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Keywords:

  • mTOR;
  • renal cell carcinoma;
  • PI3K;
  • Akt;
  • targeted therapy

Abstract

  1. Top of page
  2. Abstract
  3. mTOR
  4. mTOR Activation and Signaling
  5. The PI3K/Akt/mTOR Pathway in RCC
  6. Clinical Trials of mTOR Inhibitors in Metastatic RCC
  7. Temsirolimus
  8. Phase 3 Trial of Temsirolimus, Interferon, or Temsirolimus Plus Interferon in RCC
  9. Everolimus
  10. Combination Studies
  11. Potential Resistance Mechanisms and Countermeasures
  12. Summary and Future Considerations
  13. OPEN DISCUSSION
  14. Conflict of Interest Disclosures
  15. References

The mammalian target of rapamycin (mTOR) is clearly an important therapeutic target for advanced renal cell carcinoma (RCC), although its mechanisms of activation are not completely understood. In first-line treatment of patients who have both advanced RCC and multiple risk factors for short survival, temsirolimus improves overall survival (OS) compared with interferon. In patients whose tumors have progressed after sunitinib and/or sorafenib therapy, everolimus improves progression-free survival compared with placebo. Beyond the initial phase 3 studies demonstrating efficacy, many important questions remain in the clinical application of mTOR inhibition and in developing other inhibitors of PI3K/Akt/mTOR signaling. Important objectives of current and future clinical investigations include a more detailed description of the molecular pathology of RCC and identification of potential biomarkers that are predictive of tumor sensitivity to PI3K/Akt/mTOR targeted therapies. This information may identify other groups of RCC patients that are likely to benefit from inhibition of this signaling pathway. Additional questions concern mechanisms by which tumors become resistant to mTOR inhibitor therapy and how such resistance can be defeated. Possible mechanisms include the loss of feedback inhibition of insulin receptor substate/PI3K signaling resulting from the inhibition of mTOR complex 1 by rapamycin analogs and the activating phosphorylation of Akt by mTOR complex 2. Laboratory studies indicate that these resistance mechanisms could be countered by using other targeted agents in combination with mTOR inhibitors. Cancer 2009;115(10 suppl):2313-20. © 2009 American Cancer Society.

Signaling through phosphatidylinositol 3-kinase (PI3K), Akt, and the mammalian target of rapamycin (mTOR) regulates cell growth, metabolism, proliferation, and motility. Genetic alterations of components in this pathway, including mutation of PI3K and the tumor suppressor protein phosphatase and tensin homolog (PTEN), promote tumorigenesis and are common in human cancers.1, 2 The PI3K/Akt/mTOR pathway plays important roles in the response of cells to hypoxia and energy depletion, and the activation of this pathway in malignancy has been linked to the resistance of tumor cells to radiotherapy and chemotherapy. Consequently, much effort has been devoted to the development agents that inhibit PI3K/Akt/mTOR signaling. The relevance of PI3K/Akt/mTOR signaling in renal cell carcinoma (RCC) is highlighted by the recent success in using inhibitors of the downstream component, mTOR, to treat patients with metastatic disease. These encouraging results indicate that further success may be achieved with new inhibitors of PI3K, Akt, and mTOR, now in development.

mTOR

  1. Top of page
  2. Abstract
  3. mTOR
  4. mTOR Activation and Signaling
  5. The PI3K/Akt/mTOR Pathway in RCC
  6. Clinical Trials of mTOR Inhibitors in Metastatic RCC
  7. Temsirolimus
  8. Phase 3 Trial of Temsirolimus, Interferon, or Temsirolimus Plus Interferon in RCC
  9. Everolimus
  10. Combination Studies
  11. Potential Resistance Mechanisms and Countermeasures
  12. Summary and Future Considerations
  13. OPEN DISCUSSION
  14. Conflict of Interest Disclosures
  15. References

