Cell PRESS
The next generation of therapies for adrenocortical cancers
Lawrence S. Kirschner
Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine; and Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA
Adrenocortical carcinoma (ACC) is a rare cancer for which few treatment options have been available. Cur- rently, the best available treatment involves combina- tion chemotherapy with the adrenolytic drug mitotane, although the response rate remains modest. Over the past 10 years there has been renewed interest in the field owing to the recognition that targeted therapies may provide new avenues for effective treatment of this deadly disease. Molecular analyses have revealed spe- cific signaling alterations in ACC, and advances in drug development have generated the tools to block these pathways. Although convincing evidence for the effec- tiveness of targeted therapies is not currently available, these studies are in progress and should shift the prog- nosis of this disease in the years to come.
Introduction
Adrenocortical carcinoma (ACC) is a disease with an inci- dence of approximately one patient per million [1], sug- gesting that many endocrinologists will see patients with this disease rarely, if ever. In common with many endo- crine cancers it has a very poor prognosis, with an overall 5-year survival rate around 35% [2]. The poor prognosis is attributable in part to the fact that many ACCs are not detected until they are at advanced stage [3]. However, the cancer behaves aggressively even in tumors detected early, such that cases felt to represent a cure at initial surgery may recur later with metastatic disease. Therapies for ACC have been limited by the ineffectiveness of most cytotoxic chemotherapy regimes, although the adrenolytic agent mitotane produces a response in approximately 25-30% of cases [4]. With the recent explosion of new data on tumor genetics and the renewed interest in targeted signaling pathways using kinase inhibitors, there is reason for guarded optimism regarding the future of ACC treat- ment. In this review I will discuss the current state of therapies, provide an update on ongoing and recently completely clinical trials, and discuss how therapy for ACC is likely to evolve over the next 5-10 years.
Adrenocortical cancer therapy: the past
The past 50 years has seen the development of chemother- apy regimens that have been beneficial for the treatment of cancer, including diseases such as breast, colon, and he- matologic malignancies. As with most endocrine cancers,
the response of ACC to classical cytotoxic chemotherapy regimens was poor [5]. Progress in the field was limited by the fact that ACC is rare, and no single institution could accrue enough patients to conduct large randomized trials. Further, the fact that the care of ACC patients is split among oncologists, endocrinologists, and surgeons pre- cluded the formation of larger cooperative groups, as seen in other cancers.
The mainstay of treatment of ACC has been aggressive surgical excision, such that patients without disseminated disease (stages I and II; Table 1) who are able to obtain a complete tumor removal have a much improved prognosis. There has previously been consensus in the surgical field
Glossary
Adjuvant chemotherapy: a pharmacological or immunological agent that is administered in the absence of known cancer but is presumed to act by treating residual microscopic disease.
Adrenolytic agent: an agent that acts by destroying adrenal cells.
EDP/M combination therapy: also called the ‘Berruti’ or ‘Italian’ regimen, this chemotherapy protocol for ACC combines the use of the anti-cancer chemotherapy drugs etoposide (a topoisomerase inhibitor), doxorubicin (an anthracycline) and cisplatin (a platinum-containing anti-cancer drug), with Mitotane.
FIRM-ACT trial: this is the first-ever large, randomized, controlled clinical trial for ACC, being run under the guidance of the International ACC Consortium. Its goal is to establish a baseline for effective chemotherapy for ACC and to serve as a model for future therapy trials.
Insulin-like growth factor (IGF): humans have two forms of IGF, known as IGF1 and IGF2, which both bind to and signal through the RTK known as the IGF1 receptor (IGF1R). IGF2 overexpression is the most common molecular alteration in ACC tumors.
Mitotane: also called o’,p’-isomer of dichlorodiphenyldichloroethane (o’,p’- DDD), it is an antineoplastic medication used in the treatment of adrenocortical carcinoma in patients with persistent disease despite surgical resection, and in those who have metastatic disease or patients who are not surgical candidates. Its role as adjuvant chemotherapy is currently under investigation.
OSI-906: a dual kinase inhibitor of both IGF1R and insulin receptor (IR) and a potential first-in-class selective small molecule, OSI-906 is currently in a Phase III clinical trial in ACC and in a Phase I/II clinical trial in ovarian cancer.
Platinum-based therapy: a therapy that refers to a specific class of cytotoxic chemotherapy drugs that are derived from the element platinum.
Pharmacogenomics: the use of genetic data, either by analysis of tumor DNA or mRNA expression patterns, to select the choice of therapy
Receptor tyrosine kinases (RTKs): high-affinity cell-surface receptors for many polypeptide growth factors, cytokines, and hormones. In normal cells, RTKs typically stimulate cell growth and migration. In cancer cells, RTKs are often dysregulated, leading to abnormal signaling which drives the development and progression of many types of cancer.
Sz/M therapy: this chemotherapy protocol for ACC that combines the use of streptozocin, a chemotherapy agent, with mitotane.
Targeted therapies: drug therapies specifically chosen for a particular tumor based on the presence of a specific gene mutation or pattern of mRNA expression.
Tyrosine kinase inhibitors (TKIs): typically used as anti-cancer drug. TKIs inhibit tyrosine kinases, enzymes that activate signal transduction cascades by phosphorylating proteins on tyrosine residues.
