REVIEW: Emerging Treatment Strategies for Adrenocortical Carcinoma: A New Hope
Lawrence S. Kirschner
Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, and Human Cancer Genetics Program, The Ohio State University, Columbus, Ohio 43210
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 re- sponses, 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 dis- ease within the next few years.
Conclusions: Despite the current grim outlook, the recent applica- tions 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. (J Clin Endocrinol Metab 91: 14-21, 2006)
Adrenocortical Carcinoma: The Present Clinical presentation of adrenocortical cancer
Clinical aspects of adrenocortical carcinoma (ACC) have been presented in recent reviews (1-8) 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 some- what 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 ap- proximately 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
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.
JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the en- docrine community.
(30%) and pure virilization (20%). Feminizing (estrogen se- creting) 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 syn- drome 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 im- aging, the detection of these cancers at earlier stages is be- coming 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 tomog- raphy scan density or a rapid loss of signal enhancement after iv contrast injection (13-15). 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 stud- ied and have also been the subjects of multiple review articles (17,18), including previous reviews appearing in these pages (19-21). 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 (p57Kip2) genes.
There is also evidence that ACC may also be associated with the gastrointestinal tumor syndrome adenomatosis pol- yposis 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 syn- drome 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 pro- tein 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. (36-39) analyzed adrenal tumors for alterations at 17p (containing the TP53 gene) or at 11p15 (containing the IGF-2/CDKN1C) locus and correlated the molecular find- ings with the differentiation between benign and malig- nant 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 chro- mosomal 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 ob- served in benign adenomas larger than 5 cm. Subsequent studies of adult (41, 42) or pediatric (43) tumors have con- firmed that chromosomal abnormalities are frequent in ACC, and that these abnormalities do not cluster at specific loca- tions 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 ben- efit of surgery aimed at rendering the patient free of mea- surable disease (1).
In patients in whom surgical cure is not possible, cytotoxic chemotherapy has been used extensively, although response rates are generally poor (2, 44-46). Use of the insecticide- derivative o’,p’-DDD (mitotane), either as a single agent or in combination with other therapies, generally shows a re- sponse rate of 20-33%, which is significantly better than the response to other nonclassical agents thought to have antia- drenal 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, doxo- rubicin, and cisplatin, with concurrent mitotane administra- tion (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.org) is currently being performed by a collaborative group of in- ternational ACC investigators (Table 1).
Salvage chemotherapy with vincristine, cisplatin, tenipo- side, and cyclophosphamide has been reported to have ac- tivity in patients who had failed SO treatment (52). Others have suggested using a regimen of taxanes and gemcitabine as therapy for refractory ACC. Although this regimen has been shown to have some activity in advanced solid tumors unresponsive to other treatments (53), insufficient clinical trial data precludes making a recommendation regarding its use for ACC.
Emerging Technologies and Their Applications to ACC
Overcoming drug resistance in ACC
It has long been appreciated that ACC is resistant to stan- dard 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 inef- fectiveness of water-soluble agents such as cisplatin (59, 60).
| Trial ID | Agent | Rationale | Contact/location |
|---|---|---|---|
| NCT00094497 (FIRM-ACT) | EDP/M vs. SO chemotherapy (Phase III) | Establish best chemotherapeutic regimen Inhibit multidrug resistance to chemotherapy | www.firm-act.org International sites |
| NCT00071058 | Chemotherapy with mitotane and tariquidar (Phase II) | Dr. Tito Fojo, National Institutes of Health, Bethesda, MD (prpl@mail.cc.nih.gov) | |
| DMS 0327 | Iressa (Gefitinib) (Phase II) | Inhibit EGFR signaling | Dr. Vivek Samnotra, Norris Cotton Cancer Center, Lebanon, NH (p.simmons@fmhospital.com) |
There is an additional clinical trial for ACC, NCT00003453, which is a trial of an alternative therapy termed “anti-neoplastons.” As far as I am aware, there is little preclinical data to support the use of these agents in ACC, and this trial is not recommended, except as salvage therapy. Additional discussion may be found in Refs. 124-126. There are also approximately 100 clinical trials listed at http://clinicaltrials.gov for advanced or metastatic solid tumors, although these are not specifically targeted to patients with ACC. EDP/M, Treatment with etoposide, doxorubicin, and cisplatin, with concurrent mitotane administration. ” As of August 1, 2005.
