Clinical Cancer Research 13, 758s, January 15, 2007. doi: 10.1158/1078-0432.CCR-06-1986
© 2007 American Association for Cancer Research
Innovations and Challenges in Renal Cancer |
The Role of Mammalian Target of Rapamycin Inhibitors in the Treatment of Advanced Renal Cancer
Daniel Cho1,4,
Sabina Signoretti2,4,
Meredith Regan3,4,
James W. Mier1,4 and
Michael B. Atkins1,4
Authors' Affiliations: 1 Beth Israel Deaconess Medical Center; 2 Brigham and Women's Hospital; 3 Dana-Farber Cancer Institute; and 4 Renal Cancer Program, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts
Requests for reprints: Michael B. Atkins, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215. E-mail: matkins{at}bidmc.harvard.edu.
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Abstract
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Inhibitors of the mammalian target of rapamycin (mTOR) have shown promising efficacy in early-stage trials in patients with advanced renal cell carcinoma (RCC). Most RCCs have been shown to possess biallelic alterations in the von Hippel-Lindau (VHL) gene, resulting in accumulation of hypoxia-inducible factors 1
and 2, as well as their downstream targets including vascular endothelial growth factor (VEGF). The observed clinical efficacy of mTOR inhibitors in patients with RCC may be mediated in part by the dependence of efficient hypoxia-inducible factor translation on the mTOR pathway. mTOR inhibitors have entered more advanced phase clinical trials either as single agents or in combination with other targeted agents or IFN, which might ultimately result in regulatory approval of one or more agents. Given the likely nonoverlapping mechanism of action of mTOR inhibitors and VEGF pathway–targeted agents, mTOR inhibitors may prove useful if administered in combination or after resistance to VEGF inhibitors. With an increasing number of active agents for treatment of patients with RCC, efforts must continue to develop patient selection models based on predictive biomarkers to direct therapy to appropriate patients.
Traditionally, treatment for patients with metastatic renal cell carcinoma (RCC) has been limited. Standard chemotherapeutic agents have been largely ineffective and cytokine-based treatments with interleukin 2 (IL-2) or IFN- benefit only a small proportion of patients. Objective response rates to IL-2 range from 10% to 25%, with 5% to 10% of all patients having durable responses (1–3). Low-dose IFN has produced response rates in the 10% range, with several studies showing a modest survival benefit (4, 5). Recently, several novel agents targeting specific molecular aberrations have shown promising efficacy in RCC. One such class of agents is the inhibitors of mammalian target of rapamycin (mTOR) kinase activity, which include temsirolimus (CCI-779) and everolimus (RAD001). After promising results in preclinical and early-phase clinical studies, mTOR inhibitors have been evaluated in more advanced phase clinical trials, which might ultimately lead to regulatory approval of one or more of these agents. Given the likely nonoverlapping mechanism of action of mTOR inhibitors with vascular endothelial growth factor (VEGF)–targeted therapies, these agents may prove useful if administered in combination or after resistance to VEGF-targeted agents. In addition, the availability of these novel classes of active agents will further highlight the need to develop predictive biomarkers and patient selection models for specific agents used to treat patients with advanced RCC.
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Relevance of the mTOR Pathway in RCC
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Originally discovered during studies of the immunosuppressant rapamycin, mTOR is a highly conserved serine/threonine kinase that regulates cell growth and metabolism in response to environmental factors. The complex regulation of the mTOR pathway is illustrated in Fig. 1
and is reviewed in greater detail elsewhere (6). The response of the mTOR pathway to growth factors and nutrients is directly under the control of the phosphatidylinositol 3-kinase pathway but can also be activated by extracellular signal–regulated kinase. In the setting of nutrient sufficiency, growth factors activate phosphatidylinositol 3-kinase through activation of receptor tyrosine kinases. Phosphatidylinositol 3-kinase then stimulates the activation of the serine/threonine kinase Akt, which in turn activates mTOR through inhibition of the heterodimer formed by tuberous sclerosis complex (TSC)-1 and TSC2 proteins. This activation of Akt by the phosphatidylinositol 3-kinase pathway is opposed by the phosphatase and tensin homologue (PTEN) tumor suppressor gene. Loss of PTEN function through mutation, deletion, or epigenetic silencing can result in activation of both Akt and mTOR. Once activated, mTOR acts through its downstream effectors (i.e., the eukaryotic translation initiation factor 4E binding protein and the 40S ribosomal protein p70 S6 kinase) to stimulate protein synthesis and entrance into G1 phase of the cell cycle. The primary substrate of p70 S6 kinase, the S6 ribosomal protein, has been shown to have an important role in determining cell size whereas phosphorylation of eukaryotic translation initiation factor 4E binding protein by mTOR results in the activation of cap-dependent translation of nuclear mRNA by releasing inhibition of eukaryotic translation initiation factor 4E (7). Similar to rapamycin, inhibitors of mTOR bind with high affinity to the cytoplasmic protein FK506 binding protein-12. This resulting complex interacts with and prevents the activation of mTOR (8).