mTOR is a member of a group of structurally similar protein kinases that includes the ataxia telangiectasia mutated (ATM), ATM and rad3, and DNA protein kinases.3 Members of this family share a domain structure that includes FAT (FRAP, ATM, TRAP), FATC (FAT c-terminal), and HEAT (Huntington, EF3, alpha-subunit of protein phosphatase 2A, TOR1) sequences, the latter of which mediates protein-protein interaction. This structure underlies the interactions of mTOR with other proteins and its key role as a regulator of cellular homeostasis.4 A rapamycin binding domain is centrally located, whereas the kinase domain is located near the carboxyl terminus. Inhibition of mTOR kinase by rapamycin first requires that the drug associate with FKBP12, an abundant intracellular protein.5 This requirement also holds for temsirolimus and likely other rapamycin analogs.6 The drug-FKBP12 complex binds mTOR at the rapamycin binding domain to inhibit kinase function by an allosteric mechanism. This mechanism confers remarkable selectivity: There are no other known molecular targets of rapamycin and its analogs.

mTOR Activation and Signaling

  1. Top of page
  2. Abstract
  3. mTOR
  4. mTOR Activation and Signaling
  5. The PI3K/Akt/mTOR Pathway in RCC
  6. Clinical Trials of mTOR Inhibitors in Metastatic RCC
  7. Temsirolimus
  8. Phase 3 Trial of Temsirolimus, Interferon, or Temsirolimus Plus Interferon in RCC
  9. Everolimus
  10. Combination Studies
  11. Potential Resistance Mechanisms and Countermeasures
  12. Summary and Future Considerations
  13. OPEN DISCUSSION
  14. Conflict of Interest Disclosures
  15. References

mTOR integrates a variety of signals that reflect cellular growth stimuli, nutrient availability, energy status, and stress. Biochemical studies placed mTOR in the growth-factor–activated PI3K, Akt (protein kinase B) signaling pathway, downstream from Akt.7 mTOR kinase is also activated by genetic alterations that reduce the function of the PTEN tumor suppressor protein8 or increase the function of the catalytic (p110) subunit of PI3K,9 both of which cause abnormal activation of Akt. A parallel pathway through which mTOR is activated involves the cAMP-dependent protein kinase (AMP kinase), and the tuberous sclerosis complex 1 and 2 proteins. This pathway suppresses mTOR kinase in states of nutrient and energy depletion.

mTOR functions in 2 multiprotein complexes, TOR complex 1 (TORC1) and TOR complex 2 (TORC2).10 TORC2 is implicated in the control of cell morphology and adhesion through the regulation of protein kinase Cα. TORC2 has also been shown to phosphorylate and activate Akt.11 Through phosphorylation of 2 downstream effectors, p70S6kinase (S6K) and the binding protein for eukaryotic initiation factor 4E (4E-BP1), TORC1 controls the translation of cyclin D, c-Myc, and other key proteins involved in cell proliferation.12 TORC1 also regulates the expression and stability of hypoxia inducible factor (HIF) 1α.13, 14 These mTOR functions are relevant to RCC, which is characterized by alterations of the von Hippel-Lindau (VHL) gene, leading to the up-regulation of HIF-α subunits, vascular endothelial growth factor (VEGF), and other molecules that increase angiogenesis.15 Loss of VHL function in RCC also results in deregulation of cyclin D1, a cyclin-dependent kinase cofactor required for cell cycle progression.16, 17 Thus, mechanisms underlying the antitumor activity of temsirolimus in RCC probably include inhibition of both angiogenesis and tumor cell proliferation. Importantly, mTOR kinase associated with TORC2 is relatively resistant to inhibition by rapamycin in vitro, suggesting that temsirolimus and other rapamycin analogs may effectively inhibit the activities of TORC1, but not TORC2, a potential mechanism of resistance.18

