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Emerging Treatment Strategies for Adrenocortical Carcinoma: A New Hope

Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, and Human Cancer Genetics Program, The Ohio State University, Columbus, Ohio 43210

Address all correspondence and requests for reprints to: Lawrence S. Kirschner, 544 Tzagournis Medical Research Facility, 420 West 12th Avenue, Columbus, Ohio 43210. E-mail: lawrence.kirschner{at}osumc.edu

	Abstract

Top Abstract Adrenocortical Carcinoma: The... Emerging Technologies and Their... Summary References

 
Context: Adrenocortical carcinoma (ACC) is a rare cancer but one that has devastating consequences for affected patients. Surgery is the mainstay of therapy, although the high frequency of metastatic disease implies that it is frequently noncurative. Traditional cytotoxic chemotherapy for ACC has generally produced disappointing responses, implying the need for the new therapies for this disease.

Evidence Acquisition: Review articles and primary literature were identified by extensive PubMed searching to obtain papers evaluating the current state of knowledge regarding ACC, as well as assessing the development of new therapeutic modalities for the treatment of cancer. When needed, additional articles were identified from the reference lists of the papers obtained from the primary screen.

Evidence Synthesis: Multiple new modalities that may enhance the future treatment of ACC were identified. They include the following: combating drug resistance, targeting tumor vasculature, inhibiting signaling pathways with small molecules, and using gene and/or immunotherapy. This review provides a brief summary of the progress and prospects of each of these modalities and focuses on emerging data and treatments that may alter the course of this disease within the next few years.

Conclusions: Despite the current grim outlook, the recent applications of emerging technology to the study of ACC and the development of newer, "targeted" therapies for cancer suggest the possibility of a new hope for patients with this disease, although these therapies will need to be evaluated by rigorous clinical trials to verify their effectiveness.

	Adrenocortical Carcinoma: The Present

Top Abstract Adrenocortical Carcinoma: The... Emerging Technologies and Their... Summary References

 
Clinical presentation of adrenocortical cancer

Clinical aspects of adrenocortical carcinoma (ACC) have been presented in recent reviews (1, 2, 3, 4, 5, 6, 7, 8) and will only be summarized here. ACC is a rare disease, with an annual incidence of 0.5–2 cases per million, and it accounts for 0.04–0.2% of all cancer deaths (1, 8, 9). The exception to this demographic occurs in Southern Brazil, where the incidence is approximately 10 times higher than elsewhere in the world (10).

ACC has a bimodal age of presentation. The disease is most commonly detected in the fifth decade, although there is a secondary peak in children less than 10 yr of age. The clinical presentation of patients in these two groups is somewhat different. Forty percent of adult patients with ACC present with a nonsecretory mass detected incidentally or during evaluation for abdominal or flank pain. Of the approximately 60% of tumors that present with a secretory syndrome, a mixed Cushing’s syndrome and virilization caused by cosecretion of cortisol and adrenal androgens is most common (35%), followed by pure Cushing’s syndrome (30%) and pure virilization (20%). Feminizing (estrogen secreting) tumors are rare (10%), and aldosterone-secreting ACCs are even less common (2%) (2). In contrast, 90% of childhood ACCs are secretory, and the large majority of the tumors secrete androgens, either as the sole hormone (55%) or in combination with cortisol (30%). Pure Cushing’s syndrome is seen in fewer than 5% of pediatric ACC cases, as are other types of hormonal profiles (3, 11, 12)

At the time of presentation, the median tumor size in adults is approximately 10 cm, and 30–40% of patients have clear evidence for metastatic disease (2, 6). With the current ease of computed tomography and magnetic resonance imaging, the detection of these cancers at earlier stages is becoming more common, and consideration for an ACC is a strong indicator to remove an incidentally detected adrenal mass. Imaging characteristics strongly suggestive of a benign adrenal nodule include a low unenhanced computed tomography scan density or a rapid loss of signal enhancement after iv contrast injection (13, 14, 15). Current guidelines recommend surgical removal of lesions greater than 5 cm, although, even in these cases, 75% of the tumors are benign (16).