Keywords: adrenocortical carcinoma; cytotoxic chemotherapy; targeted chemotherapy; tyrosine kinase inhibitors.
| Tumor | Nodes | Metastases | Ref. | |
|---|---|---|---|---|
| American | Joint Committee on Cancer (AJCC) | [97] | ||
| Stage I | T1 (<5 cm) | Absent | Absent | |
| Stage II | T2 (>5 cm) | Absent | Absent | |
| Stage III | T1 or T2 | Present | Absent | |
| or | ||||
| T3 (invading local capsule) | Absent | Absent | ||
| Stage IV | T3 or | Present | Absent | |
| T4 (invading local organs) | Any | Absent | ||
| or | ||||
| Any | Any | Present | ||
| European | Network for the Study of Adrenal | Tumours (ENSAT) | [98] | |
| Stage I | T1 | Absent | Absent | |
| Stage II | T2 | Absent | Absent | |
| Stage III | T3 or T4 | Absent | Absent | |
| or | ||||
| Any | Present | Absent | ||
| Stage IV | Any | Any | Present | |
aRecent studies [99] suggest that the ENSAT classification may provide superior prognostic information, although both systems are currently in use.
that open adrenalectomy is optimal when ACC is suspected to minimize the chance of tumor spillage during the proce- dure [6]. Recently, some authors have challenged this concept and there is active debate among surgeons regard- ing the need for open adrenalectomy [7]. However, until the data are clearer, it remains the opinion of this author that open surgery is to be preferred for ACC. Although meta- static disease may appear late after initial removal, patients who remain disease-free for 5 years have a low likelihood of recurrence. In patients with localized meta- static disease there remains a clear benefit of aggressive surgery, provided that operation with curative intent is possible. Once widespread dissemination has occurred, cure is no longer possible. In these cases, the 2-year survival rate of patients left untreated is between 5-10% [2].
Toxicity studies on the pesticide DDT (dichlorodiphe- nyltrichloroethane) performed in the 1940s and 1950s demonstrated an adrenolytic effect of the drug which was eventually ascribed to the ortho’,para’-isomer of dichlorodiphenyldichloroethane (o’,p’-DDD, or mitotane). The observed effects were both anti-steroidogenic and adrenolytic. Mitotane was proposed as a treatment for ACC; numerous trials demonstrated a moderate effect and partial responses (or the rare complete response) were observed in 25-30% of patients [4]. Although mitotane may cause significant toxicity (primarily gastrointestinal and neurologic) it has better efficacy and reduced toxicity in many patients compared to cytotoxic agents.
Thus, up until about the turn of the millennium, the recommended therapy for a patient with ACC was surgery. Patients with metastatic disease could be treated with mitotane with limited expectations, with a variety of cyto- toxic agents for which there was no compelling evidence, or with palliative measures.
Adrenocortical cancer therapy: the present
Formation of the International ACC Working Group In 1998 Berruti and colleagues in Italy described the use of chemotherapy with etoposide, doxorubicin, and cisplatin
together with mitotane (EDP/M, the so-called ‘Berruti’ or ‘Italian’ regimen) [8]. With this combination of agents, 46% of patients achieved a partial response (PR), and 2/28 patients (7.1%) achieved a complete response (CR); these results were confirmed in a follow-up study on 72 patients, including 28 from the original study [9]. Around the same time, Khan and coworkers in Sweden reported the use of streptozocin with mitotane (Sz/M) for patients with ad- vanced disease [10]. In 22 patients with measurable dis- ease, a response was seen in 36.4% of cases (PR + CR), although the regimen also had an effect in prolonging the disease-free interval when administered in an adjuvant setting (see Glossary).
Although individual labs and groups (e.g. national reg- istries) remained the major drivers of new therapeutic regimens, the statistical study of a rare disease such as ACC required the collaboration of a large number of inter- ested investigators. The nucleation of a working group for ACC occurred in 2003, in Ann Arbor, Michigan. The inter- national group assembled for that conference produced not only a consensus document for the treatment of ACC, but also a blueprint aimed at moving the field forward [6] (Figure 1). At that meeting it was decided that the next step in the field was the establishment of a ‘baseline’ standard of chemotherapy against which all future trials could be compared. The resulting study, named FIRM-ACT (First international randomized trial in locally advanced and metastatic adrenocortical carcinoma treatment), sought to compare EDP/M versus Sz/M as initial therapy for patients presenting with stage III or IV ACC (Table 1). This trial of unprecedented size (150 patients per treat- ment arm) has been completed, and the study is likely to be published in early 2012. From preliminary results released as of this writing, it appears that EDP/M may be superior in terms of progression-free survival of the patients [11] (Box 1). The study was complicated by the crossover trial design such that about 60% of patients received both therapies, making alterations in overall survival difficult to assess. Although the trial data will be valuable, perhaps
Box 1. Current treatment recommendations for ACC
1. Aggressive surgical intervention aimed at curative resection
. For clinically or histologically aggressive tumors: consider mitotaneª and/or XRT.
2. Patients not amenable to curative surgery should receive EDP/M chemotherapy: administer intravenously every four weeks:
· Etoposide 100 mg/m2 on days 2-4
· Doxorubicin 40 mg/m2 on day 1
· Cisplatin 40 mg/m2 on days 3-4
with continuous oral Mitotane titrated to a serum level of 14-20 µg/ mlª.
3. Patients should be strongly encouraged to participate in clinical trials for ACC. Trials may be available at all treatment stages. Information can be found at www.ClinicalTrials.gov.
a In most patients, 3-4 g/day split into twice daily dosing will achieve these levels, although some patients may require higher dosing. Mitotane should be started at low dosage (e.g. 0.5 g twice daily) and titrated weekly to reach appro- priate dosing [12].
Present
·FIRM-ACT
·Microarray analyses
·Adjuvant mitotane
Future
·New targeted agents
.Combination therapy
Past
.Molecularly-directed therapy
·Mitotane
·Cytotoxics (limited success)
FIRM-ACT
2010
2000
1990
1980
Formation of the Int’l ACC Working Group (2003)
FIRM-ACT results (2012)
1970
GALACCTIC results (?2012)
TRENDS in Endocrinology & Metabolism
even more significant is the establishment of an appropri- ate infrastructure which will enable future trials to move forward.