The PI3K/Akt/mTOR Pathway in RCC

  1. Top of page
  2. Abstract
  3. mTOR
  4. mTOR Activation and Signaling
  5. The PI3K/Akt/mTOR Pathway in RCC
  6. Clinical Trials of mTOR Inhibitors in Metastatic RCC
  7. Temsirolimus
  8. Phase 3 Trial of Temsirolimus, Interferon, or Temsirolimus Plus Interferon in RCC
  9. Everolimus
  10. Combination Studies
  11. Potential Resistance Mechanisms and Countermeasures
  12. Summary and Future Considerations
  13. OPEN DISCUSSION
  14. Conflict of Interest Disclosures
  15. References

Robb and colleagues19 found evidence of mTOR activation as determined immunohistochemically by increased phospho–mTOR-S6 protein relative to normal renal tissue in approximately 60% of 25 primary clear cell RCC. By using similar methods, Pantuck and colleagues20 found that activation of the mTOR pathway affects prognosis for patients with localized and metastatic kidney cancer. In their tissue microarray-based immunohistochemical study, mTOR pathway activation occurred most significantly in clear cell carcinomas, high-grade tumors, and tumors with poor prognostic features. Laboratory investigations indicate that PI3K/Akt activation could be an important predictor of sensitivity to mTOR inhibitor therapy in the clinic,8 and the preliminary report of a small study that correlated phospho–Akt-S6 protein with tumor response supports this possibility.21 The frequency of mTOR pathway activation in RCC metastases and how this correlates with activation in the primary tumor have not yet been reported.

Clinical Trials of mTOR Inhibitors in Metastatic RCC

  1. Top of page
  2. Abstract
  3. mTOR
  4. mTOR Activation and Signaling
  5. The PI3K/Akt/mTOR Pathway in RCC
  6. Clinical Trials of mTOR Inhibitors in Metastatic RCC
  7. Temsirolimus
  8. Phase 3 Trial of Temsirolimus, Interferon, or Temsirolimus Plus Interferon in RCC
  9. Everolimus
  10. Combination Studies
  11. Potential Resistance Mechanisms and Countermeasures
  12. Summary and Future Considerations
  13. OPEN DISCUSSION
  14. Conflict of Interest Disclosures
  15. References

Rapamycin and 3 analogs of rapamycin (rapalogs) have undergone clinical evaluation as cancer therapeutics. The 3 rapamycin derivatives differ from the parent structure at the C43 position, which is modified to increase solubility and bioavailability by the addition of an ester, ether, or phosphonate group for temsirolimus, everolimus (RAD001), and deferolimus (AP23573), respectively (Fig. 1). Temsirolimus, the first mTOR inhibitor in cancer clinical trials, was approved in 2007 for patients with advanced or metastatic RCC. Everolimus (RAD001) was evaluated in patients with metastatic RCC whose disease has progressed after treatment with sunitinib or sorafenib. Deferolimus has not been evaluated in RCC.

thumbnail image

Figure 1. Structures of rapamycin and analogs are shown.

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Rapamycin and the rapalogs have similar pharmacologic properties. Total clearances increase with dose, whereas exposures (area under the plasma concentration vs time curve) increase less than proportionally with dose.22-26 The terminal plasma half-lives are relatively long, ranging from 24 hours to 48 hours. For temsirolimus, the ester moiety is hydrolyzed to yield sirolimus, which has a longer terminal half-life (mean of 12 hours to 15 hours for temsirolimus and 40 hours to 50 hours for sirolimus). Because temsirolimus and sirolimus bind to FKBP12 and exert similar antiproliferative effects in vitro,6 both moieties likely inhibit mTOR after administration of temsirolimus. Little or no metabolism to sirolimus is found after administration of everolimus and deferolimus.

