The Potential Role of mTOR Inhibitors in Non-Small Cell Lung Cancer

Abstract

Learning Objectives

After completing the course, the reader will be able to:

1. Describe the PI3K growth pathway.

2. Describe the molecular mechanism of action of mTOR inhibitors.

3. Describe the preliminary clinical results of mTOR inhibitors in NSCLC.

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The mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a downstream mediator in the phosphatidylinositol 3-kinase/Akt signaling pathway, which plays a critical role in regulating basic cellular functions including cellular growth and proliferation. Currently, the mTOR inhibitor rapamycin and its analogues (CCI-779, RAD001, AP23573), which induce cell-cycle arrest in the G₁ phase, are being evaluated in cancer clinical trials. The mTOR inhibitors appear to be well tolerated, with skin reactions, stomatitis, myelosuppression, and metabolic abnormalities the most common toxicities seen. These adverse events are transient and reversible with interruption of dosing. Several pieces of evidence suggest a certain antitumor activity, including tumor regressions and prolonged stable disease, which has been reported among patients with a variety of malignancies, including non-small cell lung cancer (NSCLC). These promising preliminary clinical data have stimulated further research in this setting. Here, we review the basic structure of the pathway together with current results and future developments of mTOR inhibitors in the treatment of NSCLC patients.

Mammalian target of rapamycin, Sirolimus, Temsirolimus, Everolimus, AP23573, NSCLC

Introduction

Major progress in the understanding of cancer biology and the mechanism of oncogenesis has allowed the development of several potential molecular targets for cancer treatment that are components of signaling pathways or metabolic processes contributing to the acquisition of a cancer phenotype. Better tolerability resulting from a better toxicity profile than conventional chemotherapy, better target selectivity, availability for chronic treatment, and, in some cases, oral administration have marked these new targeted compounds as the most promising investigational drugs. Several targeted agents have been introduced in clinical trials in cancer treatment, and several phase III studies have already produced definitive results. Among the possible targets for cancer therapy, the mammalian target of rapamycin (mTOR) is one of the most promising, and rapamycin (sirolimus), an antifungal agent, is its naturally occurring inhibitor [1]. Abnormal activation of signaling pathways of mTOR appears to occur frequently in human cancer [2]. This observation led to the evaluation of the antiproliferative effects of rapamycin and its most recently discovered derivates, cell cycle inhibitor (CCI)-779 (temsirolimus), RAD001 (everolimus), and AP23573, in malignant neoplasms [3].

Lung cancer remains the leading cause of malignancy-related mortality worldwide, in both men and women, with over one million cases diagnosed yearly [4]. Non-small cell lung cancer (NSCLC), including squamous carcinoma, adenocarcinoma and large cell carcinoma, accounts for >80% of all lung cancers. Only a minority of NSCLC patients are suitable for radical treatment as curative care. Because most patients have advanced disease at diagnosis, chemotherapy is the mainstay of management. Conventional treatment of NSCLC has apparently reached a plateau of effectiveness in improving the survival of NSCLC patients, and treatment outcomes must still be considered disappointing [5]. Therefore, new treatment approaches are needed.

This review is focused on the potential role of mTOR inhibitors in the management of patients affected by NSCLC, giving a perspective on the future of these agents in this setting.

