Oncologist ®
CME
Endocrinology
Current and Emerging Therapies for Advanced Adrenocortical Carcinoma
LYNDAL J. TACON,a,b RUTH S. PRICHARD,” PATSY S. H. SOON,a,d BRUCE G. ROBINSON,a,b RODERICK J. CLIFTON-BLIGH,a,b STAN B. SIDHUa,c
ªCancer Genetics Unit, Hormones & Cancer Group, Kolling Institute of Medical Research, University of Sydney, Sydney, Australia; bDepartment of Endocrinology and “Department of Endocrine and Oncology Surgery, Royal North Shore Hospital, St. Leonards, Australia; ªDepartment of Surgery, Bankstown Hospital and South West Clinical School, University of New South Wales, Sydney, Australia
Key Words. Adrenal cortex neoplasms . Adrenal cortex hormones . Mitotane . Drug therapy . Protein kinase inhibitors . Insulin-like growth factor 2
Disclosures
Lyndal J. Tacon: None; Ruth S. Prichard: None; Patsy S.H. Soon: None; Bruce G. Robinson: Consultant/advisory role: Astra Zeneca, Eisai, Bayer; Roderick J. Clifton-Bligh: Honoraria: Amgen, Servier; Stan B. Sidhu: None.
Section Editor Herbert Chen discloses research funding received from Novartis.
Reviewer “A” discloses no financial relationships.
The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. On the basis of disclosed information, all conflicts of interest have been resolved.
LEARNING OBJECTIVES
After completing this course, the reader will be able to:
1. Review the role and describe the limitations of conventional therapies for adrenocortical carcinoma.
2. Evaluate the current preclinical molecular research contributing to the rational selection of targeted therapies for adrenocortical carcinoma.
CME This article is available for continuing medical education credit at CME.TheOncologist.com.
ABSTRACT
Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with a poor prognosis. Complete surgical re- section offers the only potential for cure; however, even af- ter apparently successful excision, local or metastatic recurrence is frequent. Treatment options for advanced ACC are severely limited. Mitotane is the only recognized adrenolytic therapy available; however, response rates are
modest and unpredictable whereas systemic toxicities are significant. Reported responses to conventional cytotoxic chemotherapy have also been disappointing, and the rar- ity of ACC had hampered the ability to undertake ran- domized clinical studies until the establishment of the First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma. This yet-to-be re-
Correspondence: Lyndal Tacon, M.B.B.S., F.R.A.C.P., Cancer Genetics Unit, Hormones and Cancer Group, Kolling Institute of Medical Research, Department of Endocrinology, Royal North Shore Hospital, St. Leonards 2065 NSW Australia. Telephone: 61-2-99264763; Fax: 61-2-99265929; e-mail: lyndal.tacon@sydney.edu.au Received August 11, 2010; accepted for publication November 17, 2010; first published online in The Oncologist Express on January 6, 2011. @AlphaMed Press 1083-7159/2011/$30.00/0 doi: 10.1634/ theoncologist.2010-0270
The Oncologist 2011;16:36-48 www.TheOncologist.com
ported study seeks to identify the most effective first- and second-line cytotoxic regimens. The past decade has also seen increasing research into the molecular pathogenesis of ACCs, with particular interest in the insulin-like growth factor signaling pathway. The widespread development of small molecule tyrosine kinase inhibitors in broader onco-
logical practice is now allowing for the rational selection of targeted therapies to study in ACC. In this review, we dis- cuss the currently available therapeutic options for pa- tients with advanced ACC and detail the molecular rationale behind, and clinical evidence for, novel and emerging therapies. The Oncologist 2011;16:36-48
INTRODUCTION
Adrenocortical carcinoma (ACC) is a rare malignancy with an estimated prevalence of 4-12 per million population [1], in contrast to benign adrenocortical adenomas that occur in at least 3% of the population aged >50 years [1, 2]. ACC follows a bimodal age distribution, with peaks in childhood and in the fourth to fifth decades of life [3, 4]. At present, early identification of this aggressive malignancy with complete surgical resection offers the only potential for cure [2, 5]. The prognosis is poor, however, and even those patients with apparently localized tumors at diagnosis fre- quently develop metastatic disease within 6-24 months of surgical resection [6-9].
The majority of ACCs are sporadic neoplasms of unde- termined etiology; however, familial predisposition does occur. Rare hereditary syndromes known to predispose to either benign or malignant adrenocortical tumors (ACTs) include the Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, multiple endocrine neoplasia 1, Carney com- plex, and congenital adrenal hyperplasia. Somatic muta- tions in the genes involved in these syndromes have occasionally been identified in sporadic ACTs [10].