The adverse event (AE) profile of the mTOR inhibitors includes hyperglycemia and hyperlipidemia, which reflects the blockade of the main signaling conduit for insulin and IGF. Other common AEs for the class are fatigue, stomatitis, diarrhea, anemia, thrombocytopenia, rash, and peripheral edema. Less common effects include renal insufficiency, interstitial pneumonitis, and neutropenia.22-27

Temsirolimus

  1. Top of page
  2. Abstract
  3. mTOR
  4. mTOR Activation and Signaling
  5. The PI3K/Akt/mTOR Pathway in RCC
  6. Clinical Trials of mTOR Inhibitors in Metastatic RCC
  7. Temsirolimus
  8. Phase 3 Trial of Temsirolimus, Interferon, or Temsirolimus Plus Interferon in RCC
  9. Everolimus
  10. Combination Studies
  11. Potential Resistance Mechanisms and Countermeasures
  12. Summary and Future Considerations
  13. OPEN DISCUSSION
  14. Conflict of Interest Disclosures
  15. References

Antitumor effects of temsirolimus in patients with RCC and other tumors were observed during phase 1 evaluation. Two unconfirmed partial responses (PRs) were observed in 16 patients with RCC enrolled on the 5-day, every 2-week phase 1 trial of temsirolimus,22 and 1 confirmed PR was seen in the weekly schedule phase 1 study.23 A formal maximal tolerated dose was not defined for either of these schedules in minimally pretreated patients, but AEs were more common at higher doses in each study. The question of optimal dose was further evaluated in a randomized phase 2 study of weekly temsirolimus in patients with cytokine-refractory metastatic RCC.26 A total of 111 patients were treated with temsirolimus at a weekly dose of 25, 75, or 250 mg. The study participants had received a median of 2 prior therapies for metastatic disease, and 91% of them had received prior interleukin-2 or interferon. The median time to progression was 5.8 months, and the median overall survival (OS) was 15 months. The objective response rate was only 7%, but 51% of patients had clinical benefit, defined as either objective response or stable disease for at least 6 months. The lowest dose of temsirolimus (25 mg) seemed to be as effective as the higher dose, was better tolerated over multiple cycles, and was selected for subsequent studies. Notably, patients with 3 or more predictors of short survival according to the Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic factor model28 had a median OS of 8.2 months, significantly shorter than the median OS (approximately 23 months) of patients with fewer risk factors but longer than would be expected for patients with multiple adverse prognostic factors treated with interferon in the first-line setting.29 With these considerations, a larger randomized trial was conducted to determine whether mTOR inhibition with temsirolimus could improve the OS of patients with poor prognosis RCC.

Phase 3 Trial of Temsirolimus, Interferon, or Temsirolimus Plus Interferon in RCC

  1. Top of page
  2. Abstract
  3. mTOR
  4. mTOR Activation and Signaling
  5. The PI3K/Akt/mTOR Pathway in RCC
  6. Clinical Trials of mTOR Inhibitors in Metastatic RCC
  7. Temsirolimus
  8. Phase 3 Trial of Temsirolimus, Interferon, or Temsirolimus Plus Interferon in RCC
  9. Everolimus
  10. Combination Studies
  11. Potential Resistance Mechanisms and Countermeasures
  12. Summary and Future Considerations
  13. OPEN DISCUSSION
  14. Conflict of Interest Disclosures
  15. References

The Global Advanced Renal Cell Carcinoma trial was designed to determine whether temsirolimus, as a single agent or in combination with interferon alfa, improved the OS of patients with advanced, poor prognosis RCC.30 Several aspects of the Global Advanced Renal Cell Carcinoma trial design distinguish it from other contemporary phase 3 trials in RCC. First, the primary study endpoint was OS, targeting a 40% improvement in median OS for each of 2 comparisons, temsirolimus versus interferon and the combination of temsirolimus and interferon versus interferon. Second, the study enrolled patients with all RCC histologic types and did not exclude those with predominantly non–clear-cell tumors. Third, patients were not required to undergo cytoreductive or adjuvant nephrectomy before enrollment. Finally, the study enrolled a predominantly poor prognosis population, defined by requiring patients to have at least 3 of 6 factors known to be associated with short survival. This prognostic model used the 5 factors comprising the MSKCC model28 and added a sixth factor (multiple organ sites of metastases) as initially described by Mekhail and colleagues.31

