Review Article Therapy of adrenocortical cancer: present and future
Daniela F. Maluf1, Brás H. de Oliveira2, Enzo Lalli3,4
1Department of Pharmacy, Federal University of Paraná, 80210-170, Curitiba PR, Brazil; 2Department of Chemistry, Federal University of Paraná, 81531-990, Curitiba PR, Brazil; 3Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UMR 6097, 06560 Valbonne, France; 4Université de Nice - Sophia Antipolis, Valbonne, France.
Received November 30, 2010; accepted December 6, 2010; Epub December 7, 2010; Published January 1, 2011
Abstract: Adrenocortical carcinoma is a rare endocrine malignancy with an estimated worldwide incidence of 0.5 - 2 per million/year. This neoplasm is characterized by a high risk of recurrence and a dismal prognosis owing to unsatis- factory overall survival. Surgery represents the cornerstone of adrenocortical carcinoma therapy, which can be associ- ated to radiotherapy and adjuvant mitotane administration. In advanced cases, different chemotherapy regimens are used, but their relative efficacy is still unknown until the results of clinical trials under way will be published. Novel drugs have been recently developed based on the discovery of molecular pathways that trigger development and evolution of these tumors. More efficient treatments are widely expected in the future from these new targeted thera- pies as a hope of cure for patients affected with this aggressive malignancy.
Keywords: Adrenocortical carcinoma, targeted therapy, review, mitotane, radiotherapy, chemotherapy, ß-catenin, Steroidogenic factor 1 (SF-1) inverse, mTOR, antagonists
Introduction
Adrenocortical carcinoma (ACC) is a rare endo- crine malignancy with an estimated worldwide incidence of 0.5 - 2 per million/year. Even though adrenocortical tumors are rare in chil- dren, there is a considerable incidence in south- ern Brazil with 3.4-4.2 cases per million chil- dren under 15 years, a rate 12-18 times higher than worldwide incidence [1, 2]. This neoplasm is characterized by a high risk of recurrence and a dismal prognosis owing to unsatisfactory over- all 5-year survival that ranges between 23% and 60% [1, 3-5]. A bimodal age distribution has been observed in ACC patients with higher inci- dence occurring before the age of 5 years and in the fourth to fifth decade of life. Moreover, there is a slightly female predominance [1, 6]. Early diagnosis in adults is particularly difficult since often no signs of hormone excess are pre- sent. Conversely, approximately 90% of pediat- ric patients can be recognized by hormone ex- cess causing virilization and androgen hyper- secretion (mainly cortisol hypersecretion), and for this reason they have a better prognosis [1].
The tumor stage at diagnosis is the strongest prognostic factor. Three parameters have been identified strongly correlated to a shorter sur- vival: older age at diagnosis, stages III (involvement of local lymph nodes) to IV (local organ invasion or distant metastases) disease, and cortisol hypersecretion [7]. Complete opera- tive resection is the only hope for cure of ACC. However, because of the frequency that the disease is at an advanced stage at the moment of diagnosis, surgery often fails to remove total tumor burden. Furthermore, recurrence occurs in approximately 70% to 80% of patients after resection. The majority of patients treated with radical resection undergoes relapse and 5-year survival can be as low as 5% [8]. Chemotherapy is the first-line nonoperative therapy, used as adjuvant treatment and in cases where resec- tion is incomplete or contraindicated. Neverthe- less, lack of efficacy of the available chemother- apy for this deadly disease constitutes a matter of debate for clinical management [9].
Currently, two important international clinical studies are in development and they may soon
Therapy of adrenocortical cancer
bring clinical benefits. The first one is a Phase III, randomized clinical trial on locally advanced and metastatic ACC treatment (http:// www.firmact.org) comparing etoposide, doxorubicin, cisplatin plus mitotane (EDP/M) with streptozotocin plus mitotane (Sz/M) in 300 patients during 5 years. The results of this study are anticipated to be available in 2011 [9, 10]. The second study is a prospective randomized trial intended to evaluate the efficacy of adjuvant mitotane therapy versus follow-up only (http://www. adiuvo-trial.org) in patients with low/moderate risk of relapse. In agreement with the consensus of an international expert panel, the treatment for adrenocortical carcinoma depends on the individual risk status. The classification is based on tumor stage, resection status and expression of the proliferation marker Ki67. Patients with high risk, who are likely to develop distant metastases, may receive a more aggressive adjuvant treatment (e.g. mitotane plus streptozotocin) for at least 2 years. In R1 resection patients, radiotherapy of the tumor bed is also recommended [8-10].
Surgery
There is a common agreement that open adrenalectomy (OA) is the most important ap- proach in the treatment of ACC. It is the only curative option when a margin-free complete resection (R0 resection) is achieved. A recent retrospective study aimed to compare the out- come of patients who underwent open resection (OR) to those treated by laparoscopic adrenalec- tomy (LA) [11]. In a mean follow-up of 36.5 months (+43.6), a total of 88 patients were ana- lyzed, among which 17 were treated by LA. Tu- mor size ranged 4-14 cm for LA versus 5-27 cm to OR patients. This retrospective evaluation showed that recurrence occurred in 63% of cases at a mean time of 9.6 months (±14) in LA compared with 65% at 19.2 months (±37.5) in the OR group. Likewise, local recurrence was found in 25% of patients in the LA group and 20% of the OR group. The authors concluded that laparoscopic adrenalectomy is not suitable for patients with ACC. Higher complexity is at- tributed to LA since it is not possible to identify how to penetrate the capsule of the adrenal gland without spreading the tumor and shed- ding malignant cells [12]. Obviously, this trial presents limitations because of its small sample size, retrospective nature and selection bias. Although the role of LA is controversial, taking
into account its superiority over OA in terms of postoperative recovery, duration of hospitaliza- tion and overall costs, some studies have rec- ommended LA in localized non-invasive tumors (diameter < 10 cm) and for selected cases of stage I and II ACC, when performed by an ex- perienced endocrine surgeon [13, 14]. Interest- ingly, a recent study demonstrated a direct rela- tionship between the type of surgical approach and occurrence of peritoneal carcinomatosis (PC) [15]. In this study, 18 PC diagnosed pa- tients were evaluated. Investigation of several factors (type of surgery, size, stage, complete surgery, and hormone secretion) showed that only the type of surgery was significantly associ- ated with PC occurrence (4/6 patients treated with LA and 11/55 patients treated with OA). The authors also attested a higher risk of local recurrence after LA compared with OA (4-year rate of PC of 67% for LA compared to 27% for OA), since LA can generate tumor spillage and consequently fast carcinomatosis development. Although this study is in accordance with Gon- zalez et al. who reported a 15% risk of PC in OA and 89% in LA [16], there is an intrinsic limita- tion due to the low number of patients who un- dergo LA since this procedure is not generally recommended.