Approximately 60% of ACCs show clinical hormonal hypersecretion, whereas the remainder are considered non- functioning. Cushing’s syndrome, resulting from cortisol hypersecretion, with or without virilization, resulting from androgen excess, is the most frequent presentation in func- tioning ACC [2]. Cortisol-secreting ACCs have been re- ported to be associated with a poorer overall prognosis, showing a higher likelihood of [11] and earlier time to [12] metastatic disease. Whether this relates to the presence of hypercortisolemia, with the resultant adverse systemic met- abolic and immune sequelae, or whether cortisol secreting ACCs have an inherently more aggressive biology is cur- rently unclear [11].
Survival is dependent on stage at presentation [3, 13, 14]. For many years, the staging of ACC was largely per- formed using the MacFarlane classification as modified by Sullivan [15, 16]. Modifications were used, predominantly restricting stage IV to only patients with metastatic disease [7, 8, 17]. In 2004, the World Health Organization and the Union Internationale Contre Cancer defined tumor-node-
metastasis stages based on the MacFarlane/Sullivan system (Table 1) [18]. Subsequently the European Network for the Study of Adrenal Tumors (ENSAT) reported greater prog- nostic utility by restricting stage IV ACC to include only patients with metastatic disease and defining stage III as the presence of positive lymph node(s), any local infiltration, or venous tumor thrombosis, regardless of tumor size (Table 2) [19]. The reported 5-year survival rates in 416 patients using this classification were 82% for stage I, 61% for stage II, 50% for stage III, and 13% for stage IV. The ENSAT staging system was recently validated in an independent co- hort using the North American Surveillance, Epidemiol- ogy, and End Results registry [20].
The management of patients with ACC requires a mul- tidisciplinary approach, with initial complete surgical re- section the overriding goal in limited disease. Adjuvant medical therapy or irradiation may also be considered [21, 22]. Systemic therapies for advanced ACC are limited, and there remains a need for new and effective treatments. Mi- totane (1,1-dichloro-2(o-chlorophenyl)-2-(p-chlorophe- nyl)ethane [o,p’DDD]) has remained the only available adenolytic agent for several decades, although response rates are modest at approximately 30%. Conventional cyto- toxic therapy has been disappointing, and historically, the rarity of ACC had limited large-scale clinical trials until the recent establishment of the First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma (FIRM-ACT). That study, discussed in the sec- tion on cytotoxic chemotherapy below, sought to establish the most effective chemotherapy regimen for advanced ACC patients.
Our understanding of the molecular biology of ACC has also evolved. A number of global gene-expression profiling studies of sporadic ACCs have been completed, seeking to identify biomarkers of potential prognostic or therapeutic utility [10, 23-29]. Those studies have offered insights into the pathophysiology of adrenocortical carcinogenesis. Identification of specific molecular pathways dysregulated in ACC has the potential to allow rational testing of targeted therapies. This review describes the current therapeutic op- tions available for adults with advanced ACC, with a focus on new and emerging therapies.
| Stage | TNM staging criteria |
|---|---|
| I | T1, N0, M0 |
| II | T2, N0, M0 |
| III | T1-T2, N1, M0 or T3, NO, MO |
| IV | T4, NO, M0 or T3, N1, MO or T1-T4, NO-N1, M1 |
T1, tumor ≤5 cm; T2, tumor >5 cm; T3, tumor infiltration locally reaching neighboring organs; T4, tumor invasion of neighboring organs; NO, no positive lymph nodes; N1, positive lymph nodes; MO, no distant metastases; M1, distant metastasis.
| Stage | ENSAT staging criteria |
|---|---|
| I | T1, N0, M0 |
| II | T2, N0, M0 |
| III | T1-T2, N1, M0 or T3-T4, NO-N1, MO |
| IV | T1-T4, NO-N1, M1 |
T1, tumor ≤5 cm; T2, tumor >5 cm; T3, tumor infiltration into surrounding tissue; T4, tumor invasion into adjacent organs or venous tumor thrombosis; NO, no positive lymph nodes; N1, positive lymph nodes; MO, no distant metastases; M1, distant metastasis.
SURGERY
Surgical resection remains the cornerstone of treatment for patients presenting with stage I to stage III ACC [2, 5, 30]. The aim of surgery is to achieve a complete margin-nega- tive (R0) resection of the tumor, which may be possible even with significant local invasion in select patients [8, 31, 32]. Selection of an experienced endocrine or oncologic surgeon is critical, and prognosis is directly related to the ability of the surgeon to achieve clear margins. Patients who have a complete surgical resection have a 5-year sur- vival rate of 40%-50%, whereas those who have an incom- plete resection have a median survival duration <1 year [8, 17, 33-36]. In the event of clinical presentation with limited metastatic disease, there is evidence that complete resection of the metastatic and primary tumors provides benefit.