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Fig. 1. Regulation of the mTOR pathway. ERK, extracellular signal–regulated kinase; eIF4E, eukaryotic translation initiation factor 4E; 4E-BP, eukaryotic translation initiation factor 4E binding protein; MAPK, mitogen-activated protein kinase; PDK1, phosphoinositide-dependent protein kinase 1; PI3K, phosphatidylinositol 3-kinase; PIP3, phosphatidylinositol 3,4,5-trisphosphate; RTK, receptor tyrosine kinase; S6K, S6 kinase.
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Although the clinical benefit of mTOR inhibitors has largely been discovered empirically, the mTOR pathway may be of particular relevance to RCC because its activation has been shown to increase hypoxia inducible factor 1 (HIF-1) gene expression, both at the levels of mRNA translation and protein stabilization (9, 10). The biallelic alterations in the von Hippel-Lindau (VHL) gene with subsequent accumulation of HIF-1 and HIF-2 observed in most clear cell RCC are believed to be a critical step in RCC tumorigenesis (11, 12). The mRNAs for both HIF-1 and HIF-2 have been shown to contain 5'-terminal oligopyrimidine tracts (13). Translation of mRNA containing 5'-terminal oligopyrimidine sequences is thought to be stabilized by mTOR signaling through S6 kinase and possibly its substrate S6 ribosomal protein. Inhibition of mTOR by temsirolimus has been shown to reduce expression of HIF-1 and HIF-2 under both normoxic and hypoxic conditions in mouse xenograft models (14).
The baseline activity of the mTOR pathway in RCC has not been well established. Although PTEN mutations are rare in RCC, PTEN gene expression has been shown to be down-modulated in a large percentage of RCCs, presumably by epigenetic silencing (15, 16). In particular, lack of PTEN expression has been shown to be an independent negative prognostic factor for disease-specific survival in patients with metastatic RCC (17). In vitro studies have shown that cells deficient in PTEN are particularly sensitive to the cytostatic effects of mTOR inhibition (18). Decreased expression of PTEN has also been shown to be associated with increased phosphorylation of Akt in RCC (19). The role of PTEN and phospho-Akt expression as surrogates for mTOR activity in RCC is actively being explored.
Similar to PTEN, decreased activity of TSC1 and TSC2 has been shown to result in enhanced mTOR activity with subsequent increase in HIF activity and VEGF production (20). Inhibition of mTOR in cell lines possessing biallelic deletion of TSC2 leads to normalization of HIF levels and partial down-regulation of VEGF (21). Although loss of heterozygosity of TSC1 and TSC2 has been observed in 
40% of VHL–/– sporadic RCC, biallelic alterations in either of these genes are felt to be quite rare (22).
In addition to direct effects on tumor cells, inhibition of mTOR is believed to have an antiangiogenic effect likely due to opposition of HIF activity and resultant decrease in proangiogenic cytokines such as VEGF. mTOR may also have a direct role in endothelial cell proliferation under certain conditions (23). Inhibition of mTOR in a murine renal cancer xenograft model has produced tumor shrinkage in association with diminished tumor vascularization. Hence, mTOR inhibition may be effective in patients with renal cancer either directly by inhibiting the downstream effects of activation of the phosphatidylinositol 3-kinase-Akt-mTOR pathway within the tumor cell or indirectly by blocking the proangiogenic effect of HIF on the endothelial cells.