Mitotane
The first description of the use of mitotane (o,p’- DDD), an analogue of the insecticide DDT, was made in 1948 when it was shown to produce adrenal atrophy in dogs [17]. Twelve years later, mitotane was introduced as an adrenocortico- lytic agent for the treatment of adrenocortical carcinoma [18]. This drug acts by inhibiting 11ß- hydroxylation and cholesterol chain cleavage in the mitochondria of steroidogenic cells, there- fore blocking cortisol synthesis [19]. Up to date, ACC patients make use of adjuvant mitotane treatment despite its considerable toxicity and relatively low response rate, and mitotane ther- apy still remains the cornerstone, mainly in me- tastatic stage [20, 21].
Mitotane is poorly absorbed (60%) and, be- cause of its lipophilicity, a significant amount (40%) is stored mainly in adipose tissue and also in liver, brain and adrenal tissues. This is the major factor responsible for the need of mitotane high dose administration (up to 4-6 g/ day) and the toxicity events related to the treat- ment [22, 23]. A number of studies have de-
Therapy of adrenocortical cancer
scribed the impact of mitotane adjuvant treat- ment. An important retrospective multicenter study, published in 2007 by Terzolo et al., evalu- ated the importance of mitotane as an adjuvant treatment after radical resection of ACC in a wide cohort covering 8 Italian and 47 German centers with a 10-year follow-up [24]. Recur- rence was reported in 48.9% of patients in the mitotane group, compared to 90.9% and 73.3% of the patients in the two control groups, re- spectively. Median recurrence-free survival in the mitotane treatment group was 42 months, compared with 10 and 25 months in the control groups (p<0.01). This study also showed that death from adrenocortical cancer was reduced in the mitotane group (25.5% vs. 54.5% and 41.3% in the control groups). The authors con- cluded that in the group of adjuvant treatment with mitotane not only the risk for recurrence and death was significantly diminished but also a longer recurrence-free survival was achieved. Even though an inherent bias is related to retro- spective studies, the importance of this study is related to the large number of studied patients recruited in international centers with methodi- cal follow-up, well-suited control groups, and efficient statistical analysis. The results of Ter- zolo et al. are in agreement with the previous study by Kasperlik-Zaluska et al., which re- ported increased survival in mitotane group in which administration was started immediately after surgery [25]. In a critical analysis, Schtein- gart attested that the favorable results for adju- vant mitotane of Terzolo et al. may be explained by the fact that mitotane adjuvant therapy was most likely selected to patients whose surgical resection was outwardly complete [26]. A more recent study by Fassnacht et al. [27] concluded that a better five-year survival [87 vs. 53%, HR for death 0.35 (95% CI 0.13-0.97); P = 0.04] and disease-free survival exist for patients who received adjuvant mitotane compared to those who did not. In addition, a risk reduction of 62% was associated to adjuvant mitotane. Further- more, a long-term follow-up study analyzed 25 patients treated by surgery plus monitored mito- tane, independently of tumor stage and total resection [28]. Around 87% of patients were treated with mitotane over more than 2 years. Overall survival was found to be 52% regardless of the prevalence of high-stage tumors. All to- gether, these findings are supportive for thera- peutic benefit of adjuvant mitotane treatment.
On the other hand, Vassilopoulou-Selin et al. in
a small, prospective, randomized study, found no difference in recurrence-free survival among patients who received mitotane and those who did not [29]. Additionally, Bertherat et al., con- cluded that there is no significant advantage with adjuvant mitotane after complete removal of ACC [30]. According to these authors, it is reasonable to think that the mitotane-treated group could be selected for unfavorable prog- nostic factors and selection bias might be able to influence results of mitotane inefficacy. Grubbs et al., in a recent publication reported a study of the largest series of ACC patients treated at a single institution [31]. Throughout an 88-month follow-up, the overall survival ob- served was 47 months. Comparing the outcome of patients treated with adjuvant mitotane to those treated with an alternative strategy of withholding mitotane, the authors found no sig- nificant difference in overall survival. The au- thors justify their results at variance with the ones obtained by Terzolo et al. raising questions about possible incomplete surgery in control groups in that study, which could explain a high recurrence rate.
Some hypotheses have been proposed to ex- plain why the results of those studies are con- flicting. First, it is possible that drug metabolism be variable among apparently comparable tu- mors. This is explained by the need of mitotane to be converted in vivo to an active metabolite, an acyl chloride reactive molecule, to develop the adrenolytic effect [26]. Consequently, a therapeutic response to mitotane may be pre- sent only in tumors which are able to metabo- lize it. In contrast, a negative response may be found in those tumors which do not have this capability. Second, the rareness of ACC with a restricted statistical possibility to carry out a trustworthy assessment of treatment effective- ness and the need for a control group of pa- tients with analogous baseline characteristics is an inherent bias that challenges future re- search. Finally, retrospective analysis using dif- ferent formulations with a large range of doses (3 to 20 g daily) given for variable time periods [32], may contribute to the discordant results described in the literature [33].
Radiotherapy regimens
Radiotherapy is a worthwhile adjuvant therapy and should be considered in all patients under- going surgical resection, in consideration of the
Therapy of adrenocortical cancer
high rates of failure associated to surgery. It is also highly desirable in patients with locally ad- vanced stage, large tumors, or after metasta- sectomy. An international, prospective, random- ized study is needed to evaluate the benefit of radiotherapy to the treatment of unresectable disease [34].