Genetics of adrenocortical cancer

The genetics of adrenocortical cancer have been well studied and have also been the subjects of multiple review articles (17, 18), including previous reviews appearing in these pages (19, 20, 21). There are two syndromes in which ACC is a known component, albeit one that occurs in only a small percentage of cases. The Li-Fraumeni syndrome, which is caused by inactivating mutations in the TP53 tumor suppressor gene (22), is characterized by soft-tissue sarcomas, breast and brain cancers, and ACC (23). Intriguingly, mutations in TP53 also appear to underlie the increased incidence of ACC in Southern Brazil, because unrelated patients from this region exhibit an identical R337H mutation in TP53 (24, 25). ACC is also a component of the Beckwith-Wiedemann syndrome, which primarily involves developmental defects such as macroglossia, abdominal wall defects (exomphalos), and hemihypertrophy, as well as specific malignancies including Wilms’ tumor, hepatoblastoma, and ACC (26). At the genetic level, this syndrome is caused by alterations at 11p15, a genetic locus including the IGF-2, H19, and CDKN1C (p57^Kip2) genes.

There is also evidence that ACC may also be associated with the gastrointestinal tumor syndrome adenomatosis polyposis coli (APC) (Gardner’s syndrome), caused by mutation of the APC tumor suppressor gene (27). Genetic studies of adrenal neoplasms from these patients have shown loss of the normal APC allele in these tumors, suggesting that a genotype-specific effect contributes to tumor formation (28). Also, although multiple endocrine neoplasia type 1 syndrome has been associated with benign, nonsecretory lesions in 20–40% of patients (29, 30), more recent studies suggest that ACC with secretory features may also be observed in this disease (31). Patients with Carney Complex or McCune-Albright syndrome can develop secretory and nonsecretory adrenal nodules, although malignant degeneration has not been reported (32, 33). The genetic defects for these two disease both lead to activation of the cAMP-dependent protein kinase (protein kinase A), providing a good explanation for the clinical overlap between these conditions (34, 35).

Studies of DNA alterations in sporadic ACC have also been performed as a means to understand the genetic basis for the disease. In a series of elegant studies, Gicquel et al. (36, 37, 38, 39) analyzed adrenal tumors for alterations at 17p (containing the TP53 gene) or at 11p15 (containing the IGF-2/CDKN1C) locus and correlated the molecular findings with the differentiation between benign and malignant tumors. They found that loss of 17p and structural rearrangement of 11p15 (typically with resultant IGF-II overexpression) were both strongly associated with the malignant phenotype and, in fact, could be used for the differentiation of benign from malignant tumors, as well as to predict clinical behavior (36).

Unbiased approaches have also been used to study the chromosomal content of adrenal tumors by the technique of comparative genomic hybridization. In an initial report, Kjellman et al. (40) demonstrated that the number of chromosomal anomalies in adrenal tumors correlated quite well not only with size, but also with malignant behavior. ACCs exhibited frequent loss of 2, 11p, and 17p, as well as gains of chromosomes 4 and/or 5, whereas changes were only observed in benign adenomas larger than 5 cm. Subsequent studies of adult (41, 42) or pediatric (43) tumors have confirmed that chromosomal abnormalities are frequent in ACC, and that these abnormalities do not cluster at specific locations in the genome, with the exception of loss at 17p (the TP53 locus). Two of the studies (41, 43) detected a similar amplified region on distal 9q, although a causative locus has not yet been identified.

Current therapies for ACC

The mainstay of current therapy for ACC is complete surgical excision at the time of initial evaluation (1, 2, 5). If metastatic disease is limited, there remains an apparent benefit of surgery aimed at rendering the patient free of measurable disease (1).

In patients in whom surgical cure is not possible, cytotoxic chemotherapy has been used extensively, although response rates are generally poor (2, 44, 45, 46). Use of the insecticide-derivative o’,p’-DDD (mitotane), either as a single agent or in combination with other therapies, generally shows a response rate of 20–33%, which is significantly better than the response to other nonclassical agents thought to have antiadrenal effects (e.g. suramin and gossypol) (47, 48).

The most favorable results to date have been seen with the so-called "Italian" protocol, consisting of etoposide, doxorubicin, and cisplatin, with concurrent mitotane administration (EDP/M) (49). In the initial 28 patients receiving this regimen, the overall response rate was 53.5%, although the large majority (13 of 15) of these were partial responses. In this study, careful attention was paid to maintain mitotane serum levels between 14 and 20 µg/dl, which provided clinical benefit with minimal toxicity (50). A second active regimen is the combination of streptozotocin and mitotane (SO therapy) (51). In a study of 40 patients with ACC, a complete or partial response was observed in 36.4% of the 22 evaluable subjects. To compare these treatments directly and determine the "optimal" therapy, the FIRM-ACT study (First International Randomized Trial for Locally Advanced and Metastatic Adrenocortical Tumors; www.firm-act.orge) is currently being performed by a collaborative group of international ACC investigators (Table 1).