The mTOR Growth Pathway

mTOR was first identified in the 1990s as the kinase targeted by rapamycin linked to the cellular protein FKPB12 (FK506-binding protein). It was also named FKBP-RAP associated protein (FRAP), RAP FKBP12 target (RAFT1), and RAP target (RAPT1). It is a well-preserved, 289-kDa protein serine/threonine kinase with 95% of its amino acid identity conserved from yeast to human and mouse [6]. The mTOR belongs to a family of kinases with a C terminus domain similar to the catalytic region of the phosphatidylinositol 3-kinase (PI3K), which are known as PI3K-related kinases and which include mTOR, the ataxia-telangiectasia mutated gene, the ataxia-telangiectasia related protein, and the DNA-dependent protein kinase [2]. All these kinases are involved in checkpoint regulation of the cell cycle, DNA repair, telomere length, and cell death [1]. Following the activation of membrane receptors by a variety of growth factors, the PI3K pathway is activated. This activation is mediated by activated Ras or directly by some tyrosine kinase receptors, under the control of several growth factors and cytokines. Downstream to PI3K, protein kinase B, also named Akt, impacts cell survival at multiple levels. mTOR is also included among the substrates of Akt [7]. The PI3K family is responsible for the production of 3-phosphoinositide lipid second messengers, including phosphatidylinositol 3,4,5-trisphosphate (PIP3), which are involved in cell proliferation and survival, cytoskeletal reorganization, membrane trafficking, cell adhesion and motility, angiogenesis, and insulin action [8, 9]. Kinase activities are regulated by phosphatases that act in opposition to kinases by removing phosphatases from the target proteins. The phosphatase and tensin homologue gene (PTEN) is a tumor suppressor gene, located on human chromosome 10q23 [10]. PTEN is involved in the regulation of the PI3K pathway. There is evidence that PTEN dephosphorylates PIP3 while mutated PTEN cannot [11]. Therefore, PTEN negatively regulates the PI3K/Akt/mTOR pathway, and cancer cells in which the PTEN gene is deleted or its expression is downregulated display constitutively activated PI3K signaling, which contributes to lung carcinogenesis [12, 13]. So, mTOR activity can be related to the loss of the tumor suppressor gene PTEN and the activation of Akt. Recently, the tumor suppressors tuberous sclerosis complex 1 (TSC1, hamartin) and TSC2 (tuberin) have been considered as modulators between PI3K/Akt and mTOR [14]. TSC1 and TSC2 associate to form a heterodimer that inhibits cell-cycle progression and cell proliferation, in part, mediated through mTOR inhibition. It seems that Akt activates mTOR through direct phosphorylation and inhibition of TSC2 [15, 16].

The integrity, transcript and protein levels, phosphorylation, and activity of all the many components of the PI3K pathway are key mechanisms of signals that coordinate the activity of the cell cycle and potential targets for molecular therapeutics in different types of cancer. In fact, the deregulated PI3K/Akt/mTOR pathway was reported to contribute to lung cancer development and maintenance [17]. In particular, several preclinical data support the primary role of the PI3K pathway in proliferation, survival, disease progression, and resistance to chemo- and radiotherapy in NSCLC cell lines [18]. Frequent Akt activation and mTOR phosphorylation were found in 51% of NSCLC patient samples and in 74% of NSCLC cell lines [19].

The activity of mTOR is regulated by nutrients, especially amino acids, and growth factors. In fact, mTOR primarily appears to be a nutrient-sensing protein that is constitutively activated in the presence of growth factors and nutrients, acting as a master switch of cellular catabolism and anabolism [14]. mTOR modulates translation of specific mRNA through the phosphorylation state of translation proteins such as p70^s6k, 4E-binding protein 1 (4E-BP1), and eukaryotic elongation factor 2. The inhibition of mTOR by both starvation and targeted agents causes early G₁ cell-cycle arrest mediated by an inactivation of p70^s6k and hypophosphorylation of 4E-BP1 (the main downstream effectors of mTOR) [20–22].

However, mTOR participates in a multitude of cellular signaling processes, more than those reported here, both in normal and malignant cells, rendering it a key target to be blocked by pharmacological inhibition as a strategy for the development of anticancer therapeutics.

Inhibitors of the mTOR Growth Pathway: Rapamycin and Its Analogues

The mTOR pathway plays an important role in cell proliferation by coupling cell growth with G₁ to S progression. Compounds targeting the mTOR pathway have the potential for application in cancer treatment modalities. Such compounds include rapamycin and its derivatives CCI-779, RAD001, and AP23573.

Rapamycin (Sirolimus)

Rapamycin is a natural antibiotic, a macrocyclic lactone, produced by Streptomyces hygroscopicus, a soil bacterium native to Easter Island (Rapa Nui). Rapamycin, developed initially as an antifungal drug, also possesses immunosuppressive and antiproliferative properties [23]. Because of its ability to suppress lymphocyte activation, rapamycin was developed and received regulatory approval as an immunosuppressant for the prophylaxis of renal allograft rejection. The immunosuppressant effects of rapamycin are a result of inhibition of biochemical events required for the progression of interleukin-2–stimulated T cells from the G₁ to S phase of the cell cycle. In fact, rapamycin, via its methoxy group, crosslinks with the immunophilin FKPB12, resulting in a complex that specifically interacts with mTOR to inhibit mTOR signaling to downstream targets [24]. The actual mechanism by which rapamycin inhibits mTOR is unclear. The rapamycin–FKPB12 complex may act by altering the composition and/or conformation of the multiprotein mTOR complexes. Rapamycin, disrupting these protein complexes, may impair either upstream signaling, leading to mTOR activation, or kinase access to downstream substrates [25, 26]. Recently, rapamycin received approval as a component of cardiac arterial stents because of its potent antiproliferative effects on fibroblasts responsible for restenosis following such procedures [27].