When a preoperative diagnosis or a high level of suspi- cion of ACC exists, open surgical resection is recom- mended [36-38]. A transabdominal approach allows maximal exposure for complete en-bloc resection, mini- mizes the chance of tumor spillage, and allows vascular
control of the inferior vena cava (IVC), aorta, and renal ves- sels. En-bloc excision of the tumor may involve resection of the adrenal gland and contiguous involved organs, includ- ing the kidney, liver, spleen, pancreas, and colon. Involve- ment of the IVC or renal vein with tumor thrombus is not a contraindication to surgical intervention and may be man- aged with cardiopulmonary bypass [35, 39, 40]. Preserva- tion of the integrity of the tumor capsule is critical in preventing tumor spillage, thereby reducing the incidence of local recurrence [35, 41].
Controversy surrounds the role of laparoscopic resec- tion for ACC [42-45]. Since the first laparoscopic adrenal- ectomy performed in 1992, it has largely replaced the open technique and has become the gold standard for the man- agement of benign adrenal pathology [46, 47]. Laparo- scopic removal of large adrenal tumors can be performed safely by experienced surgeons who have the judgment to convert to an open operation if key intraoperative findings suggestive of malignancy are encountered [48]. Concern- ingly, retrospective studies have demonstrated more fre- quent or earlier locoregional recurrence and a shorter disease-free survival interval when this technique is used for the management of ACCs [5, 37, 49-53]. Postulated contributing factors include a higher risk for capsular breach and tumor spillage, a higher rate of margin-positive disease, and cell dispersion within the peritoneal cavity in association with gas insufflation. At present, laparoscopic resection is not recommended in the management of ACC [5], although a recent retrospective analysis of 152 patients from the German ACC Registry did not find this technique inferior to an open procedure in localized ACC up to 10 cm in diameter [54].
Even after an apparently complete surgical resection, 50%-80% of patients develop either locoregional or meta- static tumor recurrence [5, 55]. When complete removal is feasible, aggressive surgical resection of these deposits, with the goal of again achieving negative surgical margins, should be undertaken [7, 8, 34, 56-58]. Such patients un- dergoing complete surgical resection have been shown, in retrospective series, to have longer disease-free (41.5 months versus 15 months) and overall (5-year survival rate, 50% versus 8%) survival times than those patients who are not amenable for surgical resection [33]. Although the number of patients included in retrospective series is small, available data point toward adopting an aggressive surgical approach to recurrent disease.
Data to support the routine debulking of nonresectable tumors are lacking, although decision making should be in- dividualized, with consideration given to the underlying tu- mor biology, including the rate of progression, length of the disease-free interval, and histological grade [5]. Debulking
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of tumor in advanced metastatic disease may provide relief from hormonal excess in functioning tumors and thus facil- itate other therapeutic options [17, 33, 57, 59]. Overall, however, individuals with inoperable recurrent or meta- static disease have a particularly poor prognosis and are of- ten better palliated with medical management.
MITOTANE
Mitotane (o,p’DDD) has been the mainstay of medical management for advanced ACC since it was found to be ad- renolytic in the 1950s [2, 60, 61]. Despite this, quality, pro- spective, controlled, systematic studies of its efficacy are lacking, and available studies are heterogeneous because of variable dosing regimens used, varying study endpoints, and frequent combination of mitotane with other therapies [61]. Overall, in reported retrospective series wherein mi- totane was administered for advanced ACC, a partial or complete response of variable duration was seen in 33% of cases [62]. Unfortunately, at present, there is no widely ac- cepted method for predicting the response of an individual to mitotane therapy. A tritium-release assay has been devel- oped and is reported to correlate with the ability of the tu- mor to metabolize mitotane [62, 63].
Although not conclusively determined, the mechanism of action of mitotane is believed to require metabolic trans- formation within the tumor by an unidentified cytochrome P450 enzyme(s), with the resultant acyl chloride derivative causing cytotoxicity through covalent binding to adreno- cortical macromolecules [62, 64-66]. The identity of these targets proteins has not been elucidated [61, 62]. There is also evidence that mitotane leads to oxidative damage through free radical and superoxide formation [62]. Cyto- toxic changes are predominantly seen in the zona reticularis and zona fasciculata, whereas the zona glomerulosa ap- pears relatively resistant. In addition to its potential role as a cytotoxic, mitotane inhibits steroidogenesis and thus as- sists in the management of hormone excess in clinically hy- perfunctioning ACC [21, 61].
