT00459381 | |
FGFR | TAS-120 | Brain tumors (unavailable) | None | Phase I/II NCT02052778 |
Drug Name | Type of Glioma (Patients Enrolled) | Adjuvant Therapy | Clinical Trial |
---|---|---|---|
Sirolimus | GBM (N = 13) | None | Phase I/II NCT00047073 |
Temsirolimus | Brain and CNS tumors (N = 12) | None | Phase I NCT00784914 |
Brain and CNS tumors (N = 49) | None | Phase I/II NCT00022724 | |
GBM (N = 33) | None | Phase II NCT00016328 | |
Ridaforolimus | Glioma (N = 11) | None | Phase I NCT00087451 |
Metformin | GBM (N = 144) | None/TMZ | Phase I NCT01430351 |
AZD8055 | GBM (N = 22) | None | Phase I NCT01316809 |
Classification | Drug Name | Type of Glioma (Patients Enrolled) | Adjuvant Therapy | Clinical Trial |
---|---|---|---|---|
Pan-PI3K inhibitors | Buparlisib (BKM120) | GBM (N = 65) | None | Phase I/III NCT01339052 |
GBM (N = 38) | TMZ, radiotherapy | Phase I NCT01473901 | ||
Pilaralisib (XL147, SAR245408) | GBM (N = 40) | None | Phase I/II NCT01240460 | |
Sonolisib (PX-866) | GBM (N = 34) | None | Phase I/II NCT01259869 | |
Pictilisib (GDC-0941) | GBM (N = 58) | None | Phase I/II NCT02430363 | |
Dual PI3K/mTOR inhibitors | Voxtalisib (XL765, SAR245409) | GBM (N = 40) | None | Phase I/II NCT01240460 |
HGGs (N = 54) | TMZ | Phase I NCT00704080 | ||
GDC-0084 | HGGs (N = 29) | None | Phase I NCT01547546 | |
PQR309 | GBM (N = 28) (N = 70) (N = 10) | None | Phase I/II NCT01940133 NCT02483858 NCT02850744 |
Drug Name | Type of Glioma (Number of Patients Enrolled) | Combined Therapy | Clinical Trial |
---|---|---|---|
Erlotinib | GBM, gliosarcoma (N = 57) | + Bevacizumab | Phase II NCT00671970 |
Primary and recurrent brain tumors (astrocytoma, oligodendroglioma GBM, gliosarcoma, mixed glioma) (N = 69) | + Temsirolimus | Phase I/II NCT00112736 | |
Sirolimus | GBM(N = 32) | + Erlotinib | Phase II NCT00672243 |
Sirolimus | Brain and CNS tumors (N = 19) | + Erlotinib | Phase I NCT00509431 |
Temsirolimus | Recurrent HGGs (N = 36) | + Perifosine | Phase I/II NCT01051557 |
Pictilisib (GDC-0941) | Recurrent GBM (N = 58) | + Pembrolizumab (MK-3475) | Phase IIB NCT02430363 |
GBM | + ATB-263 | Preclinical [173] | |
GBM | + GNE-317 | Preclinical [174] | |
GBM | + Irinotecan, sunitinib and TMZ | Preclinical [175] | |
Dactolisib (NVP-BEZ235) | GBM (N = 58) | + Pembrolizumab (MK-3475) | Phase IIB NCT02430363 |
AMG 386 | GBM (N = 48) | + Bevacizumab | Phase I/II NCT01290263 |
Vandetanib | GBM (N = 33) | + Sirolimus | Phase I NCT00821080 |
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Colardo, M.; Segatto, M.; Di Bartolomeo, S. Targeting RTK-PI3K-mTOR Axis in Gliomas: An Update. Int. J. Mol. Sci. 2021, 22, 4899. https://doi.org/10.3390/ijms22094899
Colardo M, Segatto M, Di Bartolomeo S. Targeting RTK-PI3K-mTOR Axis in Gliomas: An Update. International Journal of Molecular Sciences. 2021; 22(9):4899. https://doi.org/10.3390/ijms22094899
Chicago/Turabian StyleColardo, Mayra, Marco Segatto, and Sabrina Di Bartolomeo. 2021. "Targeting RTK-PI3K-mTOR Axis in Gliomas: An Update" International Journal of Molecular Sciences 22, no. 9: 4899. https://doi.org/10.3390/ijms22094899