A total of 626 patients were randomized to 1 of 3 treatment groups: temsirolimus, 25 mg intravenously (IV) each week; interferon alfa, 3 million units (MU) subcutaneously (SC) 3 times weekly (escalating to 18 MU SC 3 times weekly or maximum tolerated dose); or a combination of temsirolimus, 15 mg IV weekly, and interferon alfa, 6 MU SC 3 times weekly. The schedule and doses of temsirolimus and interferon alfa for the combination treatment were established in a preceding phase 1-2 study.32

Most patients (80%) had clear cell histologic disease, and 67% of them had undergone nephrectomy to remove the primary tumor. Patients with a Karnofsky performance score of 70 or lower comprised 82% of the population. By the MSKCC prognostic model,28 74% of patients were in the poor prognosis category.

Compared with interferon and combination therapy, fewer patients receiving single-agent temsirolimus had grade 3 or 4 AEs. Asthenia was more frequent in the groups receiving interferon, whereas rash, peripheral edema, and stomatitis affected more patients who received temsirolimus, whether alone or in the combination treatment. Myelosuppression was more common in patients treated with the combination of temsirolimus and interferon alfa. Compared with interferon monotherapy, temsirolimus was associated with a higher incidence of hyperlipidemia, hyperglycemia, and hypercholesterolemia.

The OS was greater for patients who received temsirolimus compared with those receiving interferon (hazard ratio for death, .73; 95% confidence interval [CI], .58-.92; P = .008). Progression-free survival was also greater for patients receiving temsirolimus (P<.001). By contrast, OS for the group receiving combination therapy was not significantly different from that of the group treated with interferon, although progression-free survival was significantly longer for the combination group. The median survival times for the groups receiving temsirolimus, interferon, and the combination were 10.9 months, 7.3 months, and 8.4 months, respectively. The objective response rate was not significantly different for the temsirolimus, interferon, and combination groups (8.6%, 4.8%, and 8.1%, respectively). Planned subgroup analysis revealed that the OS advantage for temsirolimus held for patients with clear cell and non–clear-cell carcinomas and for those with and without prior nephrectomy.

Everolimus

  1. Top of page
  2. Abstract
  3. mTOR
  4. mTOR Activation and Signaling
  5. The PI3K/Akt/mTOR Pathway in RCC
  6. Clinical Trials of mTOR Inhibitors in Metastatic RCC
  7. Temsirolimus
  8. Phase 3 Trial of Temsirolimus, Interferon, or Temsirolimus Plus Interferon in RCC
  9. Everolimus
  10. Combination Studies
  11. Potential Resistance Mechanisms and Countermeasures
  12. Summary and Future Considerations
  13. OPEN DISCUSSION
  14. Conflict of Interest Disclosures
  15. References

Everolimus (RAD001) is an orally administered rapamycin analog that has been developed for weekly or daily administration. Continuous daily administration of 10 mg was selected for a phase 2 study in patients with metastatic predominantly clear cell RCC and up to 1 prior therapy. In a preliminary report of this study,33 37 of the 41 patients enrolled were evaluated for response and toxic effects. The AEs related to everolimus treatment were stomatitis, rash, hypophosphatemia, hypertriglyceridemia, hyperglycemia, anemia, thrombocytopenia, and pneumonitis—a toxicity profile similar to that of temsirolimus. Objective PR was observed in 12 patients, and 19 patients had stable disease for 3 or more months. The median duration of therapy exceeded 8 months, and the median OS exceeded 11.5 months. These results led to a randomized clinical trial comparing everolimus, 10 mg daily, with placebo for patients with disease progression after sunitinib or sorafenib therapy. Progression-free survival, the primary study endpoint, was reached at the second interim analysis. Compared with placebo, treatment with everolimus resulted in a significant improvement in progression-free survival (hazard ratio, .30; 95% CI, .22-.40; P < .0001). The median progression-free survivals for the everolimus and placebo groups were 4 months and 1.9 months, respectively.34 The OS analysis, not yet mature, will include patients assigned to the placebo who eventually received everolimus at the time of disease progression.