	Emerging Technologies and Their Applications to ACC

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Overcoming drug resistance in ACC

It has long been appreciated that ACC is resistant to standard cytotoxic chemotherapy (54). At the molecular level, ACCs express high levels of the multidrug resistance protein MDR1 (also known as P-glycoprotein). This protein, encoded by the ABCB1 gene, is an approximately 170–180,000 kDa membrane glycoprotein that functions as an ATP-dependent drug efflux pump, transporting out of the cell hydrophobic cytotoxic agents such as doxorubicin, vinblastine, and taxol. Normal adrenocortical tissue produces high levels of MDR1 (55, 56), and this expression is retained in most ACCs (55, 57, 58). Although MDR1 expression is likely a significant cause of drug resistance in ACC, there are also MDR1-independent drug-resistance mechanisms that may account for the ineffectiveness of water-soluble agents such as cisplatin (59, 60).

To overcome this drug resistance, competitive inhibitors of MDR1-mediated drug transport have been tested as a means to increase the effectiveness of chemotherapy. Early trials included compounds such as D-verapamil (which, unlike L-verapamil, is not a calcium channel blocker) and mitotane itself (61). These studies yielded low rates of response, as did a trial using a second-generation competitor known as PSC833 (Valspodar) (62). Despite these failures, the search for more potent MDR1 inhibitors has continued, and a current Phase II study (Table 1) is evaluating the effect of chemotherapy plus Tariquidar (XR9576), a third-generation noncompetitive inhibitor of the MDR1 efflux pump (63, 64, 65). One clinical study in breast cancer has suggested that Tariquidar may have some beneficial activity, but it is more modest than hoped (66).

Vascular-targeted therapies in ACC

Like all cells in the body, tumors are dependent on blood supply for the provision of oxygen and nutrients, and this knowledge has led to treatments aimed at blood supply control as a potential means to halt tumor growth and treat established tumors (67, 68). Vascular-targeted therapies can be divided into two distinct classes: those that prevent new blood vessel growth (anti-angiogenesis agents), and those that disrupt established tumor vasculature (69).

Vascular-endothelial growth factor (VEGF) is the predominant signal for both endothelial proliferation and migration into sites of neovascularization, and blockade of this signal has been a major goal of research in this field. There are three receptor tyrosine kinases that comprise the VEGF receptor family, designated as VEGFR1 (Flt-1), VEGFR2 (Flk-1/KDR), and VEGFR3 (Flt-4) (70). Of these, the major vasculogenic effect is associated with the VEGFR2, although VEGFR1 is also thought to play a role. VEGFR3 appears to be essential for lymphangiogenesis and probably does not have a significant role in vasculogenesis.

The success of anti-VEGF treatment has been demonstrated for advanced colorectal cancer (71) and has led to a validation of the anti-angiogenic concept. Treatment strategies aimed at VEGF include antibodies [e.g. bevacizumab (Avastin)] aimed at blocking the effect at the prereceptor level, as well as a variety of small-molecule inhibitors of the VEGFR kinases (Table 2). In fact, a trial testing the effectiveness of bevacizumab for ACC has been written and should be open for patient enrollment in the very near future (Dr. V. Samnotra, personal communication). Intriguingly, some of the VEGFR inhibitors also appear to inhibit other potentially relevant kinases (see below), although the specificity of these compounds is uncertain (72). Aside from VEGF, other modalities may be considered as anti-angiogenic therapy, including the inhibition of matrix metalloproteinases and the inhibition of other angiogenic molecules such as angiopoietin (69).

Microarray studies as a means to identify new therapeutic targets in ACC

Signaling pathways that are disrupted in ACCs have, up until recently, been characterized only on an piecemeal basis (for review, see Ref.78). To take a new, unbiased approach to the identification of new pathways that may be amenable to drug development, two different groups have recently undertaken a comparative microarray to study benign and malignant adrenocortical tumors (79, 80). Both studies determined that up-regulation of IGF-II expression was the dominant change, confirming previous observations (37, 38).