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Clinical Experience with mTOR Inhibitors in RCC
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Temsirolimus has shown antitumor activity and encouraging progression-free and overall survival in patients with renal cancer. In a phase 2 trial in patients with advanced RCC, patients were randomized to three different doses of temsirolimus at 250, 75, or 25 mg given i.v. once weekly (24). There were 111 patients enrolled and 110 patients received therapy: 36 at 25 mg/m2, 38 at 75 mg/m2, and 36 at 250 mg/m2. Most patients (91%) had received at least one prior therapy and 51% had two or more prior therapies. Overall, 85% had received prior IL-2 and 45% had received prior IFN. Patients also had extensive metastatic disease, with 83% of patients having more than two sites of metastasis. Sixty-five percent of patients were Eastern Cooperative Oncology Group performance status 1 and 35% were Eastern Cooperative Oncology Group performance status 0. Tumor assessments were made at baseline and 8-week intervals. Response was defined using standard bidimensional measurements in accordance with WHO criteria for complete response, partial response, and stable disease. In addition, minor response was defined as a 
25% but <50% decrease in the sum of the two greatest perpendicular dimensions of all measurable lesions.
The clinical response data are outlined in Table 1
. Although the objective response rate was only 7%, 26% of patients experienced minor responses and another 17% of patients had stable disease that lasted 6 months. The median time to tumor progression and median survival for the study patients as a whole were 5.8 and 15.0 months, respectively. The most frequently occurring adverse events of all grades were maculopapular rash (76%), mucositis (70%), asthenia (50%), and nausea (43%). The most frequently occurring grade 3 or 4 adverse events were hyperglycemia (17%), hypophosphatemia (13%), anemia (9%), and hypertriglyceridemia (6%). Neither toxicity nor efficacy was significantly influenced by temsirolimus dose level. In addition, six patients (five at the 75-mg dose level) developed a nonspecific pneumonitis during therapy. Treatment was held and four patients were able to resume therapy, with two developing recurrent pneumonitis.
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Table 1. Clinical response for patients enrolled in randomized phase 2 trial of temsirolimus at three different doses
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Patients in intermediate or poor-risk groups based on the clinical criteria used by Memorial Sloan-Kettering Cancer Institute (MSKCI) for a first-line metastatic renal cancer population were believed to particularly benefit from temsirolimus therapy with a 1.6- to 1.7-fold longer median survival than the historic control of patients treated with IFN first-line (25). Because there was no difference in clinical response between dose levels, a temsirolimus dose of 25 mg i.v. weekly was selected for exploration in future single-agent trials.
Based on promising preclinical data suggesting synergy, a subsequent phase 1/2 study was conducted combining temsirolimus with IFN- (26). The maximum tolerated dose was determined to be 15 mg of temsirolimus administered i.v. weekly with 6 million units of IFN administered s.c. thrice weekly. Clinical activity was seen in 41% of all patients, including 29% of patients treated at the maximum tolerated dose. Median time to progression for all patients was 9.1 months, and 28% of patients continued receiving treatment for more than 12 months.
Following this phase 1/2 trial, a randomized three-arm phase 3 trial comparing temsirolimus versus IFN alone versus the combination of temsirolimus and IFN was done and preliminary analysis was recently reported (27). Overall, 626 previously untreated patients with metastatic RCC and poor risk features (3 of 6 risk factors; 5 MSKCI risk factors + >1 metastatic site) were enrolled and randomized in a 1:1:1 fashion to receive either IFN up to 18 million units s.c. thrice a week; temsirolimus, 25 mg i.v. weekly; or the combination of temsirolimus, 15 mg i.v. weekly, and IFN, 6 million units s.c. thrice a week (Fig. 2
). The primary end point of the trial was overall survival, and at time of analysis 442 deaths had occurred. The overall survival of patients treated with temsirolimus alone was statistically longer than those treated with IFN alone (7.3 versus 10.9 months; hazard ratio, 0.73; P = 0.0069). There was no statistical difference between patients treated with IFN alone and the combination of IFN and temsirolimus. Temsirolimus is the first molecularly targeted agent to show a statistically significant survival benefit in first-line therapy of patients with metastatic RCC.