In a preclinical study, Cerquetti et al. sought to evaluate the antineoplastic effects of radiother- apy and o,p’-DDD used alone or in combination on H295R and SW13 adrenocortical cancer cell lines [35]. These authors found a lasting growth arrest of 70% in H295R cells and of 55% in SW13 cells after radiation treatment. They con- cluded that radiotherapy in combination with o,p’-DDD has an important antiproliferative effect on adrenocortical human cell lines, char- acterized by cell cycle arrest in G2 with overex- pression of cyclin B1 and a high Cdc2 kinase activity in H295R cells [36].
In a recent paper, Sabolch et al. described the efficacy of radiotherapy in unresectable disease and identified potential associations of patient, tumor, and treatment characteristics with local recurrence and overall survival [37]. Their most important finding is that lack of radiotherapy adjuvant treatment presented a 4.7 fold higher risk of local failure than regimens which used radiotherapy. Importantly, they showed that pa- tients treated with mitotane obtained similar results either in the surgery group or surgery and radiotherapy group (25% and 20%, respec- tively), hence they found no mitotane effect in local relapse reduction.
Chemotherapy regimens
Up to date, the recommended first line treat- ment regimens in ACC are mitotane monother- apy, etoposide, doxorubicin, cisplatin plus mito- tane, or streptozotocin plus mitotane [10]. Fareau et al, evaluated the efficacy of the most commonly described systemic agents for ACC: 1) platinum/etoposide; 2) platinum/etoposide/ mitotane; 3) platinum/etoposide/other cytotoxic agents (adryamicin); 4) other miscellaneous cytotoxic agents (gemcitabine; paclitaxel; cis- platin/adryamicin/cyclophosphamide; cisplatin/ adryamicin/iphosphamide) [38]. They found no difference in overall survival between the treat- ment groups of mitotane/platinum/etoposide and platinum/etoposide without mitotane. How- ever, time to progression was observed to be
significantly better in patients treated with mito- tane. A single institution experience, the hetero- geneity of treatment groups and the low number of patients treated with certain agents and com- binations may represent an important bias in this work. Therapy employing mebendazole has been proved to be effective in a variety of can- cers, e.g. peritoneum, lung, liver, and bone, pro- ducing significant results. For this reason, Mar- tarelli et al. recently evaluated the role of me- bendazole on human adrenocortical carcinoma cells in vitro and after implantation in nude mice [39]. They found that mebendazole treat- ment significantly reduced invasion and migra- tion of cancer cells (in vitro), metastases forma- tion (in vivo) and cancer cells growth (both in vitro and in vivo). The therapeutic effects ob- tained on H295R and SW-13 human adrenocor- tical carcinoma cells were attributed to induc- tion of apoptosis. A recent phase II trial searched to test the activity of gemcitabine ad- ministered in association with continuous 5- fluoracil infusion or metronomic capecitabine, as a second/third line approach in advanced ACC patients [40]. The patients received a com- bination of i.v. gemtacibine (800 mg/m2, on days 1 and 8, every 21 days) and i.v. 5- fluorouracil protracted infusion (200 mg/ m2/ daily without interruption until progression) in the first six patients, or oral capecitabine (1500 mg/daily) in the subsequent patients. Mitotane administration was maintained in all cases. Re- sponse according to RECIST criteria was ob- served in 7.2% of cases and 46.4% obtained a clinical stabilization.
New targeted therapies
New avenues for ACC therapy have been opened by studies investigating the biological and molecular bases of this disease. Here, we present a short overview of recent advances in the field.
IGF-I receptor antagonists
The Insulin-like Growth Factor system involves IGF-I, IGF-II and their respective tyrosine kinase receptors (IGF-IR, IGF-IIR). The IGF2 gene, highly expressed in the human adrenal gland only dur- ing the fetal life, is located at 11p15 and its expression is regulated by a mechanism of pa- rental imprinting. Genetic mutations involving the 11p15 region can induce development of adrenocortical tumors as part of a spectrum of
Therapy of adrenocortical cancer
disease involving macroglossia, abdominal wall defects, hypoglycemia, organ enlargement, tu- mor predisposition and other symptoms (Beckwith-Wiedemann syndrome) [41]. The in- teraction between IGF-II and IGF-I receptor trig- gers several intracellular phosphorylation steps that activate mainly PI3K/Akt and MAPK path- ways involved in cell proliferation, differentia- tion, and survival [42]. IGF signalling is impli- cated not only in the development and differen- tiation of the normal adrenal gland but also in tumorigenic adrenocortical growth. Overexpres- sion of IGF-II and/or IGF-IR is possibly the most frequent genetic alteration in ACC and is associ- ated to malignancy in adult, but not childhood, adrenocortical tumors [43-48]. Based on re- ported data of IGF-IR inhibition as a new treat- ment target tool in multiple myeloma and hema- tologic malignancies, Garcia-Echeverria et al. introduced a highly selective IGF-IR antagonist (NVP-AEW541, a pyrrolo[2,3-d]pyrimidine deri- vate) as a drug endowed with powerful antitu- mor activity [49]. Consistently with the pivotal role of IGF-II in regulating adrenocortical tumor cell proliferation [50], NVP-AEW541 showed antiproliferative/proapoptotic effects and inhibi- tion of cell cycle progression, leading to specific G1 arrest, on both H295R and another cell line derived from a pediatric adrenocortical tumor [51]. Another study by Barlaskar et al. [52] iden- tified increased IGF signaling in a large panel of benign and malignant human adrenal tumors and tested inhibition of adrenocortical tumor cell proliferation by IGF-IR antagonists NVP- AEW541 and IMC-A12. Both drugs were evalu- ated both in vitro and in vivo. The authors estab- lished that IMCA12 attenuated phospho- AktSer473 expression in a dose-dependent man- ner, while NVP-AEW541 treatment produced no detectable levels of IGF-IR tyrosine phosphoryla- tion and phospho-AktSer473. Tumor growth meas- ured in athymic nude mice xenograft (H295R) was significantly reduced by treatment with IGF- IR antagonists. In parallel, the authors evalu- ated a synergic effect of mitotane plus IGF an- tagonists in culture and in xenografts. Statistical analysis indicated that, as a single therapy, IGF- IR antagonists were more potent than mitotane to reduce tumor growth. Furthermore, associa- tion of mitotane and IGF-IR antagonist produced significant synergy. In order to assess safety, tolerability, and pharmacokinetics of the anti- IGF-IR figitumumab (CP-751,871), a phase I study was conducted at three large referral cen- ters in metastatic, refractory patients with ad- vanced solid tumors [53, 54]. Patients received
figitumumab by intravenous infusion at a maxi- mal dose of 20 mg/kg every 21 days and serum glucose, insulin, and growth hormone were measured. Figitumumab toxicity was usually mild (hyperglycemia, nausea, fatigue and ano- rexia), but treatment increased serum insulin and growth hormone levels. Increase in insulin is explained by a compensatory secretion effect in most of the patients and showed that the insulin receptor (IR) is active in patients treated with figitumumab, even if IR and IGF-IR are highly homologous. Considering that all 14 pa- tients were at metastatic stage and 57% experi- enced stability of disease, it would be interest- ing to evaluate combination of this agent with mitotane and/or cytotoxic chemotherapy, since blocking of AKT activation by IGF-II stimulation of IGF-IR is known to improve the anti-tumor activity of cytotoxic chemotherapy.