The tolerability of mitotane is limited by its significant systemic toxicities [2, 61]. Gastrointestinal effects are com- mon, including nausea, vomiting, anorexia, and diarrhea, whereas neurological toxicities, including lethargy, somno- lence, ataxia, confusion, and depression, are dose limiting. Abnormalities in liver function tests are common, although significant hepatotoxicity is rare. Recognized hematologi- cal abnormalities include cytopenias and prolongation of bleeding time. Skin rash and renal abnormalities, including hematuria and cystitis, have also been described [2, 21, 61]. The measurement of serum mitotane levels, targeting a range of 14-20 mg/1 [67], was validated in several studies as correlating with a therapeutic response while minimizing
neurological toxicity [68-70]. Variable dosing regimens have been proposed to maximize the prompt achievement of a therapeutic level while minimizing side effects [71- 73]. There is significant interpatient variability in the daily dose required, and the half-life of mitotane increases with prolonged administration [2, 21, 61]. Mitotane dose titra- tion and supportive therapies require close clinical supervi- sion.
In addition to its adrenal effects, mitotane therapy is asso- ciated with diverse biochemical and clinical endocrinological effects. Hypercholesterolemia and hypertriglyceridemia are commonly observed. Hepatic production of hormone-bind- ing globulins (including cortisol-, sex hormone-, thyroid-, and vitamin D-binding globulins) is augmented, thus in- creasing total hormone levels while impairing free hormone bioavailability [21, 74-76]. Mitotane may also influence estrogen receptor-dependent signaling [75]. Clinically, gy- necomastia and sexual dysfunction may be observed in men, and androgen replacement may be required. A reduc- tion in free thyroxine levels is also frequently observed, with recent in vitro work suggesting that mitotane also di- rectly inhibits pituitary thyrotroph secretion and viability [77]. Thyroxine replacement may be required if clinical hy- pothyroidism is evident [78].
The induction of hepatic cytochrome P450 enzymes by mitotane induces the metabolism of a variety of agents, in- cluding corticosteroids. High-dose glucocorticoid replace- ment is therefore typically necessary, as a result of both the inhibition of adrenocortical steroidogenesis and the in- creased metabolic clearance of corticosteroids [21, 61, 79, 80]. Mineralocorticoid supplementation may also be neces- sary. Overall, the assessment of hormonal replacement is largely based on clinical assessment, with underreplace- ment of corticosteroids recognized to exacerbate mitotane- induced side effects [81].
CYTOTOXIC CHEMOTHERAPY
The rarity of ACC has limited clinical studies of cytotoxic chemotherapeutic agents. Cisplatin-containing regimens have been the most frequently studied, but as yet, no ran- domized trial results have been published. Most reports de- scribe small series of advanced ACC that has progressed despite mitotane therapy. Reported response rates are gen- erally modest, studies lack power, and comparisons be- tween different regimens are lacking. As yet, clinical factors predictive of a cytotoxic response have not been de- termined [41, 73].
The presence of high levels of the multidrug-resistance (MDR) protein MDR-1/P-glycoprotein has been postulated to be responsible for the low response rates to some cyto- toxics [82]. MDR-1 is found in high concentrations in ACC,
where it acts as a drug efflux pump [83]. In vitro studies have demonstrated that mitotane partially reverses chemo- therapy failure by inhibiting drug efflux. This forms part of the rationale for combining mitotane with standard chemo- therapy; however, the role this plays in vivo remains to be fully elucidated [84-86]. Early-phase clinical trials involv- ing targeted MDR-1 efflux pump inhibitors are discussed in the targeted therapies section below.
Expression of the excision repair crosscomplementation group 1 (ERCC-1) protein, involved in DNA repair, has been found to influence response to platinum compounds in other malignancies, particularly non-small cell lung carci- noma [87]. High ERCC-1 expression by immunohisto- chemistry in ACC was reported, in a retrospective tissue array analysis, to predict poor prognosis in patients treated with platinum-based chemotherapy [88].
The most encouraging results to date have come from the combination of etoposide, doxorubicin, and cisplatin with low-dose mitotane (the EDP/Italian/Berruti protocol) [12, 89]. Among 72 patients with nonresectable ACC stud- ied prospectively, an overall response rate of 49% was achieved with this regimen [12]. A complete response was achieved in five patients, whereas a further 30 patients had disease stabilization. The median time to progression in re- sponding patients was 18 months. The use of chemotherapy allowed 10 patients to be downstaged such that radical sur- gical resection was possible. Those patients had a signifi- cantly longer overall survival time, again highlighting the importance of surgical resection in this disease.