The antiproliferative effects of rapamycin have been evaluated in numerous in vitro and in vivo tumor models but are not completely understood. The reduction in cyclins, particularly cyclin D, which would lead to inhibition of cyclin-dependent kinase activity and phosphorylation of retinoblastoma protein, and the increases in the cyclin-dependent kinase inhibitors p21^cip1 and p27^kip1 are consistent with the ability of rapamycin to block G₁ progression [28–31]. However, rapamycin could induce apoptosis, depending on the functions of p53, p21^cip1, and p27^kip1 [32, 33].

Inhibition of mTOR by rapamycin also potently inhibits angiogenesis and endothelial cell proliferation in vitro and in vivo. The angiogenic properties of rapamycin are associated with inhibition of endothelial cell proliferation in the presence of hypoxia, a decrease in vascular endothelial growth factor (VEGF) production through enhanced hypoxia inducible factor-1α degradation, and a reduction in the response of vascular endothelial cells to stimulation of VEGF through inhibition of mTOR [34–36].

Rapamycin was efficacious in inhibiting the growth of human NSCLC cells, and in animal models, it effectively inhibited the growth of an NSCLC tumor and alveolar epithelial neoplasia induced by Ras [37–39]. Evidence that the combination of rapamycin and docetaxel is synergistic in inhibiting the growth of lung cancer cells [40] led to the hypothesis that mTOR inhibitors could be more efficacious when combined with other agents or therapies, such as chemotherapy or other targeted agents, in lung cancer treatment. No clinical data are available with rapamycin for the treatment of NSCLC.

CCI-779 (Temsirolimus)

CCI-779 is a more water-soluble ester of rapamycin for which there are both i.v. and oral formulations. In preclinical studies, the drug resulted in significant antitumor activity in a variety of human cancer models, such as gliomas, rhabdomyosarcomas, prostate cancer, breast cancer, small cell lung cancer (SCLC), melanoma, and leukemia [41].

Several phase I trials evaluating increasing doses of CCI-779 were performed. In a phase I study, CCI-779 was administered i.v. at a dose in the range of 0.75–24 mg/m² for 5 days per week every 2 weeks to 63 patients with solid tumors. The most common drug-related toxicities were asthenia, mucositis, nausea, and cutaneous toxicity. The maximum-tolerated dose was 15 mg/m² for patients with extensive prior treatment because, in the 19-mg/m² cohort, two patients had dose-limiting toxicities (one with grade 3 vomiting, diarrhea, and asthenia and one with elevated transaminases) and three patients required dose reductions. For minimally pretreated patients, in the 24-mg/m² cohort, one patient developed a dose-limiting toxicity of grade 3 stomatitis and two patients required dose reductions, establishing 19 mg/m² as the maximum acceptable dose. The terminal half-life was 13–25 hours. One patient with NSCLC achieved a confirmed partial response (PR), which lasted for 12.7 months. Three patients had unconfirmed PRs and two patients had prolonged stable disease (SD >24 weeks), registered in patients affected by soft tissue sarcoma, cervical and uterine carcinoma, and renal cell carcinoma (RCC) [42]. In another phase I study, 24 patients received CCI-779 i.v., weekly at a dose in the range of 7.5–220 mg/m² per week. At the 220-mg/m² per week dose, dose-limiting maniac-depressive syndrome, stomatitis, and asthenia were reported in two patients, preventing further dose escalation. The most frequent drug-related toxicities were mucocutaneous. Grade 3 or 4 toxicities included elevations in total cholesterol, triglycerides, and hepatic enzymes, as well as neutropenia, thrombocytopenia, and hypophosphatemia. All toxicities were reversible on treatment discontinuation. PRs were observed in one patient with RCC and in one patient with breast adenocarcinoma [43]. The safety/tolerability of oral CCI-779 at doses of 25–100 mg for 5 days every 2 weeks was evaluated in a phase I trial in 24 patients with advanced solid malignancies. Dose-limiting toxicity, consisting of grade 3 stomatitis, aspartate transaminase elevation, or solar-plantar desquamative rash, was reached at the 100-mg dose. As a consequence, the recommended dose for the following phase II trials was 75 mg for 5 days. Prolonged SD (≥9 months) was reported in patients with RCC, NSCLC, myxoid chondrosarcoma, mesothelioma, and leiomyosarcoma [44] (Table 1).

Table 1

Clinical trials with mTOR inhibitors as single agents in solid tumors including NSCLC

CCI-779 at two weekly i.v. doses (25 and 250 mg) was tested as maintenance treatment in 86 patients affected by extensive-stage SCLC in remission after induction chemotherapy. The median progression-free survival (PFS) time was 2.2 months and the median overall survival (OS) time was 7.8 months. Patients treated with the higher dose did slightly better, with a median PFS time of 2.5 months and a median OS time of 9 months (the median OS time of patients treated with the lower dose was 6.5 months; p = .02) [45].

Recently, a phase III trial randomized 626 patients with previously untreated poor-prognosis metastatic RCC to receive CCI-779 alone, interferon-α alone, or the combination. Compared with interferon-α, CCI-779 resulted in a longer OS time (10.9 versus 7.3 months; p = .008). The combination of CCI-779 and interferon-α did not improve survival [46].

CCI-779 was administered at the i.v. dose of 25 mg/week as front-line treatment to 55 patients affected by advanced NSCLC within a two-stage phase II trial. Preliminary results in the first 50 evaluable patients were interesting, with four (8%) confirmed PRs and 15 (30%) patients with SD. The median PFS time was 2.3 months and the median OS time was 6.6 months. The most common toxicity was grade 3–4 dyspnea (12%), fatigue (10%), hyperglycemia (8%), hypoxia (8%), nausea (8%), and rash/desquamation (6%). Although the study did not meet the predefined success criteria, CCI-779 had good tolerability and similar activity to other signal transduction inhibitors [47].

RAD001 (Everolimus)

RAD001 is an orally available rapamycin analogue showing, in preclinical studies, antitumor effects in cancer cell lines and xenograft models including melanoma and lung, pancreatic, and colon cancer. Preclinical studies showed that the antitumor activity of RAD001 is related to its inhibitory effects on p70^s6k both in tumor tissue and in peripheral blood mononuclear cells [48, 49]. RAD001 is currently approved in Europe as an immunosuppressive agent to prevent rejection in adult cardiac and renal transplant recipients [50, 51].

In a phase I study, 16 patients with solid tumors received escalating doses (from 5 to 30 mg/week) of RAD001. The principal toxicities were hypercholesterolemia, hypertriglyceridemia, mild leukocytopenia, and thrombocytopenia. Skin toxicity was mild to moderate at doses ≤30 mg. Four patients (one patient each with hepatocellular carcinoma and fibrosarcoma and two with NSCLC) had SD for >16 weeks. One of the patients affected by NSCLC who achieved SD exhibited an objective response as measured by a decrease in [¹⁸F]fluorodeoxyglucose uptake on positron emission tomography (FDG-PET). The recommended dose for phase II trials was identified to be 20 mg/week based on a combination of toxicity and pharmacokinetic and pharmacodynamic endpoints [52].

RAD001 was administered in combination with gemcitabine, within a phase I trial, to 8 patients with advanced solid tumors. In that trial, gemcitabine, at a lower dose than usually administered (600 mg/m²), was not tolerated in the majority of patients receiving RAD001 at a dose of 20 mg/week, because of myelosuppression. In the absence of pharmacokinetic interaction, it seems likely (in line with preclinical data) that the toxicity is a result of a combined impact on hemopoiesis [53]. These data suggest that modifications to the dose and possibly schedule of administration of rapamycin and its analogues may be required to optimize combination treatments.

Recently, RAD001 was administered at an oral dose of 10 mg/day until progression to 85 patients with refractory advanced NSCLC. All patients were platinum-based treatment refractory and were enrolled in two separate treatment arms: patients previously treated with two or fewer chemotherapies (arm 1) and patients previously treated with two or fewer chemotherapies and small molecule epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib or gefitinib (arm 2). In arm 1, 42 patients were entered, with a reported PR rate of 4.8% and SD rate of 47.6% and with a PFS time of 2.6 months. In arm 2, 45 patients were treated, with a reported PR rate of 2.3% and SD rate of 37.2% and with a PFS time of 2.23 months. The treatment was very well tolerated, with the main grade 3 and 4 toxicities being fatigue (11.9%) and dyspnea (4.8%) in arm 1 and mucositis (7%), hypokalemia (4.7%), and hyponatremia (4.7%) in arm 2. RAD001, at a daily dose of 10 mg, was reported to be active and safe in pretreated advanced NSCLC patients [54] (Table 1).

The pharmacodynamic effects of RAD001 in patients with recurrent NSCLC have been evaluated by FDG-PET. In eight patients receiving oral RAD001 at 10 mg daily, an FDG-PET scan was performed at baseline and after 8 days. A reduction in the sum of the maximum standardized uptake value (SUV_max) on day 8 was observed in all patients, suggesting FDG-PET as a potential tool for early evaluation of the pharmacodynamic effect of RAD001 in patients with NSCLC [55].

AP23573

AP23573 is a phosphorus-containing compound synthesized with the aid of computational modeling studies. AP23573 was found to be stable in organic solvents, aqueous solutions at a variety of pHs, and plasma and whole blood, both in vitro and in vivo. These data indicate that AP23573 is not a rapamycin prodrug [56]. AP23573 has shown potent inhibition of diverse human tumor cell lines in vitro and in xenografts implanted into nude mice, alone or in combination with cytotoxic or targeted agents [57, 58]. This drug is available in both oral and i.v. formulations.

In a phase I study, AP23573 was administered as a 30-minute i.v. daily infusion for 5 days every other week to 11 patients with refractory solid malignancies, showing severe dose-limiting oral mucositis at the dose of 28 mg/day. Other, not clinically significant, toxicities reported were hyperlipidemia, thrombocytopenia, and rash. The recommended phase II study dose is 18.75 mg/day for 5 days [59]. An additional phase I trial tested a weekly schedule of AP23573. The dose-limiting toxicity was oral mucositis at the 100-mg dose level [60]. Pharmacokinetic and pharmacodynamic analyses were performed in both studies, reporting modest interindividual variability. Evidence of mTOR inhibition, measured by assessing phosphorylated 4E-BP1, was demonstrated at dose levels associated with minimal toxicity in both trials. Although further phase II trials were performed with AP23573 in advanced sarcoma and relapsed hematological malignancies showing encouraging results [61], unfortunately no clinical data are available in the treatment of NSCLC patients.

Combining mTOR and EGFR Inhibitors as a Multitargeted Approach in NSCLC

EGFR is a member of the erbB/human epidermal growth factor receptor family and is overexpressed in 40%–80% of NSCLC cases, as well as in a number of other common solid tumors, and correlates with poor prognosis [62]. A possible strategy for inhibition of EGFR is the use of small molecules that inhibit receptor autophosphorylation by inhibiting ATP binding. Such small molecules are gefitinib and erlotinib. The latter has been licensed worldwide for the second- and third-line treatment of advanced chemorefractory NSCLC [63]. However, only a small percentage of patients with relapsed NSCLC showed a response to these TKIs [64, 65]. There was an obvious lack of correlation between the ratio of EGFR overexpression and response to TKIs. Moreover, response to TKIs was found to be caused by activating mutations in the EGFR and not by the expression status of the receptor [66–68]. Although EGFR-TKIs have been successfully translated into clinical practice, many patients do not respond to these agents or, eventually, develop resistance. One of the most important mechanisms of resistance to EGFR-TKIs is the EGFR-independent or constitutive activation of intracellular molecular effectors downstream of EGFR. A typical example of such a mechanism is the activation of the PI3K pathway. Constitutive activation of PI3K can be caused by direct gene amplification, overexpression of downstream effectors such as Akt, and the loss or inactivating mutations of PTEN. The crucial role of the constitutive activation of the PI3K/Akt pathway in the development and maintenance of an EGFR-resistant phenotype has been demonstrated by several preclinical and clinical studies [69]. Overall, these results support a significant role for the activated EGFR and Akt/mTOR pathway in NSCLC, leading to the hypothesis that multitargeted strategies may be the better choice for treatment. Clinical trials testing the combination of EGFR-TKIs and mTOR inhibitors for advanced NSCLC patients are ongoing and preliminary results are available.