Indication of the benefit of adjuvant mitotane
Development of a reliable assay for serum mitotane en- abled the definition of an optimal therapeutic range for this agent at 14-20 µg/ml [12]. Although mitotane has been shown to be beneficial in a subset of ACC patients with residual tumor, its role in patients in the adjuvant setting (i.e. after complete resection of all known tumor) has been less clear. To address this issue Terzolo and colleagues retrospectively studied both the Italian and German experiences with the drug, totaling 177 patients. Their analysis demonstrated a clear prolongation of recur- rence-free survival in patients treated with adjuvant mito- tane [13]. Although the retrospective nature of the study raised some question about the findings, most experts agree that adjuvant mitotane is a therapy that should be considered in most patients with clinically or histologi- cally aggressive tumors, even after complete resection [14- 16]. The ADIUVO trial (NCT00777244) is a prospective randomized trial of adjuvant mitotane that should provide a definitive answer to the role of mitotane in this setting.
Re-emergence of local therapies
Although early data suggested that ACC was not responsive to radiation therapy (XRT), clinical experience has demon- strated that this treatment modality can be effective in treating local recurrences, particularly those in the bone [17,18]. Interest in XRT therapy for ACC drove the initiation of a pilot study of adjuvant XRT application to the tumor bed in patients with aggressive ACC. Both a pilot study [19] and a subsequent larger case series [18] demonstrated a reduc- tion in loco-regional recurrence but no effect on overall survival. Thus, although the value of prophylactic XRT
remains uncertain, it clearly has a role in selected patients [15].
In addition to regional treatment with XRT, isolated metastases in areas accessible to percutaneous therapy can be treated effectively with radiofrequency ablation (RFA) [20,21] or laser ablation [22]. Although neither of these modalities is expected to be curative, they can pro- vide symptomatic relief, particularly where hormone over- secretion is problematic.
Adrenocortical cancer therapy: the future Initiation of molecular analysis of ACC
Another significant development of the past 10 years has been the advent of platform technologies. Although over- expression of insulin-like growth factor 2 (IGF2) in ACC had been known since the mid-1990s from the work of Gicquel, Le Bouc, and colleagues [23], the use of high- throughput techniques has allowed substantial refinement of this information. Adrenocortical tumor mRNA expres- sion-profiling was first carried out by Giordano et al. in 2003 [24], and has been followed by similar studies from other groups [25-30]. These studies have begun to pave the way for future therapy of adrenocortical cancer, including not only the identification of altered gene expression but also newer approaches which include analysis of micro- RNA and integrated high-throughput approaches to the identification of new markers of malignancy and aberrant signaling pathways which are potential therapeutic tar- gets [31-33].
Receptor tyrosine kinases (RTKs)
IGF1R-targeted therapies. As described above, it has been known for many years that IGF2 overexpression is the most common molecular event in ACC. IGF2 signals through the IGF1 receptor (IGF1R), an RTK with similari- ty to the insulin receptor (IR). When IGF1R is activated it
initiates a downstream signaling cascade that helps drive proliferation, migration, and metastasis of ACC (and other cancers) [34]. The IGF2/IGF1R system can be targeted in numerous ways. Small-molecule tyrosine kinase inhibitors (TKIs) of the IGF1R have been developed, and a clinical trial of one such agent, OSI-906, has recently been com- pleted. Results from this study, termed GALACCTIC (NCT00924989), have not been released yet, but are also expected in 2012. Other similar agents have been devel- oped and are in early-phase clinical trials, although none directed towards ACC patients.
Another method by which the IGF1R can be blocked is through the use of antibodies which bind to the receptor and prevent signal transduction. IGF1R antibodies include cixutumumab (IMC-A12) and figitumumab (CP-751,871), both of which have shown activity in vitro and in Phase I clinical trials [35,36]. A clinical trial of cixutumumab has been initiated in ACC (NCT00778817), but due to stringent enrollment criteria has had difficulty in enrolling subjects.
Theoretically, there are other modalities that could be used to target the IGF2-IGF1R system, including the use of neutralizing antibodies against IGF2 and the introduction of IGF-binding proteins which function to sequester active signaling molecules [34].
EGFR-targeted therapies. The epithelial growth factor (EGF) receptor (also known as ERBB1) is an RTK whose extracellular domain binds and transduces the signal from EGF. There are three closely related family members, ERBB2, -3, and -4. Signaling through EGFR family RTKs occurs by ligand binding and induction of receptor dimer- ization. Partnerships among ERBB family members are not isoform-specific, such that all combinations of homo- and heterodimers are possible [37]. The EGFR is expressed in >75% of ACC tumors, although levels are not markedly increased when compared to normal adrenal tissue [38-40]. EGF is rarely expressed in tumors, but there is evidence to suggest that ERBB receptors are bound by other growth factors present in the tumors, such as the highly expressed transforming growth factor & (TGFa) [39]. Targeting ERBB signaling was one of the first molecular strategies, exempli- fied by the development of the humanized antibody trastu- zumab for breast cancer patients. Patients that overexpress ERBB2 (also termed HER2 or Neu) benefit from signaling blockade through a mechanism that is still somewhat un- clear [41]. The same pathway is targeted by the EGFR- specific TKI gefitinib and by lapatinib which blocks both EGFR/ERBB1 and ERBB2 [41]. The EGFR has also been targeted using humanized monoclonal antibodies (cetuxi- mab) which have been shown to be useful in the treatment of colon cancer and head and neck cancers [42].
Because of interest in inhibiting this pathway in ACC, a small clinical trial was undertaken to assess the effective- ness of gefitinib as a single agent in ACC. No significant responses were observed in a Phase II cohort of 19 patients [43]. A similar small trial of erlotinib + gemcitabine as salvage therapy for ACC also produced minimal (if any) benefit [44]. In retrospect, the failure of gefitinib as a single agent is not surprising given its lack of targeting other ERBB family members. Newer agents that target multiple receptors or inhibit receptor heterodimerization may prove to be more effective [37].