The combination of the above cytotoxic drugs and mi- totane is associated with significant toxicity. A combina- tion of streptozotocin and mitotane was studied in an attempt to achieve clinical benefit with less toxicity [90]. The combination was investigated as adjuvant therapy in 28 patients following radical resection and as active therapy in 22 patients with measurable disease. A longer disease-free interval and longer survival time were observed in those in- dividuals who received adjuvant chemotherapy, and a com- plete or partial response was seen in 36% of patients with measurable disease. The associated toxicity was minimal.
The success, albeit limited, of these two protocols led to the recommendation by the International Consensus Con- ference on Adrenal Cancer, Ann Arbor, MI, that either the EDP plus mitotane or the streptozotocin plus mitotane reg- imen be used in advanced ACC patients [5]. Subsequent to this meeting, FIRM-ACT was established (http://www. firm-act.org). This prospective study is comparing both cy- totoxic regimens as first- and second-line therapies in advanced ACC patients, with survival as the primary out- come. This study is now closed and is expected to report its findings in 2011.
Even with use of these regimens, it is predicted that a significant number of patients will develop progressive or recurrent disease. A need therefore exists for further thera- pies. A study of 11 patients who had failed streptozotocin and mitotane reported that the combination of vincristine, cisplatin, teniposide, and cyclophosphamide led to a partial response or disease stabilization in nine individuals [91]. A recent phase II clinical trial of 28 patients reported that gemcitabine plus metronomic fluoropyrimidines (5-flu- orouracil or oral capecitabine), in combination with mito- tane, was well tolerated as second-line therapy, resulting in a complete response in one patient, a partial response in one patient, and disease stabilization in a further 11 patients [92].
Paclitaxel was demonstrated, in preclinical studies, to produce dose-dependent inhibition of adrenal cancer cell line proliferation [93, 94]. An early-phase clinical trial re- ported a minor response in a single patient with ACC treated with paclitaxel and interferon-«2b [95]. Phase II studies currently under way include metronomic paclitaxel in combination with the oral multikinase inhibitor sor- afenib, and docetaxel in combination with cisplatin. An- other novel agent under preclinical investigation is decitabine, an inhibitor of DNA promoter methylation, re- ported to inhibit adrenal cancer cell proliferation, reduce cortisol secretion, and inhibit cell invasion in vitro [96].
The rarity of ACC has limited the ability of oncologists to perform large-scale clinical studies, but significant inter- national effort has now demonstrated that adequately pow- ered clinical studies of ACC therapy are possible. The outcome of the FIRM-ACT study is keenly awaited; how- ever, it is acknowledged that further advances are still re- quired, likely through the combination of conventional cytotoxics with novel targeted therapies.
RADIOTHERAPY
Traditionally, ACC was believed to be radioresistant [6, 55, 97]. A recent retrospective review of published data com- bined with German ACC Registry data found a response to palliative radiotherapy in 57% (52 of 91) of patients [98]. Radiation had been given predominantly for painful bony metastases; however, a small number of local or distant re- currences were also treated. A smaller, recent, retrospective review of the Dutch ACC Registry also reported a partial tumor response in the metastatic deposits of two patients and pain relief in six patients irradiated for bony disease [99]. Taken together, this evidence suggests that palliative radiotherapy has a role in symptomatic metastatic deposits, particularly bone disease. Interestingly, in vitro work sug- gests that mitotane has a sensitizing effect on adrenocortical cancer cells treated with ionizing radiation [100, 101].
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RADIONUCLIDE THERAPY
Radiolabeled metomidate, a tracer that binds to adrenal 11ß-hydroxylase (P450c11), shows promise in distinguish- ing neoplasms of adrenocortical origin from other lesions, such as metastatic deposits and pheochromocytoma. 11C- labeled metomidate has been used in positron emission to- mography studies and as 123I-iodometomidate in single photon emission computed tomography imaging [102- 104]. Iodine-labeled metomidate may, in the future, hold therapeutic potential as a specific adrenocortical radionu- clide [30, 104].
RADIOFREQUENCY ABLATION
Radiofrequency thermal ablation (RFA) has been reported as being effective for the short-term local control of ACCs <5 cm in size, with one study reporting that eight of 12 such tumors decreased in size and lost contrast enhancement on imaging over a mean follow-up of 10.3 months [105]. Per- cutaneous laser ablation was also reported as being useful for the palliative treatment of unresectable hepatic metasta- ses and a single primary ACC in a series of four patients [106]. Other studies have reported variable outcomes, and adverse effects include bleeding, infection, and injury to ad- jacent structures [107, 108]. Further investigation is neces- sary to evaluate long-term efficacy and to identify the clinical scenarios in which RFA should be used.