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 cur- rent Phase II study (Table 1) is evaluating the effect of che- motherapy plus Tariquidar (XR9576), a third-generation noncompetitive inhibitor of the MDR1 efflux pump (63-65). One clinical study in breast cancer has suggested that Tariq- uidar may have some beneficial activity, but it is more mod- est 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 predom- inant 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 sig- nificant role in vasculogenesis.
The success of anti-VEGF treatment has been demon- strated for advanced colorectal cancer (71) and has led to a validation of the anti-angiogenic concept. Treatment strate- gies 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 effective- ness 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 mo- dalities may be considered as anti-angiogenic therapy, in- cluding the inhibition of matrix metalloproteinases and the inhibition of other angiogenic molecules such as angiopoi- etin (69).
In addition to therapies aimed at inhibiting the develop- ment of new blood vessels, it may also be possible to develop agents that specifically target tumor vasculature. Tumor blood vessels tend to be poorly organized, with regions of hypoxia and significant acidosis due to the accumulation of the products of anaerobic glycolysis. This environment leads to a relatively “immature” phenotype of the cells (73) and also causes expression of specific markers on the endothelial lining of tumor vasculature. Such targets include Round- about-4 and the fibronectin extra domain B (74). Addition- ally, serial analysis of gene expression of tumor endothelium led to the identification of anonymous genes known as tumor endothelial markers (TEMs), of which TEM1 (endosialin), TEM5, and TEM8 have been further shown to be specific for tumor vasculature (75). These proteins, all of which are cell surface antigens, provide potential targets for the develop- ment of agents that target them directly or use as them as homing signals to direct other therapeutic molecules, such as via monoclonal antibodies (74). Additionally, the immuno- suppressive agent rapamycin (Sirolimus) may have anti-an- giogenic effects, providing good tumor control and inducing vascular thrombosis in a mouse xenograft model through an unknown mechanism (76, 77).
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 de- termined that up-regulation of IGF-II expression was the dominant change, confirming previous observations (37,38).
| Category | Type | Examples | Status |
|---|---|---|---|
| Vascular-targeted therapies | VEGFR inhibitors, monoclonal antibodies | Bevacizumab (Avastin) | Approved for NSCLC, ACC trials to start soon |
| IMC-1121B | In trials | ||
| VEGFR inhibitors | Vatalanib, CEP-701 | Phase I trials (non-ACC) | |
| Vascular disrupting agents | Combretastatin A-4-P, DMXAA | In trials (non-ACC) | |
| Rapamycin, CCI-779 | Immunosuppressants, in trials (non-ACC) | ||
| Antifibronectin | Preclinical | ||
| EDB conjugates | |||
| Receptor TKIs | IGF-I receptor inhibitors | NVP-AEW541, NVP- ADW742 | Preclinical |
| EGFR inhibitors | Gefitinib (Iressa), erlotinib (Tarceva) | Approved for NSCLC, in trials for ACC (Gefitinib) | |
| Lapatinib, canertinib | In trials (non-ACC) | ||
| EGFR inhibitors, | Trastuzumab (Herceptin), Erbitux (cetuximab) | Approved, not in ACC trials | |
| monoclonal antibodies | |||
| PDGF inhibitors | Leflunomide, PKC412 | In trials (non-ACC) | |
| VEGFR + EGFR inhibitors | ZD-6474, AEE788 | In trials (non-ACC) | |
| Other kinase inhibitors | RAF-1 | BAY43-9006 | In trials (non-ACC) |
| p38 (MAPK14) | SB203580 BIRB-796 | In trials (non-ACC) | |
| New molecules | Differentiation agents | PPARy agonists (rosiglitazone) | In trials for thyroid cancer, others |
| Hsp90 binders | 17-AAG | In trials (non-ACC) | |
| Proteasome inhibitors | Bortezomib (PS-341, Velcade) | In trials (non-ACC) | |
| New cytotoxic agents | New natural products | Various stages |
Additional details may be found at http://clinicaltrials.gov or in Refs. 69, 72-74, and 127. EDB, The fibronectin extra domain B; Hsp90, heat shock protein 90.
” Data are meant to provide examples and a summary only.
