Ignite Creation Date:
2024-05-06 @ 4:03 AM
Last Modification Date:
2024-10-26 @ 11:43 AM
Study NCT ID:
NCT02441543
Status:
COMPLETED
Last Update Posted:
2022-09-10
First Post:
2015-04-28
Brief Title:
Regulation of Lymphocyte Anti-tumor Response in Metastatic Patients Treated With the mTOR Inhibitor Everolimus
Sponsor:
Istituto Clinico Humanitas
Organization:
Istituto Clinico Humanitas
Study Overview
Official Title:
Regulation of Lymphocyte Anti-tumor Response in Metastatic Patients Treated With the mTOR Inhibitor Everolimus
Status:
COMPLETED
Status Verified Date:
2022-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Preclinical studies and clinical observations have shown the Phosphoinositide 3-kinase PI3K Protein kinase B AKT mammalian mechanistic target of Rapamycin known as the mTOR-pathway signaling to be deregulated in several tumors
Detailed Description:
Cancer is the second most-common cause of death in industrialized countries Preclinical studies and clinical observations have shown the PI3KAKTmammalian mechanistic target of Rapamycin known as the mTOR-pathway signaling to be deregulated in several tumors
The mTOR is evolutionary conserved SerineThreonine protein kinase that senses and integrates signals from different environmental cues It is a central regulator of cell growth cell cycle progression proliferation and metabolism It has been found to form two distinct multiprotein complexes based on the binding with different partners In a complex with Regulatory-Associated Protein of mTOR Raptor mTOR forms mTORC1 whereas when bound to Rapamycin-Insensitive Companion of mTOR Rictor than the mTOR Complex 2 mTORC2 is formed Not only the structure of both mTOR complexes is different but also they are characterized by distinct biological functions mediated by individual downstream targets The mTORC1 promotes cap-dependent translation and elongation increases Messenger RNA mRNA biogenesis as well as promotes ribosome biogenesis - via regulation of p70 ribosomal S6 kinase 1 p70S6K as well as the eukaryotic initiation factor 4E eIF4E binding protein 1 4EBP-1 In addition mTORC1 promotes lipid synthesis via sterol regulatory element binding protein 1 SREBP1 and peroxisome proliferator-activated receptor-γ PPARγ The role of the mTORC2 is less defined The best characterized mTORC2 target is AKT which regulates cell survival metabolism and proliferation as well as differentiation in many primary and cancer cell types Another direct targets of mTORC2 are the serum- and glucocorticoid-regulated kinase SGK controls cell survival and anabolism and protein kinase Cα PKCα involved in the control of cytoskeletal organization Thus constitutive oncogenic activation of mTOR signaling promotes protein and lipid synthesis needed for the increase in cell mass and it enhances surface transporters expression sustaining better uptake of glucose amino acids and other nutrients sustaining cell growth and proliferation of transformed cells
Since mTOR signalling pathway is critical for tumorigenesis its inhibitors have been strongly wanted As first approved by FDA in clinical setting was Rapamycin for its activity against transplant organ rejection and as a prophylactic agent in Graft-versus-Host disease after allogenic bone marrow transplantation The immunosuppressive effects of Rapamycin were initially attributed to its ability to block the Interleukin 2 IL-2 induced proliferation However later this was found not to be the case and rather work through immunomodulation in part due to the induction and expansion of T cells with regulatory phenotype Moreover in T cells mTORC1 modulates T helper cell differentiation towards Th1 and Th17 fate while mTORC2 controls Th2 development Also Rapamycin is involved in immunostimulation of long-lived memory cluster of differentiation 8 CD8 T cells In addition to the Rapamycin effect on T cells the drug exerts an inhibitory effect on the proliferation and function of other immune cells such as dendritic cells B lymphocytes Natural Killer cells NK neutrophiles and mast cells Lastly Rapamycin has been tested as a chemotherapy agent against cancer and it was shown to delay the growth and proliferation and to promote apoptosis of many cancer cell lines and also to possess anti-angiogenic properties During the past years different rapalogs have been synthesized among which is Everolimus RAD001 Afinitor that is currently tested in clinical trials phase IV in patients with renal cell carcinoma RCC or advance large cell lung cancer with neuroendocrine differentiation as well as in the phase III of metastatic breast cancer In addition it is already approved in different tumors when the first-line treatment was ineffective Even Everolimus seems to be very promising neoplastic agent there is no clinical data about its effect on the immune competence of the patients And it still remains unknown whether Everolimus exerts similar to Rapamycin effect on the modulation of the immune system when administrated into cancer patients
The mTOR is evolutionary conserved SerineThreonine protein kinase that senses and integrates signals from different environmental cues It is a central regulator of cell growth cell cycle progression proliferation and metabolism It has been found to form two distinct multiprotein complexes based on the binding with different partners In a complex with Regulatory-Associated Protein of mTOR Raptor mTOR forms mTORC1 whereas when bound to Rapamycin-Insensitive Companion of mTOR Rictor than the mTOR Complex 2 mTORC2 is formed Not only the structure of both mTOR complexes is different but also they are characterized by distinct biological functions mediated by individual downstream targets The mTORC1 promotes cap-dependent translation and elongation increases Messenger RNA mRNA biogenesis as well as promotes ribosome biogenesis - via regulation of p70 ribosomal S6 kinase 1 p70S6K as well as the eukaryotic initiation factor 4E eIF4E binding protein 1 4EBP-1 In addition mTORC1 promotes lipid synthesis via sterol regulatory element binding protein 1 SREBP1 and peroxisome proliferator-activated receptor-γ PPARγ The role of the mTORC2 is less defined The best characterized mTORC2 target is AKT which regulates cell survival metabolism and proliferation as well as differentiation in many primary and cancer cell types Another direct targets of mTORC2 are the serum- and glucocorticoid-regulated kinase SGK controls cell survival and anabolism and protein kinase Cα PKCα involved in the control of cytoskeletal organization Thus constitutive oncogenic activation of mTOR signaling promotes protein and lipid synthesis needed for the increase in cell mass and it enhances surface transporters expression sustaining better uptake of glucose amino acids and other nutrients sustaining cell growth and proliferation of transformed cells
Since mTOR signalling pathway is critical for tumorigenesis its inhibitors have been strongly wanted As first approved by FDA in clinical setting was Rapamycin for its activity against transplant organ rejection and as a prophylactic agent in Graft-versus-Host disease after allogenic bone marrow transplantation The immunosuppressive effects of Rapamycin were initially attributed to its ability to block the Interleukin 2 IL-2 induced proliferation However later this was found not to be the case and rather work through immunomodulation in part due to the induction and expansion of T cells with regulatory phenotype Moreover in T cells mTORC1 modulates T helper cell differentiation towards Th1 and Th17 fate while mTORC2 controls Th2 development Also Rapamycin is involved in immunostimulation of long-lived memory cluster of differentiation 8 CD8 T cells In addition to the Rapamycin effect on T cells the drug exerts an inhibitory effect on the proliferation and function of other immune cells such as dendritic cells B lymphocytes Natural Killer cells NK neutrophiles and mast cells Lastly Rapamycin has been tested as a chemotherapy agent against cancer and it was shown to delay the growth and proliferation and to promote apoptosis of many cancer cell lines and also to possess anti-angiogenic properties During the past years different rapalogs have been synthesized among which is Everolimus RAD001 Afinitor that is currently tested in clinical trials phase IV in patients with renal cell carcinoma RCC or advance large cell lung cancer with neuroendocrine differentiation as well as in the phase III of metastatic breast cancer In addition it is already approved in different tumors when the first-line treatment was ineffective Even Everolimus seems to be very promising neoplastic agent there is no clinical data about its effect on the immune competence of the patients And it still remains unknown whether Everolimus exerts similar to Rapamycin effect on the modulation of the immune system when administrated into cancer patients
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None