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Fig. 2. Randomization for a three-arm phase 3 study of temsirolimus (CCI-779) or IFN- or the combination of temsirolimus + IFN in the treatment of first-line, poor-risk patients with advanced renal cell carcinoma.
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In addition to temsirolimus, other inhibitors of mTOR are at various stages of development. Preliminary results from a phase 2 trial of everolimus, an oral derivative of rapamycin, in patients with metastatic RCC were recently reported (28). Primary end points included time to progression, response rate, toxicity, and changes in metabolic imaging using computed tomography-positron emission tomography. Everolimus was given at a daily dose of 10 mg orally without interruption. At the time of presentation, 28 patients had been enrolled and treated. Twenty patients had received prior therapy, the majority with cytokine-based regimens, and 82% of patients had an Eastern Cooperative Oncology Group performance status of 0. The objective response rate was 28% and the median time to progression had not yet been reached but was already >6 months. Treatment-related adverse events to date included mucositis, rash, pneumonitis, hypophosphatemia, hyperglycemia, thrombocytopenia, anemia, and elevated liver function test results. Everolimus is currently entering more advanced stage testing in patients with RCC both as a single agent and in combination with other targeted agents. In addition, studies in patients who are refractory to VEGF receptor–targeted tyrosine kinase inhibitors are being contemplated.
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Patient Selection Opportunities in RCC
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Efforts have proceeded to identify potential molecular predictive biomarkers for response or clinical benefit to temsirolimus in the hopes of further defining the appropriate treatment population. Similar studies in patients treated with immunotherapy have identified certain histologic features and carbonic anhydrase IX expression as promising predictive biomarkers for IL-2 therapy (29). Efforts to identify predictive biomarkers for response to temsirolimus have been directed by observations from preclinical and in vitro experiments. As discussed earlier, preclinical studies have suggested that cells deficient in PTEN and with high levels of Akt activation were more sensitive to the effects of temsirolimus in vitro (18). Additionally, a recent study shows that loss of VHL may sensitize RCC cells to temsirolimus in both in vitro and mouse xenograft models, presumably mediated by the dependence of the translation of HIF-1 and HIF-2 on mTOR (14).
These potential predictive biomarkers must now be explored both retrospectively and prospectively in human tumor tissue samples. Preliminary efforts from a cohort of patients treated on the randomized phase 2 trial of temsirolimus suggest that, in contrast to patients treated with IL-2 therapy, carbonic anhydrase IX expression or pathology risk group does not correlate with response to temsirolimus (30). However, similar to IL-2, patients with very low carbonic anhydrase IX expression do not seem to respond to temsirolimus, and median survival is longer in patients with high carbonic anhydrase IX–expressing tumors. More recent analyses suggest that patients whose tumors express low levels of the upstream modulator of mTOR activity, phospho-Akt, or the downstream target of mTOR activation, phospho-S6, are unlikely to respond to temsirolimus (31). High phospho-S6 expression frequency or intensity, in particular, seemed to be associated with clinical benefit, freedom from disease progression, and prolonged survival in patents treated with temsirolimus. Although these results require independent validation, they suggest that phospho-S6 expression might help select patients who could benefit from mTOR inhibitor therapy. Additional studies to explore the relationship between temsirolimus response and tumor expression of PTEN and VHL mutational status are currently under way and could yield additional predictive biomarkers for mTOR therapy.