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 en- hanced Wnt signaling, as evidenced by increased transcrip- tion of some of the downstream targets of this pathway. Interestingly, Wnt signaling has also been implicated in ad- renal proliferation in the setting of ACTH-independent ma- cronodular 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 ima- tinib (Gleevec, originally STI-571) (84), there has been an explosion in research aimed at developing small-molecule inhibitors of protein kinases, typically (although not exclu- sively) 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 tri- als, 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 (87-89). 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 ac- tivity 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 (92-94), although it appears that levels are not increased relative to benign ad- renal adenomas. EGF itself is not overexpressed in ACC, but the receptor may be liganded by TGFa, 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 inhib-
itors of other tyrosine kinases [e.g. the PDGF (platelet-de- rived 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 sim- plex 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 excel- lent 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 metas- tases 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 re- sults 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 ad- vances in oligonucleotide chemistry suggest that systemic administration may be feasible (102). Promising targets to date include antiapoptotic proteins such as BCL2 (B-cell lym- phoma); MDM2 (murine double minute 2), which enhances p53 degradation, may also be a useful target. A lack of suc- cess in clinical trials in lung cancer and hematologic malig- nancies has dampened enthusiasm for this approach, but combination with other therapies may enhance its effective- ness (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 re- sponses 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 anti- gens. Studies in endocrine neoplasms (106) have focused on neuroendocrine malignancies, and modest results have been observed for metastatic medullary thyroid cancer using cal- citonin 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 y (PPARy) 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 PPARy, because “PPAR agonists” may affect many cellular systems (114, 115).
Other agents suggested to reduce adrenal growth in vitro include TNFa in combination with cAMP (116) and steroi- dogenesis inhibitors such as aminoglutethimide, metyrap- one, and etomidate (117). Intriguingly, there have been stud- ies 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 (118-120). 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 adreno- cortical cells include the bisphophonate clodronate (122) and novel natural products from marine sponges (123).
Summary
ACC remains a disease with a poor prognosis, with little expectation of long-term survival if complete surgical re- moval 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 pos- sible 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 tu- mor 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 mo- lecular abnormalities driving this cancer. Thus, in the near fu- ture, 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.
Received August 2, 2005. Accepted October 7, 2005.
Address all correspondence and requests for reprints to: Lawrence S. Kirschner, 544 Tzagournis Medical Research Facility, 420 West 12th Ave- nue, Columbus, Ohio 43210. E-mail: lawrence.kirschner@osumc.edu.
References
1. Crucitti F, Bellantone R, Ferrante A, Boscherini M, Crucitti P 1996 The Italian Registry for Adrenal Cortical Carcinoma: analysis of a multiinstitu- tional series of 129 patients. The ACC Italian Registry Study Group. Surgery 119:161-170
2. Dackiw AP, Lee JE, Gagel RF, Evans DB 2001 Adrenal cortical carcinoma. World J Surg 25:914-926
3. Ribeiro RC, Figueiredo B 2004 Childhood adrenocortical tumours. Eur J Cancer 40:1117-1126
4. Stratakis CA, Chrousos GP 2000 Adrenal cancer. Endocrinol Metab Clin North Am 29:15-25, vii-viii
5. Allolio B, Hahner S, Weismann D, Fassnacht M 2004 Management of ad- renocortical carcinoma. Clin Endocrinol (Oxf) 60:273-287
6. Ng L, Libertino JM 2003 Adrenocortical carcinoma: diagnosis, evaluation and treatment. J Urol 169:5-11
7. Stojadinovic A, Ghossein RA, Hoos A, Nissan A, Marshall D, Dudas M, Cordon-Cardo C, Jaques DP, Brennan MF 2002 Adrenocortical carcinoma: clinical, morphologic, and molecular characterization. J Clin Oncol 20:941-950
8. Wajchenberg BL, Albergaria Pereira MA, Medonca BB, Latronico AC, Cam- pos Carneiro P, Alves VA, Zerbini MC, Liberman B, Carlos Gomes G, Kirschner MA 2000 Adrenocortical carcinoma: clinical and laboratory ob- servations. Cancer 88:711-736
9. Lipsett MB, Hertz R, Ross GT 1963 Clinical and pathophysiologic aspects of adrenocortical carcinoma. Am J Med 35:374-383
10. Sabbaga CC, Avilla SG, Schulz C, Garbers JC, Blucher D 1993 Adrenocor- tical carcinoma in children: clinical aspects and prognosis. J Pediatr Surg 28:841-843
11. Ribeiro RC, Michalkiewicz EL, Figueiredo BC, DeLacerda L, Sandrini F, Pianovsky MD, Sampaio G, Sandrini R 2000 Adrenocortical tumors in children. Braz J Med Biol Res 33:1225-1234
12. Mendonca BB, Lucon AM, Menezes CA, Saldanha LB, Latronico AC, Zer- bini C, Madureira G, Domenice S, Albergaria MA, Camargo MH, Halpern A, Liberman B, Arnhold IJP, Bloise W, Andriolo A, Nicolau W, Silva FAQ, Wroclaski E, