Introduction
mTOR Structure and Function
mTOR Is Implicated in the Development and Progression of Various Tumor Types
Target | Type of Protein | Genetic Aberration | Tumor Types |
---|---|---|---|
EGFR [88] | Tyrosine kinase receptor | Amplification, mutation | Colorectal, lung, gastric, pancreas, liver, lung, others |
HER2 [89] | Tyrosine kinase receptor | Expression | Breast |
ER [90] | Hormone receptor | Expression | Breast, endometrial |
PTEN [91] | Lipid phosphatase | Silencing, allele loss | Glioma, endometrial, prostate, melanoma, breast |
PI3KCA [92] | Serine-threonine kinase | Mutations | Colorectal, breast, lung, brain |
TSC1 [93] | TSC complex protein | Mutation | Bladder |
Serine-threonine kinase | Mutation, silencing | Colorectal, lung | |
K-ras [96] | GTP-binding kinase | Mutation | Colorectal, pancreas, lung, melanoma |
BCR-ABL [97] | Tyrosine kinase | Translocation | CML, ALL |
VHL [98] | Ubiquitin ligase | Loss of heterozygosity, mutation, silencing | Kidney, hemangioblastomas |
Target | Type of Protein | Genetic Aberration | Potential Relevance in RCC |
---|---|---|---|
IGF-1, IGF-1R [99] | Growth factor, tyrosine kinase receptor | Overexpression | Patients with IGF-1R+ clear cell RCC (ccRCC) have shorter survival than those with IGF-1R-negative ccRCC [100] |
PTEN [91] | Lipid phosphatase | Silencing, allele loss | PTEN expression may be lost early in RCC carcinogenesis [101] PTEN-deficient tumor cells have increased sensitivity to mTOR inhibition [102] |
TSC1/TSC2 [12] | TSC complex protein | Hereditary loss | Hereditary loss leads to an increased incidence of several tumor types, including kidney tumors [12]. The TSC tumor suppressors are key components in the upstream regulation of mTOR [103]. |
VHL [98] | Ubiquitin ligase | Loss of heterozygosity, mutation, silencing | Up to 75% of clear cell RCCs have lost the function of the von Hippel-Lindau (VHL) gene [11], resulting in accumulation of HIF-1α, a protein that controls the expression of genes involved in angiogenesis. |
The Development of mTOR Inhibitors
Phase I Studies and Safety of mTOR Inhibitors
mTOR Inhibitor | T1/2 (h) | Primary Metabolite | Dose and Schedule | MTD | DLTs (all grade 3) | Suggested Phase II Dose |
---|---|---|---|---|---|---|
Ridaforolimus [22] | 56-74 | Not sirolimus pro-drug | 3-28 mg/d IV × 5 d q 2 wk | 18.75 mg | Mouth sores | 12.5 mg IV × 5 d q 2 wk |
~30 | Not sirolimus pro-drug | Oral daily: 5-10 mg/d Oral weekly: 5-70 mg/wk | NR | Daily: hyperglycemia, stomatitis Weekly: stomatitis, fatigue, neutropenia, hyperglycemia | Daily: 10 mg Weekly: 50-70 mg | |
Temsirolimus [26] | 13-22 | Sirolimus | 7.5-220 mg/m2/wk | Formal definition of MTD not met | Neutropenia, thrombocytopenia, hypophosphatemia; asthenia, diarrhea; manic-depressive syndrome, stomatitis; ALT elevation | 25, 75, and 250 mg (flat dose) wkly |