Combination Studies

  1. Top of page
  2. Abstract
  3. mTOR
  4. mTOR Activation and Signaling
  5. The PI3K/Akt/mTOR Pathway in RCC
  6. Clinical Trials of mTOR Inhibitors in Metastatic RCC
  7. Temsirolimus
  8. Phase 3 Trial of Temsirolimus, Interferon, or Temsirolimus Plus Interferon in RCC
  9. Everolimus
  10. Combination Studies
  11. Potential Resistance Mechanisms and Countermeasures
  12. Summary and Future Considerations
  13. OPEN DISCUSSION
  14. Conflict of Interest Disclosures
  15. References

Ideally, combination therapies should use effective agents with differing mechanisms of action and adverse effect profiles. Accordingly, the possibility of achieving greater efficacy in metastatic RCC with the combination of an mTOR inhibitor and a VEGF or VEGFR inhibitor seems appealing. Preliminary results of a phase 1 study of temsirolimus and bevacizumab have been the most encouraging. Each agent was delivered at the standard single-agent dose for multiple cycles, and 8 PRs were observed in 14 patients.35 By contrast, the combination of temsirolimus with sorafenib, a Raf kinase, and a VEGFR tyrosine kinase inhibitor, required a 50% reduction of the single-agent dose of sorafenib. The recommended doses for phase 2 evaluation were sorafenib, 200 mg twice daily, and temsirolimus, 25 mg IV weekly.36 As noted herein, the combination of temsirolimus and interferon was feasible only at reduced doses of each agent and was not more effective than single-agent interferon in metastatic RCC.30

Temsirolimus combinations will be further evaluated in E2804, the Eastern Cooperative Oncology Group randomized phase 2 study of 3 combinations, including the aforementioned temsirolimus/bevacizumab and temsirolimus/sorafenib doublets and single-agent bevacizumab as first-line treatment for patients with metastatic RCC.

Additional combination trials that have commenced use mTOR inhibitors together with other targeted agents to more effectively inhibit mTOR and/or block signaling in multiple pathways. For example, the crosstalk between the PI3K/Akt/mTOR and Raf/MEK/Erk pathways observed in experimental systems37, 38 provides a rationale for combining inhibitors of both pathways, such as an mTOR inhibitor with a MEK inhibitor, to achieve antitumor effects greater than can be gained from inhibition of a single pathway.39, 40 Another combination strategy draws on the additive effects of histone deacetylase inhibition and mTOR inhibition in reducing HIF-α expression and activity.41, 42 Other combinations, such as an mTOR inhibitor with an IGF receptor antagonist, are based on the possibility of overcoming resistance to mTOR inhibition.

Potential Resistance Mechanisms and Countermeasures

  1. Top of page
  2. Abstract
  3. mTOR
  4. mTOR Activation and Signaling
  5. The PI3K/Akt/mTOR Pathway in RCC
  6. Clinical Trials of mTOR Inhibitors in Metastatic RCC
  7. Temsirolimus
  8. Phase 3 Trial of Temsirolimus, Interferon, or Temsirolimus Plus Interferon in RCC
  9. Everolimus
  10. Combination Studies
  11. Potential Resistance Mechanisms and Countermeasures
  12. Summary and Future Considerations
  13. OPEN DISCUSSION
  14. Conflict of Interest Disclosures
  15. References

As discussed herein, TORC2 signals back to Akt, phosphorylating the protein on Ser 473.11 This positive feedback loop may limit the therapeutic effects of the rapamycin analogs, which mainly inhibit mTOR associated with TORC1. Although earlier in development, catalytic inhibitors of mTOR that inhibit the kinase activity in both TORC1 and TORC2 should inhibit mTOR kinase more completely than the rapalogs, with the possibility of greater antitumor effects.