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Rationale for Future Trials
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There will likely be great enthusiasm for the development combination regimens including mTOR inhibitors. Combinations must be selected both rationally and carefully, however, as the combination of temsirolimus with IFN in the phase 3 trial did not result in the clinical benefit observed for temsirolimus alone. It is possible that this may be due to the toxicity profiles of the combined agents requiring a lower and possibly suboptimal dose of temsirolimus (15 versus 25 mg i.v. weekly). In the case of RCC, there is strong rationale for the use of mTOR inhibitors either in combination or given sequentially with tyrosine kinase inhibitors targeting VEGF receptor-2 such as sorafenib or sunitinib. Both classes of agents have now established single-agent efficacy in RCC therapy. The observed toxicities of mTOR inhibitors and VEGF-directed therapies seem to be nonoverlapping, potentially allowing for full doses of each to be given in combination. Both classes of agents target the HIF-VEGF pathway, mTOR inhibitors by attenuating expression of the HIFs and sorafenib or sunitinib by inhibiting VEGF receptor-2 signaling, resulting in a serial block of HIF signaling. Preliminary results from the phase 1 trial of sorafenib and bevacizumab in advanced RCC suggest that similar serial inhibition of the VEGF pathway may have additive effects (32). Combinations of mTOR inhibitors with VEGF-directed therapies would also allow for the parallel inhibition of two distinct pathways (phosphatidylinositol 3-kinase-Akt-mTOR and HIF-VEGF) believed to be critical to RCC progression. Inhibitors of mTOR may also be useful in patients who have progressed on single-agent, VEGF-directed therapies for similar reasons, particularly because they may attenuate HIF activity that may be enhanced by the relative hypoxia induced by antiangiogenic agents such as sorafenib or sunitinib.
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Conclusions
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Similar to agents directed against VEGF, temsirolimus has shown promising activity in cytokine-refractory RCC and may have particular benefit in patients with poor prognosis based on traditional models. Whereas temsirolimus has successfully shown a survival benefit in the first-line setting, survival data remain pending from large randomized trials of both sorafenib and sunitinib, and head-to-head comparisons of these agents with temsirolimus are unlikely to be forthcoming soon. Thus, the role of mTOR inhibitors with respect to therapies that inhibit the VEGF pathway in any subgroup of patients with RCC remains to be established. Efforts must continue toward identification of factors that allow further selection of patients likely to derive significant clinical benefit from mTOR inhibitors. Preclinical and early retrospective analysis has identified VHL gene expression status and pathologic surrogates of mTOR pathway activation as promising predictive biomarkers. These factors must now undergo more robust retrospective analysis and, if promising, be validated prospectively in future clinical trials. These efforts will be critical as mTOR inhibitors move into more widespread use, likely given sequentially and in combination with other targeted agents (Table 2
), so as to allow the direction of this promising therapy to the most appropriate patients.
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Open Discussion
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Dr. Sosman: If the phase 3 study demonstrates a benefit, would you aim subsequent combinations at the patients with poor prognostic characteristics? What would you do with their subset-directed information?
Dr. Atkins: If the phase 3 trial is positive, this should become the standard of therapy for high-risk patients. The harder decision is when to use that agent in other subclinical subsets. Clearly, this is a good agent to combine with some of the VEGF pathway inhibitors as temsirolimus is hitting a slightly different pathway and therefore may not produce as much VEGF starvation in normal tissue that is produced with combinations of VEGF receptor inhibitors and bevacizumab. It also has a larger margin of safety because temsirolimus is still tolerable when administered at 10 times the effective dose.
Dr. Figlin: Intermittent mTOR blockade may not be the optimal way of achieving mTOR inhibition. As shown in animal trials, long-term blockade with lower doses over a longer period may be a better way of inhibiting that target.
Dr. Flaherty: Are you able to avoid immunosuppression if you take the dose low enough?
Dr. Figlin: Yes, it appears that the dose necessary to block mTOR is much lower than the dose necessary to immunosuppress. So, you may be able to give it more long term without worrying about the immunosuppressive effects of the drug.
Dr. Rini: Do you know what that tumor shrinkage rate was in your study?
Dr. Atkins: The 50% stable disease group represents mostly people who had some degree of tumor shrinkage.
Dr. Rini: What was the rate for the combination with IFN?
Dr. Atkins: I don't know for sure. My guess is that temsirolimus is probably not the agent to combine with immunotherapy because it is clearly immunosuppressive. If the immunotherapeutic effect of IFN is critical to its efficacy in patients with RCC, it would probably not do much when given with temsirolimus. If it is working as an antiangiogenic or antiproliferative agent, it might be fine.
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Footnotes
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Presented at the Second Cambridge Conference on Innovations and Challenges in Renal Cancer, March 24–25, 2006, Cambridge, Massachusetts.
Received 8/ 9/06;
revised 10/12/06;
accepted 10/13/06.
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Abstract
Relevance of the mTOR...