ß-catenin antagonists
The ß-catenin gene (CTNNB1) is an important element of signal transduction in canonical Wnt signaling, which is involved in cell-cell adhesion, cell renewal, maintenance and commitment of progenitor cells in numerous tissues and cy- toskeleton dynamics regulation [55]. Wnt stimu- lation produces inactivation of GSK3-ß and sta- bilization of ß-catenin in the cytoplasm. B- catenin induces target gene expression by a sequence of events that includes ß-catenin nu- clear translocation after release from phos- phorylation by casein dependent kinase-1 and glycogen synthase kinase-3 and interaction with T-cell factor/lymphoid enhancer factor (TCF/ LEF) transcription factor. Deficiency in Wnt extra -cellular ligands leads to ß-catenin phosphoryla- tion on N-terminal serine/threonine residues, which is bound to a multi-protein scaffolding complex composed of Casein Kinase I (CKI), GSK3ß, AXIN and APC and is further degraded by the proteasome [56]. CTNNB1 mutation is a frequent event found in adrenocortical tumors, both benign and malignant, and may be associ- ated with a more aggressive phenotype in ACC [57-60]. The oncogenic role of ß-catenin in adre- nal tumorigenesis was investigated by Berthon et al. in a mouse model. In this work, Cre- mediated ß-catenin activation in the adrenal cortex was produced [61]. This caused marked adrenocortical zonation defects leading to pri- mary hyperaldosteronism and further malignant characteristics, coupled to uncontrolled neovas- cularization in aged mice. The authors con- cluded that activation of ß-catenin in the mouse
Therapy of adrenocortical cancer
cell number (% of control)
150
100
50
0
DOX
+
+
+
+
PKF115-584 (u.M)
0
0.1
0.5
1
adrenal cortex produces aldosterone-secreting tumors that can later become malignant. Since clinical data evidenced ß-catenin involvement in ACC pathogenesis, Doghman et al. evaluated the effect of PKF115-584, an inhibitor of TCF/ß -catenin complex formation, on proliferation of the human ACC cell line H295R, which harbors a constitutively active ß-catenin due to the CTNNB1 S45P mutation [62]. This compound not only inhibited cell proliferation but also over- ruled the effect of enhanced Steroidogenic Fac- tor-1 (SF-1) levels on H295R proliferation [63] (Figure 1). Complementarily, no effect was ob- served on HeLa cell proliferation, in which the ß- catenin pathway is not activated. PKF115-584 inhibited entry of H295R cells into S phase and induced their apoptosis. Although these results are promising, possible side effects of in vivo use of Wnt pathway inhibitors need to be taken into account for further evaluation of ß-catenin antagonists.
Steroidogenic factor 1 (SF-1) inverse agonists
Steroidogenic Factor-1 (SF-1/Ad4BP; NR5A1) is a nuclear receptor transcription factor that was primarily identified to act in the regulation of promoter activity of cytochrome P450 steroid hydroxylases genes in steroidogenic cell lines [64, 65]. Today it is known that SF-1 plays a decisive role on the regulation of adrenal and gonadal development and in the regulation of
steroidogenic enzymes expression [reviewed in 66, 67]. SF-1 amplification and overexpression is frequently found in pediatric ACC and is also found in adults, where it is correlated to more severe prognosis [68-71]. Studies performed in human adrenocortical cells and in a mouse model of Sf-1 overexpression demonstrated that an increased SF-1 dosage is a critical factor in triggering adrenocortical tumorigenesis [63]. For this reason, Doghman et al. investigated the effect of SF-1 inverse agonists, identified through high-throughput screening (HTS) cam- paigns [72, 73], on adrenocortical tumor cell proliferation [74]. SF-1 inverse agonists of the isoquinolinone class selectively downregulated H295R proliferation induced by an increased SF -1 dosage, while they had no effect on prolifera- tion of the SW-13 cell line, which does not ex- press SF-1. SF-1 inverse agonists also sup- pressed steroid hormone production by adreno- cortical tumor cells, which may be beneficial to reduce symptoms due to hormone excess in the clinical setting. While these results are encour- aging and SF-1 constitutes an appealing thera- peutic target because of its restricted expres- sion in steroidogenic tissues, further studies are required to assess the effects of SF-1 inverse agonists in in vivo models of adrenocortical tu- mors.
mTOR antagonists
Phosphatidylinositol 3-kinase (PI3K)/Akt/ mammalian target of rapamycin inhibitor (mTOR) deregulation is commonly associated to human cancer pathogenesis. Several new drugs have been developed to inhibit activation of PI3K/Akt signaling in cancer [75, 76]. Recently, IGF-IR/mTOR signaling was demonstrated to be activated in childhood ACT at multiple levels by the effect of reduced expression of miR-99a and miR-100 miRNAs in the tumors [77]. Dogh- man et al. showed that a specific mTOR inhibi- tor (RAD001; everolimus) potently suppresses adrenocortical tumor cell proliferation in vitro and when grown as xenografts in immunodefi- cient mice (Figure 2). These results reveal a novel important mechanism of IGF-IR/mTOR signaling regulation and suggest that mTOR antagonists can represent a new potential therapeutic approach in ACC.