A second mechanism of resistance involves inhibition of S6K, a downstream consequence of mTOR (TORC1) inhibition. Insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) link insulin and IGF 1 (IGF-1) signaling to PI3K and, subsequently, to activation of Akt and mTOR. S6K phosphorylates IRS-1 and IRS-2, a modification that destabilizes these proteins and uncouples IGF/insulin signaling to PI3K.43 Thus, mTOR/S6K activation exerts negative feedback to restrict insulin and IGF-1 signaling. Loss of this negative feedback mechanism has been shown to occur in cells and tumors exposed to rapamycin,44, 45 everolimus,46 and temsirolimus47 and, in certain contexts, it could limit the antitumor effects of mTOR inhibition with these agents. This specific mechanism of resistance, increased IGFR/PI3K/Akt signaling, may be overcome by simultaneous inhibition of IGF-1R45-47 or with inhibitors of PI3K and Akt.

Finally, evidence for a rapamycin-insensitive, mTOR-independent mechanism of protein translation that requires PI3K signaling, but not mTOR, S6K, or phosphorylation of the S6 ribosomal protein, is another potential barrier to effective therapy with mTOR inhibitors.48 Depending on the expression of the alternate pathway in tumor cells, inhibition of TORC1 and its downstream effectors (S6K, 4E-BP1) may not be sufficient to reduce the translation of HIFs and cell cycle regulators such as cyclin D.

Summary and Future Considerations

  1. Top of page
  2. Abstract
  3. mTOR
  4. mTOR Activation and Signaling
  5. The PI3K/Akt/mTOR Pathway in RCC
  6. Clinical Trials of mTOR Inhibitors in Metastatic RCC
  7. Temsirolimus
  8. Phase 3 Trial of Temsirolimus, Interferon, or Temsirolimus Plus Interferon in RCC
  9. Everolimus
  10. Combination Studies
  11. Potential Resistance Mechanisms and Countermeasures
  12. Summary and Future Considerations
  13. OPEN DISCUSSION
  14. Conflict of Interest Disclosures
  15. References

Inhibitors of PI3K/Akt/mTOR signaling have proven activity in advanced RCC. These agents are generally well tolerated, with fatigue, metabolic abnormalities, stomatitis, diarrhea, and myelosuppression the most common toxic effects.

How to use mTOR inhibitors most effectively in RCC and other tumors is an active area of clinical research. Monotherapy with rapalogs is modestly effective in metastatic RCC, but this is probably not the optimal way to block PI3K/Akt/mTOR signaling to key downstream effectors that promote cell proliferation and survival. Greater success may be possible with newer enzymatic inhibitors of PI3K and mTOR, and with combinations that include an mTOR inhibitor with other signaling inhibitors, or with cytotoxic agents. Many of the studies testing these newer approaches will include correlations of potential tumor biomarkers with treatment outcomes toward the important goal of determining who will benefit the most from inhibition of PI3K/Akt/mTOR signaling.

OPEN DISCUSSION

  1. Top of page
  2. Abstract
  3. mTOR
  4. mTOR Activation and Signaling
  5. The PI3K/Akt/mTOR Pathway in RCC
  6. Clinical Trials of mTOR Inhibitors in Metastatic RCC
  7. Temsirolimus
  8. Phase 3 Trial of Temsirolimus, Interferon, or Temsirolimus Plus Interferon in RCC
  9. Everolimus
  10. Combination Studies
  11. Potential Resistance Mechanisms and Countermeasures
  12. Summary and Future Considerations
  13. OPEN DISCUSSION
  14. Conflict of Interest Disclosures
  15. References

The questions and discussion below follow from the oral presentation given at the Third Cambridge Conference on Innovations and Challenges in Renal Cancer and do not correspond directly to the written article, which is a more general review.

Discussion after Dr. Gary R. Hudes' presentation.