Fibroblast growth factor receptor (FGFR)-targeted ther- apies. Although the IGF2-IGF1R system represents the most consistently overexpressed RTK, analysis of the microarray data has shown that members of the (FGFR) family are also frequently elevated in ACC [24,25,27,45]. As with EGFR, there are four FGFR family members designated FGFR1-4 [46]. Elevated FGFR1 and/or FGFR4 have been observed in ACC, and one study indicated a correlation between FGFR1 expression and malignant potential [27]. Unlike the EGFR/ERBB receptors, drug development aimed at the FGFR has proceeded very slow- ly. This is beginning to change with the recognition that FGFR activation is common in multiple myeloma and other cancers, including renal, hepatocellular, and endo- metrial cancers. Agents targeting the FGFRs to date in- clude tyrosine kinase inhibitors (dovitinib, BGJ398) as well as an FGF-binding peptide (FP-1039) designed to block ligand availability. Dovitinib, which also inhibits other RTKs including the PDGFR and VEGFRs, has shown preclinical activity in a variety of models [47,48] as well as in early-stage clinical trials for melanoma [49] and myeloma [48]. BGJ398 appears to have much better spec- ificity for the FGFRs compared to dovitinib. It was effective in a preclinical xenograft model, but human studies are still pending [50]. Preclinical models have also supported the efficacy of FP-1039 [51], and a Phase I trial demon- strated reasonable tolerability and suggested some anti- tumor activity in advanced tumors [52]. A Phase II trial of this agent in endometrial cancers with known mutations in FGFR2 is underway (NCT01244438).
Vascular-endothelial growth factor (VEGF) receptor- targeted therapies. Since the pioneering work of Folkman and colleagues [53], it has been recognized that tumors are critically dependent on an adequate blood supply, and that targeting blood vessels may provide valuable therapeutic benefit. Blood vessel formation is promoted by the VEGFs and their receptors, VEGFR1-3. Inhibition of VEGFR signaling by the monoclonal antibody bevacizumab has modest activity against a number of cancers, including colon, breast, and lung. TKIs directed against the VEGFRs tend to block multiple RTKs, as is the case with the inhibitors sunitinib and sorafenib. In the adrenal field, a trial of bevacizumab in combination with capecitabine did not show any responses in a pilot study of this combination as a salvage therapy for ACC [54]. Similarly, a small trial of sunitinib as a salvage therapy for ACC did not show benefit [55]. This latter trial may have been confounded by en- hanced drug metabolism induced by concomitant mitotane therapy because the compound has been shown to be a strong inducer of CYP3A4 [56]. A case report of one patient described a durable response induced by sorafenib [57], but a prospective trial of sorafenib in combination with metro- nomic paclitaxel was stopped early due to lack of benefit [58]. Because anti-angiogenic therapy has in general been clinically disappointing, there has not been significant excitement to pursue this therapeutic strategy in isolation.
Mammalian target of rapamycin (mTOR)-targeted therapy
mTOR is a downstream signaling node for a variety RTKs (including IGF1R), and it has emerged as a therapeutic
target in many cancers [59-62]. Studies of ACC cell lines in vitro have demonstrated that agents that target this path- way (e.g. temsirolimus) reduce cell growth [63,64]. Howev- er, inhibition of mTOR alone leads to rebound activation of other tumorigenic pathways [59]. Thus, trials of single agents targeted to mTOR have been disappointing and have not been undertaken in ACC [60-62]. However, there may be value in targeting mTOR as part of combination therapy, as discussed below.
Wnt/B-catenin targeted therapies
Although the Wnt/B-catenin pathway was initially de- scribed as a developmental pathway, the connection to cancer was appreciated early in humans with the discovery that familial adenomatosis polyposis (FAP, or adenoma- tosis polyposis coli, APC) was caused by mutation of one of the key regulators of this pathway. Since that time, muta- tions in APC and CTNNB1 (encoding ß-catenin) have been detected in many types of cancer [65]. Knockout mouse studies have demonstrated that ß-catenin is required for normal adrenal gland formation and maintenance [66]; conversely, both benign and malignant adrenal tumors demonstrate activation of this signaling pathway [67- 69]. Interestingly, a reassessment of microarray expres- sion data has identified a subset of tumors with Wnt pathway mutations that appear to behave differently from other subclasses of tumors [29]. More work is needed to understand this phenomenon.
Based on the importance of the Wnt/B-catenin in a wide variety of tumors, there has been significant interest in developing Wnt inhibitors as anti-neoplastic agents [70]. CWP232291 is a small molecule discovered during a drug screen for agents that inhibit Wnt signaling. This agent has shown activity against multiple myeloma cells in preclinical models, both in vitro and in vivo, by promoting degradation of ß-catenin [71]. It is currently in a Phase I trial for refractory acute myeloid leukemia (AML) [NCT01398462], although no results have yet been de- scribed. Proof of concept of the utility of this approach in ACC comes from a study using a small-molecule inhibitor which blocks B-catenin interaction with the TCF transcrip- tion factors; this analysis demonstrated that the compound (PKF115-584) was able to inhibit the proliferation the H295R ACC cell line in vitro [72]. Because Wnt signaling is a ubiquitous signaling pathway, clinical use of agents targeting must proceed with caution in view of concerns about significant toxicity [73].
Phamacogenomics and selection of chemotherapy agents
In addition to identifying potentially druggable targets for therapy, molecular analysis may play a role in identifying the most appropriate therapies for cancer patients, an approach known as ‘pharmacogenomics’ [74], For ACC there may be some applicability in the analysis of the DNA repair gene ERCC1 (excision repair cross comple- mentation group 1). High levels of this protein appear to be associated with a poorer response to platinum-based ther- apies [75], suggesting that alternative therapies may be more appropriate. A newer analysis suggests that analysis of topoisomerase 2A and multidrug resistance 1 gene levels
may help to identify patients with high susceptibility to anthracyclines [76], although this has not yet been dem- onstrated clinically. As this approach matures, further data may aid the identification of targeted cytotoxic thera- pies.