In addition, the study of Giordano et al. (79) reported up-regulation of proliferation-related genes such as TOP2A (topoisomerase) and Ki-67. No other growth factor receptors were increased, with the exception of the fibroblast growth factor receptor type 1 (FGFR1). They also suggested enhanced Wnt signaling, as evidenced by increased transcription of some of the downstream targets of this pathway. Interestingly, Wnt signaling has also been implicated in adrenal proliferation in the setting of ACTH-independent macronodular hyperplasia (81). In the analysis of de Fraipont et al. (80), the investigators found increased mRNA levels not only for IGF-II but also for a set of related proteins that included TGFß, TGFß receptor 1, and two isotypes of FGFR (1 and 4). They also reported down-regulation of a series of steroidogenic enzymes such as CYP11A (side-chain cleavage enzyme), CYP11B1 (11ß-hydroxylase), and CYP21A2 (21-hydroxylase). This group also identified a group of genes associated with ACC recurrence, including genes such as the protein tyrosine phosphatase PTPN2 and VIL2, encoding the metastasis-associated protein ezrin (82, 83).

Role of small-molecule tyrosine kinase inhibitors (TKIs) in ACC treatment

Due to the ground-breaking efforts in treating chronic myelogenous leukemia (CML) with the BCR-ABL TKI imatinib (Gleevec, originally STI-571) (84), there has been an explosion in research aimed at developing small-molecule inhibitors of protein kinases, typically (although not exclusively) receptor tyrosine kinases (85, 86).

Based on the microarray data presented above, it would appear that the most appropriate target for an ACC TKI would be an inhibitor of the IGF-I receptor. At present, no compounds targeted against this receptor are in clinical trials, although two recently developed compounds appear to show good in vitro and in vitro activity against the IGF-I receptor in tissue culture and rodent models (87, 88, 89). Clinical trials for these agents have not been started, but, if they remain promising in additional testing, ACC would seem to be an excellent target malignancy for their use. The other consistent signaling abnormality from the microarray studies (79, 80) is up-regulation of the FGFR1. No specific therapies targeted against the FGFRs have been developed, although molecular studies indicate that compounds developed for other uses [e.g. the nonspecific kinase inhibitor ZD-6474, currently in trials for non-small cell lung cancer (NSCLC) and thyroid cancer (see http://clinicaltrials.gov)] may have activity against these receptors (72).

Of the TKIs currently in trials (Table 2), epithelial growth factor receptor (EGFR) inhibitors, already approved for NSCLC (90, 91), may also have application to ACC. EGFR is expressed in the large majority of ACCs (92, 93, 94), although it appears that levels are not increased relative to benign adrenal adenomas. EGF itself is not overexpressed in ACC, but the receptor may be liganded by TGF, which is often found in adrenal tumors (94). As of this writing, a clinical trial of gefitinib (Iressa) is currently underway (Table 1), although no results are yet available from this trial. Although there has been substantial investment into the development of inhibitors of other tyrosine kinases [e.g. the PDGF (platelet-derived growth factor) receptor], it is unclear whether this will add to therapy, because neither PDGF receptor nor other kinases appear to be overexpressed in ACC (79).

Gene therapy and immunotherapy

Gene therapy is a technology that has been evolving for years, and this therapy can include the specific expression in tumors of a toxin or drug-sensitizing gene (e.g. herpes simplex virus thymidine kinase) or the restoration of a tumor-suppressor protein lost during oncogenesis (e.g. p53). The most promising trial of gene therapy to date showed excellent results at replacing an enzyme missing in children with X-linked severe combined immunodeficiency (95). However, as was widely reported, the trial has been marred by the development in two patients of acute leukemias due to the integration of the gene therapy vector into an oncogenic locus (96, 97), making future prospects less certain.

Although localized therapy for tumors or isolated metastases may be beneficial (98), the aggressive spread of ACC suggests that systematic administration of a gene therapy vector targeted to function only in adrenal tissues will likely be necessary. Advances in transcriptional control suggest that this should theoretically be possible (99), and the use of a steroidogenic enzyme promoter produced encouraging results in vitro (100). However, as noted above, adrenal cancers tend to lose expression of the steroidogenic enzymes (80), lessening the prospects for success of this approach. Another approach is to use a promoter that is induced under the hypoxic, acidic conditions found in tumors; to date, this approach has not yielded positive practical data (101). The introduction of antisense oligonucleotides into the body may also be considered a form of gene therapy, and recent advances in oligonucleotide chemistry suggest that systemic administration may be feasible (102). Promising targets to date include antiapoptotic proteins such as BCL2 (B-cell lymphoma); MDM2 (murine double minute 2), which enhances p53 degradation, may also be a useful target. A lack of success in clinical trials in lung cancer and hematologic malignancies has dampened enthusiasm for this approach, but combination with other therapies may enhance its effectiveness (102).