MANAGEMENT OF HORMONAL EXCESS
Hormonal excess causes significant morbidity in advanced ACC patients. Although mitotane reduces steroidogenesis, its slow onset of action often necessitates the introduction of alternative adrenostatic drugs. Adrenal insufficiency is a potentially life-threatening risk of these therapies, and close endocrinological supervision is required to ensure that cor- tisol levels are kept in the desired range or to titrate adrenal hormone replacement therapy if required [21, 109, 110].
Ketoconazole
Ketoconazole is an antifungal agent that inhibits multiple adrenal steroidogenic enzymes including C17-20 desmo- lase (P450c17), as well as the cholesterol side-chain cleav- age enzyme (P450scc) and 11ß-hydroxylase (P450c11) [111-114]. It may also act as a glucocorticoid receptor an- tagonist [115]. The use of ketoconazole is limited by hepa- totoxicity and gastrointestinal side effects. Because of its effective hepatic cytochrome enzyme inhibition, interac- tion with other agents can significantly increase drug tox- icity [21].
Metyrapone
Metyrapone inhibits 11ß-hydroxylase (P450c11 hydroxy- lase), blocking the final step in cortisol synthesis. The re-
sultant increase in circulating precursors may cause adverse clinical effects, including induction of hypertension through the weak mineralocorticoid 11-deoxycortisol, and acne and hirsutism through the accumulation of androgenic precursors [116]. Like ketoconazole, metyrapone is an in- hibitor of hepatic cytochrome enzymes, with a resultant high risk for drug interactions.
Aminoglutethimide
Aminoglutethimide inhibits the cholesterol side chain cleavage (P450scc) enzyme as well as the aromatization of androgens to estrogens, thus blocking the synthesis of cor- tisol, aldosterone, androgens, and extra-adrenal estrogen production. Adverse effects include lethargy, somnolence, headache, ataxia, nausea, and rash [117]. Interestingly, in vitro data have demonstrated that aminoglutethimide and etomidate inhibit proliferation in a human ACC cell line, in addition to their effects on steroidogenesis [118].
Etomidate
Intravenous etomidate inhibits 11 ß-hydroxylase (P450c11) and the cholesterol side chain cleavage (P450scc) enzyme with prompt reduction in corticosteroid levels. It therefore has a role in acute hypercortisolemia, whereby patients are unable to take oral adrenostatic medications, including the intensive care unit setting [21, 119].
TARGETED THERAPIES
The understanding of growth factors and receptor tyrosine kinases in human malignancies has evolved in recent years. These cell surface transmembrane proteins activate intra- cellular signaling pathways and thus modulate biological activities, including cell proliferation, migration, and inva- sion. In vitro work, in combination with gene-expression profiling and immunohistochemical studies, has allowed for rational selection of targeted therapies to trial in ACC patients [73, 120]. The following section summarizes the current experience with these therapies, including those in preclinical and early-phase clinical investigations.
Insulin-Like Growth Factor 2
The most consistent molecular event identified in ACCs is overexpression of insulin-like growth factor (IGF)-2 [23, 24, 29, 121-124], known to signal predominantly through the IGF-1 receptor (IGF-1R) [125-127]. Preclinical studies have demonstrated that antagonism of IGF-1R inhibits the growth of ACC cells in vitro and in xenograft models [124, 128, 129]. A phase I study of figitumumab, an anti-IGF-1R monoclonal antibody, demonstrated stable disease in eight of 14 patients [130], and a phase I study of a small-molecule tyrosine kinase IGF-1R inhibitor (OSI-906) demonstrated a
partial tumor response in one of three patients with ad- vanced ACC [131]. Targeting the IGF signaling pathway is seen as one of the most promising therapies in advanced ACC, and further clinical studies using IGF-1R antagonists in advanced ACC patients are currently in progress (http:// www.clinicaltrials.gov) [30].
Epidermal Growth Factor Receptor
Overexpression of the epidermal growth factor receptor (EGFR) protein in ACCs [132-135] has provided the ratio- nale for the use of EGFR inhibitors. Unfortunately, results to date have been disappointing. The EGFR antagonist ge- fitinib failed to demonstrate any activity in 19 patients with advanced ACC [136], and a recent report of 10 patients with advanced ACC also found the EGFR inhibitor erlotinib to show limited efficacy in combination with gemcitabine. That study reported a minor response in one individual, whereas the remainder experienced progressive disease or toxicities [137].
