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In many tumors, components of this pathway are dysregulated Table 1 , permitting unrestricted cancer cell growth and proliferation and evasion of apoptosis, contributing to tumorigenesis [ 3 , 4 ]. The pathobiology of RCC, and tumors with clear cell histology in particular, involves mutation or loss of expression of the von Hippel-Lindau VHL gene.

Hereditary loss of TSC is associated with an increased incidence of several tumor types, including kidney tumors [ 12 ]. This defined role for mTOR activity in the cellular processes that contribute to the development and progression of multiple tumor types has established mTOR as a major link in tumorigenesis.

Preclinical data have supported the pivotal role of mTOR in cancer and led to the development of mTOR inhibitors as a therapeutic target [ 13 ]. Rapamycin sirolimus , an antifungal agent with immunosuppressive properties, was isolated in on the island of Rapa Nui [ 14 ]. Rapamycin was analyzed for anticancer activity against a panel of human cancer cell lines by the US National Cancer Institute in the s and was found to have broad anticancer activity [ 15 ]. However, clinical development of mTOR inhibitors as anticancer agents was less than successful at that time due to unfavorable pharmacokinetic properties [ 13 ].

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In the interim, sirolimus Rapamune, Wyeth Pharmaceuticals has been used in combination with corticosteroids and cyclosporine as a preventive therapy for kidney transplant rejection in the United States and Europe [ 16 ]. Additionally, an orally available rapamycin analogue, everolimus, is approved for use as a preventive therapy for transplant rejection in renal and cardiac transplantation patients in Europe [ 17 — 19 ]. The revival of mTOR inhibitor evaluation as anticancer agents began with rapamycin analogues that have a more favorable pharmacokinetic profile than the parent molecule.

The chemical structures of these compounds are shown in Figure 2. These agents have a similar mechanism of action, though they have disparate pharmacokinetic properties. These drugs are small molecule inhibitors that function intracellularly, forming a complex with the FK binding protein FKBP , which is then recognized by mTOR. The resultant complex prevents mTOR activity [ 4 ]. The function of mTORC2 and its role in normal and cancerous cells remains relatively undefined. Many of the key acquired capabilities of cancer cells can be affected by the inhibition of dysregulated mTOR activity, including cell cycle progression, cellular metabolism, cellular survival, and angiogenesis [ 3 , 13 ].

Differences among the mTOR inhibitors include metabolism, formulation, and schedule of administration. Temsirolimus is a pro-drug, and its primary active metabolite is rapamycin sirolimus [ 20 ]. It is administered intravenously on a once-weekly schedule.

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It is supplied in vials that must be refrigerated and protected from light, and it must be diluted twice before administration [ 21 ]. Ridaforolimus is not a pro-drug [ 22 ], but like temsirolimus, it is also administered intravenously on an intermittent schedule, although an oral formulation is currently being evaluated in sarcoma [ 23 , 24 ].

Everolimus is an orally available mTOR inhibitor that is typically administered on a continuous daily schedule. Everolimus is also being administered in clinical trials on a weekly schedule, but the continuous, daily dosing schedule appears to be optimal for certain tumor types [ 25 ].

mTOR Inhibition for Cancer Therapy: Past, Present and Future - eBook -

Weekly administration is being investigated in combination regimens. The phase I dose-finding studies for temsirolimus and ridaforolimus were conventional in design, in that they attempted to establish a maximum tolerated dose through dose escalation [ 22 , 26 , 27 ]. In contrast, the everolimus studies relied on pharmacokinetic and pharmacodynamic modeling, as well as traditional dose-escalation methodology, to provide for rational selection of the optimal doses and schedules for exploration in future clinical trials [ 25 , 28 , 29 ].

Data from these studies showed that mTOR inhibition with everolimus was dose dependent and that continuous daily dosing produced more profound mTOR inhibition than weekly dosing, [ 25 , 28 , 29 ] and everolimus had acceptable tolerability at the highest dosages studied [ 25 , 29 ]. The results of phase I studies conducted with ridaforolimus, everolimus, and temsirolimus are summarized in Table 3 [ 22 , 25 , 26 , 29 ]. Phase I safety analyses showed that the mTOR inhibitors are generally well tolerated. Noninfectious pneumonitis also appears to be a class effect of mTOR inhibitors and has been reported with everolimus and temsirolimus [ 25 , 30 , 31 ].

Temsirolimus has been associated with infusion reactions, and the administration protocol was altered to include diphenhydramine pretreatment before temsirolimus infusion in subsequent studies [ 20 ]. The pivotal role that mTOR plays in cellular signaling suggests a broad range of clinical utility, and indeed, phase I clinical evaluations of all 3 mTOR inhibitors provided preliminary evidence of anticancer activity in multiple tumor types. Activity in RCC was seen with each agent.

Clinical programs for each of these agents continue to develop in multiple tumor types.