Other emerging therapies
Peroxisome proliferator-activated receptor y (PPARy) is a nuclear transcription factor which mediates the anti-dia- betic effect of the thiazolidinedione (TZD) class of drugs. Studies in a variety of cell types have suggested that TZDs have anti-proliferative effects [77], and these effects have been demonstrated in ACC cell lines in vitro [78-81] and in a xenograft model [82]. PPARy is expressed in ACC tumors, although levels are similar to those in normal adrenals and benign tumors [78,81]. Although the TZDs rosiglitazone and pioglitazone induce a modest reduction in cell proliferation, detailed analysis has suggested that anti-proliferative effects are PPARy-independent [78,79], echoing older studies of another TZD, troglitazone [83]. Thus, although TZDs may have anti-proliferative effects, their prospects as chemotherapeutics remain uncertain until their mechanism of action is better understood.
SF1 (AD4BP) is a transcription factor essential for the development of the adrenal glands and gonads [84]. Muta- tion of the gene in humans causes adrenal insufficiency and a variety of gonad-related phenotypes, including XY sex reversal, premature ovarian failure, and spermatogenic failure. SF1 (formally known as NR5A1) is highly expressed in steroidogenic adrenal tumors, and at least one study has suggested that expression levels may hold independent prognostic value for ACC [85]. Clinical pros- pects for targeting this protein are unknown at present, but in vitro studies with SF1 inverse agonists demonstrat- ed that the drugs were able to inhibit the growth of ACC cell lines that overexpress the protein, whereas those with low levels (or none) were unaffected [86].
Metomidate is an analog of the anesthetic etomidate, and biochemical studies have demonstrated that the agent is concentrated within adrenocortical tissue. Labeling of metomidate with radioiodine (123I) has enabled the pro- duction of positron emission tomography (PET) and single- photon emission computed tomography (SPECT) tracers suitable for imaging adrenocortical tissue [87,88]. Replace- ment of 123I with 131I was proposed as a means to generate a therapeutic radiopharmaceutical, and pilot studies have confirmed the potential of this agent to treat ACC [89]. More experience is necessary to understand the place of this compound in the therapeutic arsenal.
Combination therapy
Although the initial development of new therapies has typically been carried out using single-agent trials, past experience indicates that combination therapy is likely to provide additional benefit. This synergy may be realized by simultaneously blocking multiple pathways required for tumor growth/survival, or it may occur by the prevention of resistance to single pathway agents [90].
One of the best documented examples of receptor co- signaling involves EGFR and IGF1R [91]. It is well docu- mented that tumors treated with EGFR inhibitors develop
enhanced IGF1R signaling, and this significantly contrib- utes to resistance to anti-EGFR therapies [92]. Conversely, treating cells with TKIs or antibodies targeted to IGF1R signaling leads to upregulation of the EGFR pathway [93]. Based on these observations, studies performed to target both pathways simultaneously have demonstrated thera- peutic cooperatively for both antibody- and small-molecule based therapy, both in vitro using cell lines [91] and in a mouse model for intestinal tumorigenesis [94].
A clinical trial of the IGF1R-targeting OSI-906 and the EGFR-targeting Erlotinib is already underway. Phase I studies have shown moderate but manageable toxicity of the combination, and an expansion cohort using non-small- cell lung cancer patients is planned along with a Phase II effort (NCT01221077). This study indicates the feasibility of combination therapy, and should lead to new trials in this area. Another combination that may be worthy of consideration is joint IGF1R/FGFR blockade. An agent (XL228) that targets both receptors (together with others) had been in Phase I trials, although these have since been discontinued. Targeting both pathways individually has not yet been attempted.
As mentioned above, there has been significant interest in the development of inhibitors of the mTOR pathway because it plays a central role in cellular metabolism [62]. A recent Phase I trial described the use of the IGF1R antibody cixitumumab with temsirolimus in 24 patients with heavily treated advanced cancers, including 10 with ACC [95]. Although no complete or partial responses were observed, four of the 10 exhibited stable disease lasting >8 months, suggesting further studies are worth pursuing in ACC.
Concluding remarks
Although the prognosis for patients with ACC remains guarded, data from the past 10 years have begun to show signs of progress. There is a much improved vision of the signaling pathways that drive ACC, and this is now being matched by new therapeutics that might inhibit these pathways.
In the setting of this optimism, there are important questions which remain and should continue to drive research into ACC (Box 2). First, newer technologies have enabled the identification of serum and tissue biomarkers, but markers which can predict disease and define the extent of disease need to be identified for ACC. Second, with the success of the FIRM-ACT trial and establishment
Box 2. Outstanding questions for the future of ACC
· What are the biomarkers that identify residual tumor?
· What are the biomarkers that predict aggressive versus non- aggressive disease?
· What are the most effective targeted therapies for ACC?
· What is the most appropriate combination therapy for ACC patients? o Is the combination of cytotoxic and targeted therapies more effective than multiple targeted agents?
o What is the role of mitotane in patients receiving cytotoxic or targeted therapies?
· How can genetic/genomic data be utilized to select most effective therapies for ACC (pharmacogenomics)? Can effective second- and third-line therapies for ACC be defined?
of the appropriate infrastructure for future clinical trials, the international ACC community will need to identify the next set of clinical trials that will move therapy forward for patients with advanced disease. Finally, the role of mito- tane needs further refinement, as is planned in the ADIUVO trial. The design of future trials will need to bear in mind that mitotane is a CYP3A4 inducer, and thus may affect the metabolism of other drugs, particularly small- molecule TKIs [96].
All in all, although we have better tools to treat patients with ACC, it remains vitally important that these rare patients are referred to centers conducting clinical trials such that the ideas presented both in this paper and in other reviews can be tested, and that revisiting this topic in 10 years can present the therapy of today in the past tense, and the more effective therapies of tomorrow can lead to a better future.
Note added in proof
The FIRM-ACT study was published online in the New England Journal of Medicine on May 2, 2012. As noted in the text, EDP/M was found to be superior to Sz/M, with response rates of 23.2% and 9.2% respectively. Treatment recommendations remain as described in Box 1.