Conclusion
Adrenocortical carcinoma is a deadly disease
Therapy of adrenocortical cancer
Tumor volume (mm3)
600-
- Placebo
500-
- RAD001
400-
300-
200-
**
100-
0
0
5
10
15
20
25
30
35
Days
with poor prognosis and lack of efficient treat- ment options. Poor therapeutic results led to the need of collaborative international trials with the intention to establish a common proto- col for treatment to produce more comparable results and improve the clinical outcome of pa- tients with ACC. Indeed, there is a common un- derstanding that the available drugs are not suited for a satisfactory treatment. Novel drugs have been recently developed based on the discovery of molecular pathways that trigger development and evolution of these tumors. An improved understanding of the molecular patho- genesis of ACC has conducted to the first phase III study of an IGF-I receptor antagonist. More efficient treatments are widely expected from these new targeted therapies as a hope of cure for patients affected with this aggressive malig- nancy.
Acknowledgements
D. M. is supported by a CAPES doctoral fellow- ship. Research in E.L. laboratory is supported by Institut National du Cancer , FP7 ENS@T CAN- CER and CNRS (LIA NEOGENEX).
Please address correspondence to: Dr. Enzo Lalli, Institut de Pharmacologie Moléculaire et Cellulaire, 660 route des Lucioles, 06560 Valbonne, France. Phone: +33 4 93 95 77 55; fax : +33 4 93 95 77 08; E-mail: ninino@ipmc.cnrs.fr
References
[1] Michalkiewicz E, Sandrini R, Figueiredo B, Miranda EC, Caran E, Oliveira-Filho AG, Marques R, Pianovski MA, Lacerda L, Cristofani LM, Jenkins J, Rodriguez-Galindo C, Ribeiro RC. Clinical and outcome characteristics of children with adrenocortical tumors. An analysis of 254 cases from the International Pediatric Adreno- cortical Tumor Registry. J Clin Oncol 2004; 22: 838-845.
[2] Pianovski MA, Maluf EM, de Carvalho DS, Ribeiro RC, Rodriguez-Galindo C, Boffetta P, Zancanella P, Figueiredo BC. Mortality rate of adrenocortical tumors in children under 15 years of age in Curitiba, Brazil. Pediatr Blood Cancer 2006; 47: 56-60.
[3] Wajchenberg BL, Albergaria Pereira MA, Medonca BB, Latronico AC, Campos Carneiro P, Alves VA, Zerbini MC, Liberman B, Carlos Gomes G, Kirschner MA. Adrenocortical carcinoma: clinical and laboratory observations. Cancer 2000; 88: 711-736.
[4] Bilimoria KY, Shen WT, Elaraj D, Bentrem DJ, Winchester DJ, Kebebew E, Sturgeon C. Adreno- cortical carcinoma in the United States: treat- ment utilization and prognostic factors. Cancer 2008; 113: 3130-3136.
[5] Icard P, Goudet P, Charpenay C, Andreassian B, Carnaille B, Chapuis Y, Cougard P, Henry JF, Proye C. Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World J Surg 2001; 25: 891-897.
[6] Fassnacht M, Allolio B. What is the best ap- proach to an apparently nonmetastatic adreno- cortical carcinoma? Clin Endocrinol 2010; 73: 561-565.
[7] Veytsman I, Nieman L, Fojo T. Management of endocrine manifestations and the use of mito- tane as a chemotherapeutic agent for adreno- cortical carcinoma. J Clin Oncol 2009; 27: 4619-4629.
[8] Berruti A, Fassnacht M, Baudin E, Hammer G, Haak H, Leboulleux S, Skogseid B, Allolio B, Terzolo M. Adjuvant therapy in patients with adrenocortical carcinoma: a position of an in- ternational panel. J Clin Oncol 2010; 28: e401- 402.
[9] Berruti A, Ferrero A, Sperone P, Daffara F, Rei- mondo G, Papotti M, Dogliotti L, Angeli A, Ter- zolo M. Emerging drugs for adrenocortical carci- noma. Expert Opin Emerg Drugs 2008; 13: 497 -509.
[10] Berruti A, Terzolo M, Sperone P, Pia A, Casa SD, Gross DJ, Carnaghi C, Casali P, Porpiglia F, Mantero F, Reimondo G, Angeli A, Dogliotti L. Etoposide, doxorubicin and cisplatin plus mito- tane in the treatment of advanced adrenocorti- cal carcinoma: a large prospective phase II trial. Endocr Relat Cancer 2005; 12: 657-666.
Therapy of adrenocortical cancer
[11] Miller BS, Ammori JB, Gauger PG, Broome JT, Hammer GD, Doherty GM. Laparoscopic resec- tion is inappropriate in patients with known or suspected adrenocortical carcinoma. World J Surg 2010; 34: 1380-1385.
[12] Gumbs AA, Gagner M. Laparoscopic adrenalec- tomy. Best Pract Res Clin Endocrinol Metab 2006; 20: 483-499.
[13] Brix D, Allolio B, Fenske W, Agha A, Dralle H, Jurowich C, Langer P, Mussack T, Nies C, Riedmiller H, Spahn M, Weismann D, Hahner S, Fassnacht M. Laparoscopic versus open adrenalectomy for adrenocortical carcinoma: surgical and oncologic outcome in 152 pa- tients. Eur Urol 2010; 58: 609-615.
[14] Porpiglia F, Fiori C, Daffara F, Zaggia B, Bollito E, Volante M, Berruti A, Terzolo M. Retrospec- tive evaluation of the outcome of open versus laparoscopic adrenalectomy for stage I and II adrenocortical cancer. Eur Urol 2010; 57: 873- 878.
[15] Leboulleux S, Deandreis D, Al Ghuzlan A, Au- perin A, Goere D, Dromain C, Elias D, Caillou B, Travagli JP, De Baere T, Lumbroso J, Young J, Schlumberger M, Baudin E. Adrenocortical car- cinoma: is the surgical approach a risk factor of peritoneal carcinomatosis? Eur J Endocrinol 2010; 162: 1147-1153.