Temsirolimus was administered intravenously once weekly at fixed doses of 25 mg, 75 mg, or mg. This study supported the activity of temsirolimus seen in phase I trials. One complete response CR , 7 partial responses PRs , and 29 minor responses were observed. Dose level did not appear to influence response, but more dose reductions and discontinuations were observed at the higher dose levels, suggesting that the mg dose should be used for future studies.

In addition, 5 patients treated with temsirolimus 75 mg developed pneumonitis. Retrospective classification of patients into good, intermediate, and poor risk groups similar to the Memorial Sloan-Kettering Cancer Center MSKCC prognostic risk criteria for previously untreated patients [ 32 ] suggested that temsirolimus was more effective in patients with intermediate and poor risk than in those with favorable risk [ 31 ].

Temsirolimus was administered at a dose of 25 mg weekly. Combination therapy did not improve survival compared with IFN alone. Based on the results of this study, temsirolimus was approved for use in metastatic RCC in the United States and Europe in [ 16 ]. A subset analysis of the phase III trial showed that the benefit of temsirolimus may be primarily in the poor-risk, non-clear-cell RCC population. The common adverse events observed with temsirolimus were asthenia, stomatitis, rash, nausea, anorexia, and dyspnea. The common abnormal laboratory findings in this trial were hyperglycemia, hypercholesterolemia, and anemia.

Most adverse events were manageable with supportive care or dose reduction [ 34 ]. An ongoing phase III trial is evaluating temsirolimus plus bevacizumab vs. Currently, sorafenib and sunitinib are among the recommended first-line treatment agents for metastatic RCC [ 37 ]. When these VEGFR-targeted therapies are exhausted, until recently there was no evidence that demonstrated clearly which therapy should be offered next.

Previous treatment with cytokines or bevacizumab was permitted. A total of patients from 86 centers were enrolled and stratified by the number of previous treatments sorafenib or sunitinib [1 TKI] vs. Patients were then randomized to treatment with everolimus 10 mg daily and best supportive care BSC or to placebo and BSC. Treatment was continued until disease progression, unacceptable toxicity, death, or discontinuation for other reasons. Patients randomized to placebo and BSC were allowed to cross over to everolimus at disease progression.

After the second interim analysis, the study was terminated early after progression events were observed because the prespecified efficacy endpoint was met [ 38 ]. Based on analyses from the end of the double-blind period, everolimus significantly improved PFS vs. Similar to another mTOR inhibitor, temsirolimus, the most common adverse events of all grades observed in everolimus-treated patients included fatigue, stomatitis, rash, nausea, anorexia, and stomatitis.

The classic mTOR inhibitor-related abnormal laboratory findings, including anemia, hypercholesterolemia, hypertriglyceridemia, and hyperglycemia were observed [ 38 ]. Most adverse events were manageable with supportive care or dose reduction. Noninfectious pneumonitis associated with rapamycin or rapamycin derivative treatment was previously reported [ 31 ] and also was seen with everolimus in this trial.

Based on these clinical trial data, algorithms that define evidence-based treatment options for metastatic RCC have been developed to include mTOR inhibitors, including temsirolimus for the treatment of patients with metastatic RCC with selected risk features and everolimus for the treatment of metastatic RRC in patients whose disease recurred following prior TKI therapy [ 40 , 41 ]. Further development of mTOR inhibitors for the treatment of RCC is ongoing in combination with antiangiogenic agents such as bevacizumab, sorafenib, and sunitinib.

The combination of everolimus and bevacizumab is active and well tolerated in patients with metastatic clear cell RCC; cohorts of first-line and previously treated patients were examined in the study [ 42 ]. The results of preclinical and phase I studies, as well as data from biomarker studies showing oncogenic transformation in mTOR-linked pathways Table 1 suggest that mTOR inhibitors may have anticancer activity in many tumor types. In addition to RCC, pivotal clinical trials with mTOR inhibitors are ongoing in many cancers, including but not limited to: neuroendocrine tumors NET , pancreatic islet cell tumors, breast cancer, diffuse large B-cell lymphoma, hepatocellular carcinoma, and gastric cancer.

Phase II studies have also been performed in pancreatic adenocarcinoma, sarcoma, endometrial cancer, and non-small cell lung cancer NSCLC. Neuroendocrine tumors are characterized by their ability to manufacture and secrete peptides that cause hormonal syndromes [ 45 ].

Although these tumor types are rare, their incidence appears to be increasing. Metastatic low-grade NETs are generally resistant to chemotherapy and are relatively incurable, though hormonal symptoms are managed with somatostatin analogues [ 46 , 47 ]. Temsirolimus and everolimus have both been studied in patients with advanced NET.

The ORR by central radiology was 9. Median PFS by central radiology was 9. Treatment was generally well tolerated in both strata. In breast cancer, resistance to treatment with endocrine therapies and HER-2 targeted agents inevitably develops in many patients [ 52 , 53 ]. A phase III study of temsirolimus in combination with letrozole did not demonstrate benefit over letrozole alone in patients with MBC and was terminated at an interim analysis [ 56 ].