Recently, in a pilot trial, stopping treatment in 10 patients with acquired resistance to erlotinib and gefitinib resulted in symptomatic progression, an increase in SUV_max on FDG-PET scan, and an increase in tumor size. Symptoms improved and SUV_max decreased after restarting erlotinib or gefitinib, suggesting that some tumor cells remain sensitive to EGFR blockade. Three weeks after restarting erlotinib or gefitinib, RAD001 was added to the treatment with no responses observed [70].

In a phase I trial, 10 advanced NSCLC patients received the combination of RAD001 and gefitinib administered orally and daily. The maximum-tolerated dose of RAD001 was 5 mg daily when combined with gefitinib at a dose of 250 mg. Two patients who were treated at the 10-mg RAD001 dose level experienced dose-limiting toxicities, including grade 5 hypotension and grade 3 stomatitis. Among the eight evaluable patients, two PRs were identified. The recommended phase II doses were 250 mg for gefitinib and 5 mg for RAD001, both given orally and daily [71]. To date, only preliminary results from the subsequent phase II trial are available. In that trial, untreated or platinum-based pretreated advanced NSCLC patients were enrolled. All patients were current or former smokers. In total, 17 untreated patients were evaluable, with a reported PR rate of 18%, median OS time of 12 months, and 1-year survival rate of 36%. In the 15 pretreated evaluable patients, the PR rate was 13%, median OS time was not reached, and 1-year survival rate was 68%. All PRs occurred in male former smokers. EGFR exon 19 deletion mutations were detected in two patients with PRs and a KRAS exon 2 mutation was detected in another. The main toxicities were oral mucosa ulcerations, pustular rash, diarrhea, and hypertriglyceridemia, and all were manageable [72] (Table 2).

Table 2

Clinical trials employing RAD001 plus gefitinib in NSCLC

Collectively, these data indicate that combining mTOR inhibitors with EGFR-TKIs might be clinically promising for NSCLC patients.

Conclusion and Perspectives

mTOR plays a critical role in transducing proliferative signals mediated through the PI3K and Akt signaling pathways, principally activating downstream protein kinases that are required for both ribosomal biosynthesis and translation of mRNAs of proteins that are essential for G₁ to S phase traverse. mTOR inhibitors appear to be well tolerated, with some evidence suggesting antitumor activity. The most common toxicities seen are skin reactions, stomatitis, myelosuppression, and metabolic abnormalities. These adverse events are transient and reversible with interruption of dosing. Antitumor activity, including tumor regressions and prolonged SD, has been reported among patients with a variety of malignancies, including NSCLC.

Promising preliminary clinical data in the treatment of NSCLC have been reported, stimulating further research in this setting. Currently, several ongoing phase I and II trials with mTOR inhibitors in NSCLC (with no results yet available) have been registered in the National Cancer Institute Clinical Trials database as of October 28, 2007 (Table 3) [73]. In our group, a phase II randomized study of RAD001 or pemetrexed as second-line treatment of elderly, advanced NSCLC patients is ongoing [74].

Table 3

Phase I and II ongoing trials with mTOR inhibitors in the treatment of NSCLC [73]

In conclusion, cancer treatments should no longer be chosen empirically, but rather on the basis of key cancer molecular profiles to be targeted. In fact, the lesson from EGFR-TKIs may represent a proof of this concept. Optimization of the therapeutic impact of mTOR inhibitors in NSCLC will be further defined when reliable predictive factors are identified. A series of studies is planned to contribute to our understanding of the role of mTOR inhibitors in NSCLC treatment with regard to the optimal dose, schedule, patient selection, and combination strategies.

Author Contributions

Conception/design: Cesare Gridelli

Manuscript writing: Cesare Gridelli, Paolo Maione, Antonio Rossi

Final approval of manuscript: Cesare Gridelli, Paolo Maione, Antonio Rossi

Author notes

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.