References
1 Golden, S.H. et al. (2009) Clinical review: prevalence and incidence of endocrine and metabolic disorders in the United States: a comprehensive review. J. Clin. Endocrinol. Metab. 94, 1853-1878
2 Crucitti, F. et al. (1996) The Italian Registry for Adrenal Cortical Carcinoma: analysis of a multiinstitutional series of 129 patients. The ACC Italian Registry Study Group. Surgery 119, 161-170
3 Ng, L. and Libertino, J.M. (2003) Adrenocortical carcinoma: diagnosis, evaluation and treatment. J. Urol. 169, 5-11
4 Hahner, S. and Fassnacht, M. (2005) Mitotane for adrenocortical carcinoma treatment. Curr. Opin. Investig. Drugs 6, 386-394
5 Sullivan, M. et al. (1978) Adrenal cortical carcinoma. J. Urol. 120, 660-665
6 Schteingart, D.E. et al. (2005) Management of patients with adrenal cancer: recommendations of an international consensus conference. Endocr. Relat. Cancer 12, 667-680
7 Porpiglia, F. et al. (2011) A debate on laparoscopic versus open adrenalectomy for adrenocortical carcinoma. Horm. Cancer 2, 372-377
8 Berruti, A. et al. (1998) Mitotane associated with etoposide, doxorubicin, and cisplatin in the treatment of advanced adrenocortical carcinoma. Italian Group for the Study of Adrenal Cancer. Cancer 83, 2194-2200
9 Berruti, A. et al. (2005) Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr. Relat. Cancer 12, 657-666
10 Khan, T.S. et al. (2000) Streptozocin and o,p’DDD in the treatment of adrenocortical cancer patients: long-term survival in its adjuvant use. Ann. Oncol. 11, 1281-1287
11 Fassnacht, M. et al. (2011) Etoposide, doxorubicin, cisplatin, and mitotane vs. streptozotocin and mitotane in adrenocortical carcinoma - (preliminary) results of the FIRM-ACT trial. Endocr. Rev. 32, P1-619
12 Terzolo, M. et al. (2000) Low-dose monitored mitotane treatment achieves the therapeutic range with manageable side effects in patients with adrenocortical cancer. J. Clin. Endocrinol. Metab. 85, 2234-2238
13 Terzolo, M. et al. (2007) Adjuvant mitotane treatment for adrenocortical carcinoma. N. Engl. J. Med. 356, 2372-2380
14 Balasubramaniam, S. and Fojo, T. (2010) Practical considerations in the evaluation and management of adrenocortical cancer. Semin. Oncol. 37, 619-626
15 Fassnacht, M. et al. (2011) Adrenocortical carcinoma: a clinician’s update. Nat. Rev. Endocrinol. 7, 323-335
Review
16 Lacroix, A. (2010) Approach to the patient with adrenocortical carcinoma. J. Clin. Endocrinol. Metab. 95, 4812-4822
17 Polat, B. et al. (2009) Radiotherapy in adrenocortical carcinoma. Cancer 115, 2816-2823
18 Sabolch, A. et al. (2011) Adjuvant and definitive radiotherapy for adrenocortical carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 80, 1477-1484
19 Fassnacht, M. et al. (2006) Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma. J. Clin. Endocrinol. Metab. 91, 4501-4504
20 Ripley, R.T. et al. (2011) Liver resection and ablation for metastatic adrenocortical carcinoma. Ann. Surg. Oncol. 18, 1972-1979
21 Del Pizzo, J.J. (2006) Radiofrequency ablation for adrenal lesions. Curr. Urol. Rep. 7, 68
22 Pacella, C.M. et al. (2008) Percutaneous laser ablation of unresectable primary and metastatic adrenocortical carcinoma. Eur. J. Radiol. 66, 88-94
23 Gicquel, C. et al. (1994) Rearrangements at the 11p15 locus and overexpression of insulin-like growth factor-II gene in sporadic adrenocortical tumors. J. Clin. Endocrinol. Metab. 78, 1444-1453
24 Giordano, T.J. et al. (2003) Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. Am. J. Pathol. 162, 521-531
25 de Fraipont, F. et al. (2005) Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic acid microarrays identifies several candidate genes as markers of malignancy. J. Clin. Endocrinol. Metab. 90, 1819-1829
26 Velazquez-Fernandez, D. et al. (2005) Expression profiling of adrenocortical neoplasms suggests a molecular signature of malignancy. Surgery 138, 1087-1094
27 Slater, E.P. et al. (2006) Analysis by cDNA microarrays of gene expression patterns of human adrenocortical tumors. Eur. J. Endocrinol. 154, 587-598
28 de Reynies, A. et al. (2009) Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival. J. Clin. Oncol. 27, 1108-1115
29 Gaujoux, S. et al. (2011) Beta-catenin activation is associated with specific clinical and pathologic characteristics and a poor outcome in adrenocortical carcinoma. Clin. Cancer Res. 17, 328-336
30 Durand, J. et al. (2011) Characterization of differential gene expression in adrenocortical tumors harboring beta-catenin (CTNNB1) mutations. J. Clin. Endocrinol. Metab. 96, E1206-E1211
31 Patterson, E.E. et al. (2011) MicroRNA profiling of adrenocortical tumors reveals miR-483 as a marker of malignancy. Cancer 117, 1630-1639
32 Ozata, D.M. et al. (2011) The role of microRNA deregulation in the pathogenesis of adrenocortical carcinoma. Endocr. Relat. Cancer 18, 643-655
33 Tombol, Z. et al. (2009) Integrative molecular bioinformatics study of human adrenocortical tumors: microRNA, tissue-specific target prediction, and pathway analysis. Endocr. Relat. Cancer 16, 895-906
34 Rosenzweig, S.A. and Atreya, H.S. (2010) Defining the pathway to insulin-like growth factor system targeting in cancer. Biochem. Pharmacol. 80, 1115-1124