[16] Gonzalez RJ, Tamm EP, Ng C, Phan AT, Vassi- lopoulou-Sellin R, Perrier ND, Evans DB, Lee JE. Response to mitotane predicts outcome in pa- tients with recurrent adrenal cortical carci- noma. Surgery 2007; 142: 867-875.
[17] Nelson AA, Woodard G. Adrenal cortical atrophy and liver damage produced in dogs by feeding 2,2-bis-(parachloro-phenyl)-1,1-dichloroethane. Fed Proc 1948; 7: 277.
[18] Bergenstal DM, Hertz R, Lipsett MB, Moy RH. Chemotherapy of adrenocortical cancer with o,p’-DDD. Ann Int Med 1960; 53: 672-682.
.9] Touitou Y, Bogdan A, Luton JP. Changes in corti- costeroid synthesis of the human adrenal cor- tex in vitro, induced by treatment with o,p’-DDD for Cushing’s syndrome: evidence for the sites of action of the drug. J Steroid Biochem 1978; 9: 1217-1224.
[20] Wandoloski M, Bussey KJ, Demeure MJ. Adrenocortical cancer. Surg Clin North Am 2009; 89: 1255-1267.
[21] Lacroix A. Approach to the patient with adreno- cortical carcinoma. J Clin Endocrinol Metab 2010; 95: 4812-4822.
[22] Heilmann P, Wagner P, Nawroth PP, Ziegler R. [Therapy of the adrenocortical carcinoma with Lysodren (o,p’-DDD). Therapeutic management by monitoring o,p’-DDD blood levels]. Med Klin 2001; 96: 371-377.
[23] Phan AT. Adrenal cortical carcinoma — review of current knowledge and treatment practices. Hematol Oncol Clin North Am 2007; 21: 489- 507.
[24] Terzolo M, Angeli A, Fassnacht M, Daffara F,
Tauchmanova L, Conton PA, Rossetto R, Buci L, Sperone P, Grossrubatscher E, Reimondo G, Bollito E, Papotti M, Saeger W, Hahner S, Koschker AC, Arvat E, Ambrosi B, Loli P, Lombardi G, Mannelli M, Bruzzi P, Mantero F, Allolio B, Dogliotti L, Berruti A. Adjuvant mito- tane treatment for adrenocortical carcinoma. N Engl J Med 2007; 356: 2372-2380.
[25] Kasperlik-Zaluska AA, Migdalska BM, Zgliczyn- ski S, Makowska AM. Adrenocortical carcinoma. A clinical study and treatment results of 52 patients. Cancer 1995; 75: 2587-2591.
[26] Schteingart DE. Adjuvant mitotane therapy of adrenal cancer - use and controversy. N Engl J Med 2007; 356: 2415-2418.
[27] Fassnacht M, Johanssen S, Fenske W, Weis- mann D, Agha A, Beuschlein F, Fuhrer D, Ju- rowich C, Quinkler M, Petersenn S, Spahn M, Hahner S, Allolio B. Improved survival in pa- tients with stage II adrenocortical carcinoma followed up prospectively by specialized cen- ters. J Clin Endocrinol Metab 2010; 95: 4925- 4932.
[28] Wangberg B, Khorram-Manesh A, Jansson S, Nilsson B, Nilsson O, Jakobsson CE, Lindstedt S, Oden A, Ahlman H. The long-term survival in adrenocortical carcinoma with active surgical management and use of monitored mitotane. Endocr Relat Cancer 2010; 17: 265-272.
[29] Vassilopoulou-Sellin R, Guinee VF, Klein MJ, Taylor SH, Hess KR, Schultz PN, Samaan NA. Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer 1993; 71: 3119-3123.
[30] Bertherat J, Coste J, Bertagna X. Adjuvant mito- tane in adrenocortical carcinoma. N Engl J Med 2007; 357: 1256-1257.
[31] Grubbs EG, Callender GG, Xing Y, Perrier ND, Evans DB, Phan AT, Lee JE. Recurrence of adre- nal cortical carcinoma following resection: sur- gery alone can achieve results equal to surgery plus mitotane. Ann Surg Oncol 2010; 17: 263- 270.
[32] Terzolo M, Berruti A. Adjunctive treatment of adrenocortical carcinoma. Curr Opin Endocrinol Diabetes Obes 2008; 15: 221-226.
[33] Allolio B, Fassnacht M. Clinical review: Adreno- cortical carcinoma: clinical update. J Clin Endo- crinol Metab 2006; 91: 2027-2037.
[34] Hermsen IG, Groenen YE, Dercksen MW, Theuws J, Haak HR. Response to radiation ther- apy in adrenocortical carcinoma. J Endocrinol Invest. 2010; Mar 10 [Epub ahead of print].
[35] Cerquetti L, Bucci B, Marchese R, Misiti S, De Paula U, Miceli R, Muleti A, Amendola D, Pier- grossi P, Brunetti E, Toscano V, Stigliano A. Mitotane increases the radiotherapy inhibitory effect and induces G2-arrest in combined treat- ment on both H295R and SW13 adrenocortical cell lines. Endocr Relat Cancer 2008; 15: 623- 634.
[36] Cerquetti L, Sampaoli C, Amendola D, Bucci B,
Therapy of adrenocortical cancer
Misiti S, Raza G, De Paula U, Marchese R, Bru- netti E, Toscano V, Stigliano A. Mitotane sensi- tizes adrenocortical cancer cells to ionizing radiations by involvement of the cyclin B1/CDK complex in G2 arrest and mismatch repair en- zymes modulation. Int J Oncol 2010; 37: 493- 501.
[37] Sabolch A, Feng M, Griffith K, Hammer G, Do- herty G and Ben-Josef E. Adjuvant and defini- tive radiotherapy for adrenocortical carcinoma. Int J Radiat Oncol Biol Phys 2010; [Epub ahead of print].
[38] Fareau GG, Lopez A, Stava C, Vassilopoulou- Sellin R. Systemic chemotherapy for adrenocor- tical carcinoma: comparative responses to con- ventional first-line therapies. Anticancer Drugs 2008; 19: 637-644.