Immunotherapy is a relatively new therapeutic concept based on the premise that the immune cells of the body can be stimulated to produce antitumor effects, particularly through cytotoxic T-lymphocytes. This goal can be achieved either by the use of "cancer vaccines" (103) or the infusion of ex vivo expanded antigen-specific cells (104). Although responses in clinical trials have been limited, an increased understanding of immune system biology continues to drive ongoing work (105). The critical feature for therapy has been the identification of high-affinity immunogenic tumor antigens. Studies in endocrine neoplasms (106) have focused on neuroendocrine malignancies, and modest results have been observed for metastatic medullary thyroid cancer using calcitonin as a target (107, 108). Analogous to the case for gene therapy, an appropriate antigen target for disseminated ACC is less certain. Most ACCs express the steroidogenic acute regulatory protein, and this antigen has been used to evoke a therapeutic immune response in a highly manipulated xenograft mouse model (109). At present, immunotherapy remains early in its development as a therapy, although it may eventually have a role, likely in combination with other treatments (110).

New directions in ACC: leads from in vitro studies

Studies in the adrenocortical cell lines H295 (human), SW-13 (human), and Y-1 (mouse) have been used for analysis of signaling pathways in adrenal cells and have also been tested to identify compounds that may interfere with cellular proliferation. One of the most intriguing prospects is the use of the peroxisome proliferator-activated receptor (PPAR) agonist rosiglitazone, which was shown recently to decrease the growth of H295 cells in vitro (111, 112). Similar findings in pituitary tumor cells (113) have spurred interest in treating pituitary lesions with these agents, but there is no clinical data to date. It is unclear at present whether these effects are due to activation of PPAR, because "PPAR agonists" may affect many cellular systems (114, 115).

Other agents suggested to reduce adrenal growth in vitro include TNF in combination with cAMP (116) and steroidogenesis inhibitors such as aminoglutethimide, metyrapone, and etomidate (117). Intriguingly, there have been studies suggesting that androgens (dihydrotestosterone) reduce cell proliferation and colony formation in soft agar of H295 cells through up-regulation of TGFß1 and the TGFß receptor 2 (118, 119, 120). The effects of TGFß on tumors in vivo have not been performed, although mouse models support the notion that TGF signaling may inhibit adrenal growth (121). Other compounds that have been found in vitro to inhibit adrenocortical cells include the bisphophonate clodronate (122) and novel natural products from marine sponges (123).

	Summary

Top Abstract Adrenocortical Carcinoma: The... Emerging Technologies and Their... Summary References

 
ACC remains a disease with a poor prognosis, with little expectation of long-term survival if complete surgical removal is not achieved. However, there are factors in place now that suggest that it may be possible to alter the course of this devastating disease. First, a current Herculean effort is being undertaken by an international consortium to define the "standard" of chemotherapy against which all future studies can be fairly judged. This will not only provide data but will establish an infrastructure for the future. Second, the availability of the internet and the strong presence of patient advocacy and support groups (e.g.http://www.adrenocorticalcarcinoma.com/) implies that it will be possible to inform and recruit patients to these clinical trials, even for a disease as rare as ACC. Finally, the development of small-molecule inhibitors that can target generalized tumor pathways (e.g. angiogenesis) or ACC-specific signaling pathways suggests that we will someday be able to use these clinical trials to identify agents that effectively target the molecular abnormalities driving this cancer. Thus, in the near future, there is the expectation that the combined strengths of endocrinologists, oncologists, and surgeons, in concert with the pharmaceutical industry, may take the steps that will provide a new hope to patients diagnosed with this cancer.

	Acknowledgments

 
I thank those researchers who shared their thoughts and unpublished clinical trial data: Drs. A. Fojo, V. Samnotra, D. E. Schteingart, and S. R. Burzynski.

	Footnotes

 
First Published Online October 18, 2005

Abbreviations: ACC, Adrenocortical carcinoma; APC, adenomatosis polyposis coli; CML, chronic myelogenous leukemia; EGFR, epithelial growth factor receptor; FGFR, fibroblast growth factor receptor; MDR1, multidrug resistance protein 1; NSCLC, non-small cell lung cancer; PDGF, platelet-derived growth factor; SO, streptozotocin and mitotane therapy; TEM, tumor endothelial marker; TKI, tyrosine kinase inhibitor; VEGF, vascular-endothelial growth factor; VEGFR, VEGF receptor.

Received August 2, 2005.

Accepted October 7, 2005.

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Top Abstract Adrenocortical Carcinoma: The... Emerging Technologies and Their... Summary References

 

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