Angiogenesis Inhibitors
Angiogenesis and neovascularization are critical for tumor growth. Vascular endothelial growth factor (VEGF) is a proangiogenic growth factor that binds to the tyrosine ki- nase VEGF receptor, resulting in the activation of several intracellular signaling pathways [138]. VEGF is upregu- lated in ACC tumor tissue [30, 139, 140]. Circulating VEGF is also elevated in the serum of patients with both benign or malignant ACTs and pheochromocytomas [141, 142], and levels fall after successful tumor resection [143, 144]. Some studies have found circulating VEGF levels to be significantly greater in patients with ACCs than in those with benign adrenal disease [141, 144]. These findings have led to interest in the targeting of VEGF signaling in ACC therapy; however, again the limited results to date have been disappointing. A study of 10 patients with advanced ACC reported no response to bevacizumab, an anti-VEGF humanized monoclonal antibody, in combination with capecitabine [145].
Thalidomide, an antiangiogenic agent that inhibits the activity of basic fibroblast growth factor-2 [138], is in wide- spread clinical use in multiple myeloma patients. A single case report detailed a partial response to thalidomide in a patient with advanced chemoresistant ACC [146]. Newer antiangiogenic agents for which there is no current experi- ence in ACC therapy include the soluble VEGF receptors, including aflibercept, and the vascular-disrupting agents (reviewed in [138, 147]). The antiangiogenic multitarget ty- rosine kinase inhibitors sorafenib and sunitinib are dis- cussed below.
Multikinase Inhibitors
Sorafenib is an oral tyrosine kinase inhibitor targeting the cell proliferation molecule Raf-1, as well as the RET proto- oncogene, KIT (stem cell ligand receptor) tyrosine kinase, platelet-derived growth factor (PDGF) receptor, and VEGF receptor subtypes 2 and 3 [138]. A phase I study reported stable disease in two patients with ACC treated with sor- afenib and the farnesyltransferase inhibitor tipifarnib [148], and a subsequent single case report described a sustained response to sorafenib in an advanced ACC patient [149]. A phase II study investigating sorafenib in combination with metronomic paclitaxel is ongoing.
Sunitinib also inhibits multiple receptor tyrosine ki- nases, including the PDGF receptor, VEGF receptor (sub- types 1, 2, and 3), KIT, RET, FLT3, and colony-stimulating factor 1 receptor [138]. A partial response to sunitinib in a single patient with advanced ACC was recently reported [150]. The results of a phase II study investigating sunitinib in patients with advanced ACC who have progressed after cytotoxic chemotherapy (Sunitinib in Refractory ACC) are awaited.
Imatinib mesylate is an oral tyrosine kinase receptor in- hibitor that primarily targets the fusion protein Bcr-Abl, in addition to inhibiting the PDGF receptor and KIT tyrosine kinases. In a phase II study, imatinib was not found to pro- duce an objective response in the four patients enrolled with advanced ACC [151].
Mammalian Target of Rapamycin Signaling
The mammalian target of rapamycin (mTOR) signaling pathway has emerged in recent years as a potential thera- peutic target in cancer. Agents that inhibit mTOR signaling include the immunosuppressant rapamycin (sirolimus) and its derivatives everolimus and temsirolimus [152]. Interest- ingly, rapamycin was found to demonstrate antiangiogenic effects through a reduction in VEGF production and signal- ing in vitro [153, 154]. Rapamycin may also have a direct vascular-disrupting role, with reports of endothelial cell toxicity and thrombosis in tumor vasculature when com- bined with gemcitabine in a pancreatic cancer xenograft model [155]. mTOR signaling had not been investigated in ACC until a novel study recently identified everolimus as able to reduce adrenocortical tumor growth both in vitro and in vivo in a mouse xenograft model, and demonstrated that the IGF-1R and mTOR signaling cascades were regu- lated by specific microRNAs [156]. Temsirolimus is cur- rently being evaluated in a phase I clinical trial in combination with the anti-IGF-1R recombinant monoclo- nal antibody cixutumumab in advanced malignancies, in- cluding ACC.
MDR-1/P-Glycoprotein
Data suggest that the expression of MDR-1 is associated with a poor response to chemotherapy in a number of hu- man malignancies [157]. This led to a search for com- pounds that may interfere with MDR-1 function [158]. The calcium channel blocker verapamil was identified as a first- generation MDR-1 modulator, improving chemosensitivity to both vincristine and doxorubicin in leukemic and ovarian cancer cells in vitro; however, subsequent clinical studies reported conflicting results [157]. Similarly, cyclosporine showed in vitro promise as an MDR-1 inhibitor; however, trials in hematologic malignancies and colorectal carci- noma have been disappointing [157]. Preclinical studies in- vestigating the cotreatment of primary human ACC cultures with verapamil, cyclosporine, doxorubicin, and vincristine also failed to identify a large additive effect on cytotoxicity, nor could an effect be correlated with MDR-1 expression [159]. Second-generation analogs of MDR-1 modulators include D-verapamil and valspodar (PSC833), an analog of cyclosporin D. The combination of valspodar with vinblastine and paclitaxel in early-phase clinical trials identified complex pharmacokinetic interactions with vari- able clinical responses and toxicities [160-162]. Third- generation MDR-1 modulators have since been developed in an attempt to avoid such drug interactions [157]. One agent, tariquidar (XR9576), a MDR-1/P-glycoprotein drug efflux pump inhibitor [158, 163], is now in clinical trial in advanced ACC patients [30, 120, 164].