[39] Martarelli D, Pompei P, Baldi C, Mazzoni G. Mebendazole inhibits growth of human adreno- cortical carcinoma cell lines implanted in nude mice. Cancer Chemother Pharmacol 2008; 61: 809-817.
[40] Sperone P, Ferrero A, Daffara F, Priola A, Zaggia B, Volante M, Santini D, Vincenzi B, Badala- menti G, Intrivici C, Del Buono S, De Francia S, Kalomirakis E, Ratti R, Angeli A, Dogliotti L, Papotti M, Terzolo M, Berruti A. Gemcitabine plus metronomic 5-fluorouracil or capecitabine as a second-/third-line chemotherapy in ad- vanced adrenocortical carcinoma: a multicenter phase II study. Endocr Relat Cancer 2010; 17: 445-453.
[41] Weksberg R, Smith AC, Squire J, Sadowski P. Beckwith-Wiedemann syndrome demonstrates a role for epigenetic control of normal development. Hum Mol Genet 2003; 12: R61- 68.
[42] Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 2008; 8: 915-928.
[43] Ilvesmaki V, Kahri AI, Miettinen PJ, Voutilainen R. Insulin-like growth factors (IGFs) and their receptors in adrenal tumors: high IGF-II expres- sion in functional adrenocortical carcinomas. J Clin Endocrinol Metab 1993; 77: 852-858.
[44] Gicquel C, Raffin-Sanson ML, Gaston V, Bertagna X, Plouin PF, Schlumberger M, Louvel A, Luton JP, Le Bouc Y. Structural and func- tional abnormalities at 11p15 are associated with the malignant phenotype in sporadic adrenocortical tumors: study on a series of 82 tumors. J Clin Endocrinol Metab 1997; 82: 2559-2565.
[45] Boulle N, Logie A, Gicquel C, Perin L, Le Bouc Y. Increased levels of insulin-like growth factor II (IGF-II) and IGF-binding protein-2 are associated with malignancy in sporadic adrenocortical tumors. J Clin Endocrinol Metab 1998; 83: 1713-1720.
[46] Gicquel C, Bertagna X, Gaston V, Coste J, Lou- vel A, Baudin E, Bertherat J, Chapuis Y, Duclos JM, Schlumberger M, Plouin PF, Luton JP, Le
Bouc Y. Molecular markers and long-term recur- rences in a large cohort of patients with spo- radic adrenocortical tumors. Cancer Res 2001; 61: 6762-6767.
[47] West AN, Neale GA, Pounds S, Figueredo BC, Rodriguez-Galindo C, Pianovski MA, Oliveira Filho AG, Malkin D, Lalli E, Ribeiro R, Zambetti GP. Gene expression profiling of childhood adrenocortical tumors. Cancer Res 2007; 67: 600-608.
[48] Rosati R, Cerrato F, Doghman M, Pianovski MA, Parise GA, Custodio G, Zambetti GP, Ribeiro RC, Riccio A, Figueiredo BC, Lalli E. High frequency of loss of heterozygosity at 11p15 and IGF2 overexpression are not related to clinical out- come in childhood adrenocortical tumors posi- tive for the R337H TP53 mutation. Cancer Genet Cytogenet 2008; 186: 19-24.
[49] Garcia-Echeverria C, Pearson MA, Marti A, Meyer T, Mestan J, Zimmermann J, Gao J, Brueggen J, Capraro HG, Cozens R, Evans DB, Fabbro D, Furet P, Porta DG, Liebetanz J, Mar- tiny-Baron G, Ruetz S, Hofmann F. In vivo anti- tumor activity of NVP-AEW541- A novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell 2004; 5: 231-239.
[50] Logié A, Boulle N, Gaston V, Perin L, Boudou P, Le Bouc Y, Gicquel C. Autocrine role of IGF-II in proliferation of human adrenocortical carcinoma NCI H295R cell line. J Mol Endocrinol 1999; 23: 23-32.
[51] Almeida MQ, Fragoso MC, Lotfi CF, Santos MG, Nishi MY, Costa MH, Lerario AM, Maciel CC, Mattos GE, Jorge AA, Mendonca BB, Latronico AC. Expression of insulin-like growth factor-II and its receptor in pediatric and adult adrenocortical tumors. J Clin Endocrinol Metab 2008; 93: 3524-3531.
[52] Barlaskar FM, Spalding AC, Heaton JH, Kuick R, Kim AC, Thomas DG, Giordano TJ, Ben-Josef E, Hammer GD. Preclinical targeting of the type I insulin-like growth factor receptor in adrenocor- tical carcinoma. J Clin Endocrinol Metab 2009; 94: 204-212.
[53] Karp DD, Paz-Ares LG, Novello S, Haluska P, Garland L, Cardenal F, Blakely LJ, Eisenberg PD, Langer CJ, Blumenschein G, Jr., Johnson FM, Green S, Gualberto A. Phase II study of the anti-insulin-like growth factor type 1 receptor antibody CP-751,871 in combination with pacli- taxel and carboplatin in previously untreated, locally advanced, or metastatic non-small-cell lung cancer. J Clin Oncol 2009; 27: 2516- 2522.
[54] Haluska P, Worden F, Olmos D, Yin D, Schtein- gart D, Batzel GN, Paccagnella ML, de Bono JS, Gualberto A, Hammer GD. Safety, tolerability, and pharmacokinetics of the anti-IGF-1R mono- clonal antibody figitumumab in patients with refractory adrenocortical carcinoma. Cancer Chemother Pharmacol 2010; 65: 765-773.
[55] Ivan Amerongen R, Nusse R. Towards an inte-
Therapy of adrenocortical cancer
grated view of Wnt signaling in development. Development 2009; 136: 3205-3214.
[56] El Wakil A, Lalli E. The Wnt/beta-catenin path- way in adrenocortical development and cancer. Mol Cell Endocrinol. 2010; Nov 19 [Epub ahead of print].
[57] Tissier F, Cavard C, Groussin L, Perlemoine K, Fumey G, Hagneré AM, René-Corail F, Jullian E, Gicquel C, Bertagna X, Vacher-Lavenu MC, Per- ret C, Bertherat J. Mutations of beta-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res 2005; 65: 7622-7627.