35 Barlaskar, F.M. et al. (2009) Preclinical targeting of the type I insulin- like growth factor receptor in adrenocortical carcinoma. J. Clin. Endocrinol. Metab. 94, 204-212
36 Haluska, P. et al. (2010) Safety, tolerability, and pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma. Cancer Chemother. Pharmacol. 65, 765-773
37 Baselga, J. and Swain, S.M. (2009) Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat. Rev. Cancer 9, 463-475
38 Kamio, T. et al. (1990) Immunohistochemical expression of epidermal growth factor receptors in human adrenocortical carcinoma. Hum. Pathol. 21, 277-282
39 Sasano, H. et al. (1994) Transforming growth factor alpha, epidermal growth factor, and epidermal growth factor receptor expression in normal and diseased human adrenal cortex by immunohistochemistry and in situ hybridization. Mod. Pathol. 7, 741-746
40 Adam, P. et al. (2010) Epidermal growth factor receptor in adrenocortical tumors: analysis of gene sequence, protein expression and correlation with clinical outcome. Mod. Pathol. 23, 1596-1604
41 Gutierrez, C. and Schiff, R. (2011) HER2: biology, detection, and clinical implications. Arch. Pathol. Lab. Med. 135, 55-62
42 Shim, H. (2011) One target, different effects: a comparison of distinct therapeutic antibodies against the same targets. Exp. Mol. Med. 43, 539-549
43 Samnotra, V. et al. (2007) A phase II trial of gefitinib monotherapy in patients with unresectable adrenocortical carcinoma (ACC). J. Clin. Oncol. 25, 15527
44 Quinkler, M. et al. (2008) Treatment of advanced adrenocortical carcinoma with erlotinib plus gemcitabine. J. Clin. Endocrinol. Metab. 93, 2057-2062
45 West, A.N. et al. (2007) Gene expression profiling of childhood adrenocortical tumors. Cancer Res. 67, 600-608
46 Turner, N. and Grose, R. (2010) Fibroblast growth factor signalling: from development to cancer. Nat. Rev. Cancer 10, 116-129
47 Xin, X. et al. (2006) CHIR-258 is efficacious in a newly developed fibroblast growth factor receptor 3-expressing orthotopic multiple myeloma model in mice. Clin. Cancer Res. 12, 4908-4915
48 Loilome, W. et al. (2009) Glioblastoma cell growth is suppressed by disruption of fibroblast growth factor pathway signaling. J. Neurooncol. 94, 359-366
49 Kim, K.B. et al. (2011) Phase I/II and pharmacodynamic study of dovitinib (TKI258), an inhibitor of fibroblast growth factor receptors and VEGF receptors, in patients with advanced melanoma. Clin. Cancer Res. 17, 7451-7461
50 Guagnano, V. et al. (2011) Discovery of 3-(2,6-dichloro-3,5-dimethoxy- phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}- 1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J. Med. Chem. 54, 7066-7083
51 Zhang, H. et al. (2007) FP-1039 (FGFR1:Fc), a soluble FGFR1 receptor antagonist, inhibits tumor growth and angiogenesis, In AACR-NCI- EORTC International Conference Molecular Targets and Cancer Therapeutics Discovery, Biology and Clinical Applications, San Francisco
52 Tolcher, A. et al. (2009) Preliminary results of a phase 1 study of FP- 1039 (FGFR1:Fc), a novel antagonist of multiple fibroblast growth factor (FGF) ligands, in patients with advanced malignancies. Mol. Cancer Ther. 8, A103
53 Zetter, B.R. (2008) The scientific contributions of M. Judah Folkman to cancer research. Nat. Rev. Cancer 8, 647-654
54 Wortmann, S. et al. (2010) Bevacizumab plus capecitabine as a salvage therapy in advanced adrenocortical carcinoma. Eur. J. Endocrinol. 162, 349-356
55 Quinkler, M. et al. (2011) Sunitinib in refractory adrenocortical carcinoma: results of a phase II trial. Endocr. Rev. 32, OR13-11
56 van Erp, N.P. et al. (2011) Mitotane has a strong and a durable inducing effect on CYP3A4 activity. Eur. J. Endocrinol. 164, 621-626
57 Butler, C. et al. (2010) Sustained remission with the kinase inhibitor sorafenib in stage IV metastatic adrenocortical carcinoma. Endocr. Pract. 16, 441-445
58 Berruti, A. et al. (2012) Phase II study of weekly paclitaxel and sorafenib as second/third-line therapy in patients with adrenocortical carcinoma. Eur. J. Endocrinol. 166, 451-458
59 Memmott, R.M. and Dennis, P.A. (2009) Akt-dependent and - independent mechanisms of mTOR regulation in cancer. Cell. Signal. 21, 656-664
60 Zhou, H. et al. (2010) Updates of mTOR inhibitors. Anticancer Agents Med. Chem. 10, 571-581
61 Yuan, R. et al. (2009) Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy. J. Hematol. Oncol. 2, 45
62 Populo, H. et al. (2012) The mTOR signalling pathway in human cancer. Int. J. Mol. Sci. 13, 1886-1918
63 Doghman, M. et al. (2010) Regulation of insulin-like growth factor- mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors. Cancer Res. 70, 4666-4675
64 De Martino, M.C. et al. (2009) Expression of mTOR pathway in human adrenocortical carcinomas and in vitro effects of mTOR inhibitors in human adrenocortical cell lines. Endocr. Abstracts 20,52
65 Takahashi-Yanaga, F. and Sasaguri, T. (2007) The Wnt/beta-catenin signaling pathway as a target in drug discovery. J. Pharmacol. Sci. 104, 293-302
Review
66 Kim, A.C. et al. (2008) Targeted disruption of beta-catenin in Sf1- expressing cells impairs development and maintenance of the adrenal cortex. Development 135, 2593-2602
67 Tadjine, M. et al. (2008) Frequent mutations of beta-catenin gene in sporadic secreting adrenocortical adenomas. Clin. Endocrinol. (Oxf.) 68, 264-270