Robert Figlin: We have a set of agents that have the ability to inhibit both HIF and tumor cells, yet the response rates to both temsirolimus and RAD are modest. In designing future trials of agents that target this pathway, whether it is upstream or rapalogs, what are the primary aims of the trials?

Dr. Hudes: The more robust activity is tumor shrinkage, but, clearly, if you can delay tumor progression a long time, that is promising. However, we need to do better than 5-month median progression-free survival. We need to look at progression-free survival as an endpoint with these drugs, but the goal in developing the combinations is to identify tumor shrinkage.

Dr. Figlin: With the PI3 kinase inhibitors that are now about to enter phase 2, what do you think is a go/no go decision based on the response in a cohort of 50 patients?

Dr. Hudes: In a renal cell cancer population?

Dr. Figlin: Yes.

Dr. Hudes: It is going to be tough to use progression-free survival in the current landscape.

Dr. Figlin: What I worry about for these trials is that we will not be able to determine how to use active drugs because they will not be robust enough as single agents.

Dr. Hudes: That is a real challenge of our success.

William Kaelin: I am cautiously optimistic that the second-generation agents will be more active precisely because of this phenomenon with the rapalogs, where you get this paradoxical increase in Akt. Akt is doing some important things in tumor cells with respect to survival, and we also know that Akt is playing a role in angiogenesis not only through HIF, but also through FOXO, and the FOXO seems to be mTOR independent. We may get pleasantly surprised and see more of a signal with combined inhibition of TORC 1 and TORC 2.

Michael Atkins: We now have RAD001 as a standard in patients whose disease has progressed after VEGFR TKI therapy. Do you think that it is the standard and do you think that comparing RAD001 to placebo is a fair test?

Dr. Hudes: If you go by pure evidence-based results, you can get this result probably with other TKIs and temsirolimus. The target and the pharmacology of the mTOR inhibitors are more similar than those of the TKIs. If one works, it is likely that the others will too.

Jeffrey Sosman: If you are confused over which of these drugs to choose, what would be the most important question to ask in a clinical trial?

Dr. Hudes: First, I would like to turn off the counterregulatory pathway involving insulin receptor substrates and see if you could inhibit the feedback mechanism that increases Akt activation. Second, would be to inhibit both TOR complexes.

Conflict of Interest Disclosures

  1. Top of page
  2. Abstract
  3. mTOR
  4. mTOR Activation and Signaling
  5. The PI3K/Akt/mTOR Pathway in RCC
  6. Clinical Trials of mTOR Inhibitors in Metastatic RCC
  7. Temsirolimus
  8. Phase 3 Trial of Temsirolimus, Interferon, or Temsirolimus Plus Interferon in RCC
  9. Everolimus
  10. Combination Studies
  11. Potential Resistance Mechanisms and Countermeasures
  12. Summary and Future Considerations
  13. OPEN DISCUSSION
  14. Conflict of Interest Disclosures
  15. References

The program was made possible by educational grants provided by Genentech, Novartis Pharmaceuticals, Pfizer, Inc., and Wyeth Pharmaceuticals. Program management and CME sponsorship were provided by InforMEDical Communications, Inc., Carlisle, Massachusetts.

Gary H. Hudes has served as a consultant for Genentech, Pfizer, and Wyeth and has received honoraria from Pfizer and Wyeth.

References

  1. Top of page
  2. Abstract
  3. mTOR
  4. mTOR Activation and Signaling
  5. The PI3K/Akt/mTOR Pathway in RCC
  6. Clinical Trials of mTOR Inhibitors in Metastatic RCC
  7. Temsirolimus
  8. Phase 3 Trial of Temsirolimus, Interferon, or Temsirolimus Plus Interferon in RCC
  9. Everolimus
  10. Combination Studies
  11. Potential Resistance Mechanisms and Countermeasures
  12. Summary and Future Considerations
  13. OPEN DISCUSSION
  14. Conflict of Interest Disclosures
  15. References
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