[58] Tadjine M, Lampron A, Ouadi L, Bourdeau I. Frequent mutations of beta-catenin gene in sporadic secreting adrenocortical adenomas. Clin. Endocrinol 2008; 68: 264-270.
[59] Gaujoux S, Tissier F, Groussin L, Libe R, Ragaz- zon B, Launay P, Audebourg A, Dousset B, Bertagna X, Bertherat J. Wnt/beta-catenin and 3’,5’-cyclic adenosine 5’-monophosphate/ protein kinase A signaling pathways alterations and somatic beta-catenin gene mutations in the progression of adrenocortical tumors. J Clin Endocrinol Metab 2008; 93: 4135-4140.
[60] Ragazzon B, Libé R, Gaujoux S, Assié G, Frat- ticci A, Launay P, Clauser E, Bertagna X, Tissier F, de Reyniès A, Bertherat J. Transcriptome analysis reveals that p53 and {beta}-catenin alterations occur in a group of aggressive adrenocortical cancers. Cancer Res 2010; 70: 8276-8281.
[61] Berthon A, Sahut-Barnola I, Lambert-Langlais S, de Joussineau C, Damon-Soubeyrand C, Louiset E, Taketo MM, Tissier F, Bertherat J, Lefrancois- Martinez AM, Martinez A, Val P. Constitutive beta-catenin activation induces adrenal hyper- plasia and promotes adrenal cancer develop- ment. Hum Mol Genet 2010; 19: 1561-1576.
[62] Doghman M, Cazareth J, Lalli E. The T cell fac- tor/beta-catenin antagonist PKF115-584 inhib- its proliferation of adrenocortical carcinoma cells. J Clin Endocrinol Metab 2008; 93: 3222- 3225.
[63] Doghman M, Karpova T, Rodrigues GA, Arhatte M, De Moura J, Cavalli LR, Virolle V, Barbry P, Zambetti GP, Figueiredo BC, Heckert LL, Lalli E. Increased Steroidogenic Factor-1 dosage trig- gers adrenocortical cell proliferation and can- cer. Mol Endocrinol 2007; 21: 2968-2987.
[64] Lala DS, Rice DA, Parker KL. Steroidogenic factor I, a key regulator of steroidogenic en- zyme expression, is the mouse homolog of fu- shi tarazu-factor I. Mol Endocrinol 1992; 6: 1249-1258.
[65] Morohashi K, Honda S, Inomata Y, Handa H, Omura T. A common trans-acting factor, Ad4- binding protein, to the promoters of steroido- genic P-450s. J Biol Chem 1992; 267: 17913- 17919.
[66] Schimmer BP, White PC. Minireview: Steroido-
genic Factor 1: its roles in differentiation, devel- opment, and disease. Mol Endocrinol. 2010; 24: 1322-1337.
[67] Lalli E. Adrenocortical development and cancer: focus on SF-1. J Mol Endocrinol 2010; 44: 301- 307.
[68] Figueiredo BC, Cavalli LR, Pianovski MA, Lalli E, Sandrini R, Ribeiro RC, Zambetti G, DeLacerda L, Rodrigues GA, Haddad BR. Amplification of the Steroidogenic Factor 1 gene in childhood adrenocortical tumours. J Clin Endocrinol Me- tab 2005; 90: 615-619.
[69] Pianovski MA, Cavalli LR, Figueiredo BC, Santos SC, Doghman M, Ribeiro RC, Oliveira AG, Michalkiewicz E, Rodrigues GA, Zambetti G, Haddad BR, Lalli E. 2006 SF-1 overexpression in childhood adrenocortical tumours. Eur J Can- cer 2006; 42: 1040-1043.
[70] Almeida MQ, Soares IC, Ribeiro TC, Fragoso MC, Marins LV, Wakamatsu A, Ressio RA, Nishi M, Jorge AA, Lerario AM, Alves VA, Mendonca BB, Latronico AC. Steroidogenic Factor 1 over- expression and gene amplification are more frequent in adrenocortical tumors from children than from adults. J Clin Endocrinol Metab 2010; 95: 1458-1462.
[71] Sbiera S, Schmull S, Assie G, Voelker HU, Kraus L, Beyer M, Ragazzon B, Beuschlein F, Willen- berg HS, Hahner S, Saeger W, Bertherat J, Allo- lio B, Fassnacht M. High diagnostic and prog- nostic value of Steroidogenic Factor-1 expres- sion in adrenal tumors. J Clin Endocrinol Metab 2010; 95: E161-E171.
[72] Del Tredici AL, Andersen CB, Currier EA, Ohr- mund SR, Fairbain LC, Lund BW, Nash N, Ols- son R, Piu F. Identification of the first synthetic steroidogenic factor 1 inverse agonists: phar- macological modulation of steroidogenic en- zymes. Mol Pharmacol 2008; 73: 900-908.
[73] Madoux F, Li X, Chase P, Zastrow G, Cameron MD, Conkright JJ, Griffin PR, Thacher S and Hodder P. Potent, selective and cell penetrant inhibitors of SF-1 by functional ultra-high- throughput screening. Mol Pharmacol 2008; 73: 1776-1784.
[74] Doghman M, Cazareth J, Douguet D, Madoux F, Hodder P and Lalli E. Inhibition of adrenocorti- cal carcinoma cell proliferation by steroidogenic factor-1 inverse agonists. J Clin Endocrinol Me- tab 2009; 94: 2178-2183.
[75] Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006; 7: 606-619.
[76] Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, Brachmann S, Chene P, De Pover A, Schoemaker K, Fabbro D, Gabriel D, Simonen M, Murphy L, Finan P, Sellers W, Gar- cia-Echeverria C. Identification and characteri- zation of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo
Therapy of adrenocortical cancer
antitumor activity. Mol Cancer Ther 2008; 7: 1851-1863.
[77] Doghman M, El Wakil A, Cardinaud B, Thomas E, Wang J, Zhao W, Peralta-Del Valle MH, Fi- gueiredo BC, Zambetti GP, Lalli E. Regulation of
insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors. Cancer Res 2010; 70: 4666-4675.