Peroxisome Proliferator-Activated Receptor y Signaling
The nuclear receptor peroxisome proliferator-activated re- ceptor (PPAR)-y is expressed in the normal and neoplastic adrenal cortex [165, 166]. The treatment of human adreno- cortical cancer cells in vitro with rosiglitazone, a PPAR-y ligand, led to a lower rate of proliferation and greater ste- roidogenesis, suggesting antineoplastic and prodifferentia- tion effects [165-167]. A preclinical study in a xenograft model also demonstrated less tumor growth with rosiglita- zone therapy, in association with less histopathologic infil- tration, neovascularization, and VEGF gene expression [168]. As yet, there are no clinical studies of PPAR-y li- gands in ACC patients, and despite in vitro promise, the use of these agents as monotherapy in advanced breast cancer, prostate cancer, and liposarcoma patients has been disap- pointing [169].
ß-Catenin and Wnt Signaling
ß-catenin gene mutations are reported in benign and malig- nant ACTs, resulting in activation of the Wnt signaling pathway [170-172]. Transgenic mice demonstrating con-
stitutive activation of B-catenin in the adrenal cortex develop progressive adrenocortical cell dysplasia, hyperal- dosteronism, and locoregional metastatic invasion [173]. Preclinical in vitro studies have reported that a small-mol- ecule inhibitor of Wnt signaling (PKF115-584) reduced ad- renocortical cancer cell line proliferation and increased apoptosis [174]. At present, Wnt signaling inhibitors re- main in preliminary preclinical investigation.
Steroidogenic Factor-1
Steroidogenic factor (SF)-1 is a nuclear transcription factor with a primary role in adrenal and gonadal development and in the regulation of cytochrome P450 steroidogenic enzyme expression in the adrenal cortex [175]. The demonstration of SF-1 overexpression in pediatric ACTs triggered interest in a potential role in tumorigenesis [176, 177]. In vitro stud- ies reported that higher SF-1 expression led to greater pro- liferation and steroidogenesis in a human adrenocortical cancer cell line, with greater SF-1 signaling, resulting in ACT formation in mice [178]. SF-1 inverse agonists have been recently identified, and studies have demonstrated that compounds of the isoquinolinone class inhibit adrenocorti- cal cell proliferation and steroidogenesis in vitro [179]. Fur- ther work is required to explore the potential role of such agents in ACC therapeutics.
CONCLUSION
Advanced ACC remains an aggressive malignancy with limited therapeutic options, and the rarity of the disease has historically frustrated systematic research efforts. The es- tablishment in the past decade of collaborative ACC net- works, combining tumor banking with annotated clinical data, is overcoming this impediment, and international ef- forts have demonstrated that multinational clinical trials are possible. The results of FIRM-ACT will establish the stan- dard of care chemotherapy for advanced disease; however, it is acknowledged that novel therapeutic options are still desperately required. Despite recent advances in the under- standing of the molecular pathways that are dysregulated in adrenocortical tumorigenesis, these findings have yet to be translated into meaningful clinical benefit. Basic and col- laborative clinical research efforts are continuing, and at present, individuals with advanced ACC are encouraged to be managed at specialized centers with access to clinical trial enrollment.
ACKNOWLEDGMENTS
Lyndal J. Tacon is supported by an Australian Post-Gradu- ate Award Research Scholarship and a Cancer Institute New South Wales Research Scholars Award. Stan B. Sidhu is a New South Wales Cancer Institute Fellow.
AUTHOR CONTRIBUTIONS
Conception/Design: Lyndal J. Tacon, Ruth S. Prichard, Patsy S.H. Soon, Bruce G. Robinson, Roderick J. Clifton-Bligh, Stan B. Sidhu Collection and/or assembly of data: Lyndal J. Tacon, Ruth S. Prichard
Data analysis and interpretation: Lyndal J. Tacon, Ruth S. Prichard Manuscript writing: Lyndal J. Tacon, Ruth S. Prichard
Final approval of manuscript: Lyndal J. Tacon, Ruth S. Prichard, Patsy S.H. Soon, Bruce G. Robinson, Roderick J. Clifton-Bligh, Stan B. Sidhu
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