68 Gaujoux, S. et al. (2008) 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. 93, 4135-4140
69 Tissier, F. et al. (2005) 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. 65, 7622-7627
70 Curtin, J.C. and Lorenzi, M.V. (2010) Drug discovery approaches to target Wnt signaling in cancer stem cells. Oncotarget 1, 563- 577
71 Cha, J.Y. et al. (2010) Anti-tumor activity of novel small molecule Wnt signaling inhibitor, CWP232291, in multiple myeloma. In 52nd American Society for Hematology Annual Meeting (Abstract 3038)
72 Doghman, M. et al. (2008) The T cell factor/beta-catenin antagonist PKF115-584 inhibits proliferation of adrenocortical carcinoma cells. J. Clin. Endocrinol. Metab. 93, 3222-3225
73 Garber, K. (2009) Drugging the Wnt pathway: problems and progress. J. Natl. Cancer Inst. 101, 548-550
74 Freedman, A.N. et al. (2010) Cancer pharmacogenomics and pharmacoepidemiology: setting a research agenda to accelerate translation. J. Natl. Cancer Inst. 102, 1698-1705
75 Ronchi, C.L. et al. (2009) Expression of excision repair cross complementing group 1 and prognosis in adrenocortical carcinoma patients treated with platinum-based chemotherapy. Endocr. Relat. Cancer 16, 907-918
76 Demeure, M.J. et al. (2011) Targeted therapies for adrenocortical carcinoma: IGF and beyond. Horm. Cancer 2, 385-392
77 Blanquicett, C. et al. (2008) Thiazolidinediones as anti-cancer agents. Cancer Ther. 6, 25-34
78 Betz, M.J. et al. (2005) Peroxisome proliferator-activated receptor- gamma agonists suppress adrenocortical tumor cell proliferation and induce differentiation. J. Clin. Endocrinol. Metab. 90, 3886- 3896
79 Cantini, G. et al. (2008) Rosiglitazone inhibits adrenocortical cancer cell proliferation by interfering with the IGF-IR intracellular signaling. PPAR Res. 2008, 904041
80 Cerquetti, L. et al. (2011) Rosiglitazone induces autophagy in H295R and cell cycle deregulation in SW13 adrenocortical cancer cells. Exp. Cell Res. 317, 1397-1410
81 Ferruzzi, P. et al. (2005) Thiazolidinediones inhibit growth and invasiveness of the human adrenocortical cancer cell line H295R. J. Clin. Endocrinol. Metab. 90, 1332-1339
82 Luconi, M. et al. (2010) Rosiglitazone impairs proliferation of human adrenocortical cancer: preclinical study in a xenograft mouse model. Endocr. Relat. Cancer 17, 169-177
83 Weng, J.R. et al. (2006) Beyond peroxisome proliferator-activated receptor gamma signaling: the multi-facets of the antitumor effect of thiazolidinediones. Endocr. Relat. Cancer 13, 401-413
84 Schimmer, B.P. and White, P.C. (2010) Minireview: steroidogenic factor 1: its roles in differentiation, development, and disease. Mol. Endocrinol. 24, 1322-1337
85 Sbiera, S. et al. (2010) High diagnostic and prognostic value of steroidogenic factor-1 expression in adrenal tumors. J. Clin. Endocrinol. Metab. 95, E161-E171
86 Doghman, M. et al. (2009) Inhibition of adrenocortical carcinoma cell proliferation by steroidogenic factor-1 inverse agonists. J. Clin. Endocrinol. Metab. 94, 2178-2183
87 Hahner, S. et al. (2008) [123I]Iodometomidate for molecular imaging of adrenocortical cytochrome P450 family 11B enzymes. J. Clin. Endocrinol. Metab. 93, 2358-2365
88 Khan, T.S. et al. (2003) 11C-metomidate PET imaging of adrenocortical cancer. Eur. J. Nucl. Med. Mol. Imaging 30, 403-410
89 Hahner, S. et al. (2012) [131I] Iodometomidate for targeted radionuclide therapy of advanced adrenocortical carcinoma. J. Clin. Endocrinol. Metab. 97, 914-922
90 Sierra, J.R. et al. (2010) Molecular mechanisms of acquired resistance to tyrosine kinase targeted therapy. Mol. Cancer 9, 75
91 Jin, Q. and Esteva, F.J. (2008) Cross-talk between the ErbB/HER family and the type I insulin-like growth factor receptor signaling pathway in breast cancer. J. Mammary Gland Biol. Neoplasia 13, 485-498
92 Jameson, M.J. et al. (2011) Activation of the insulin-like growth factor- 1 receptor induces resistance to epidermal growth factor receptor antagonism in head and neck squamous carcinoma cells. Mol. Cancer Ther. 10, 2124-2134
93 Huang, F. et al. (2009) The mechanisms of differential sensitivity to an insulin-like growth factor-1 receptor inhibitor (BMS-536924) and rationale for combining with EGFR/HER2 inhibitors. Cancer Res. 69, 161-170
94 Shaw, P.H. et al. (2011) Dual inhibition of epidermal growth factor and insulin-like 1 growth factor receptors reduce intestinal adenoma burden in the Apcmin/+ mouse. Br. J. Cancer 105, 649-657
95 Naing, A. et al. (2011) Phase I trial of cixutumumab combined with temsirolimus in patients with advanced cancer. Clin. Cancer Res. 17, 6052-6060
96 Kroiss, M. et al. (2011) Drug interactions with mitotane by induction of CYP3A4 metabolism in the clinical management of adrenocortical carcinoma. Clin. Endocrinol. (Oxf.) 75, 585-591
97 Edge, S.G. et al. eds (2010) Adrenal, In AJCC Cancer Staging Manual (7th edn), pp. 515-517, Springer
98 Fassnacht, M. et al. (2009) Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification. Cancer 115, 243-250
99 Lughezzani, G. et al. (2010) The European Network for the Study of Adrenal Tumors staging system is prognostically superior to the international union against cancer-staging system: a North American validation. Eur. J. Cancer 46, 713-719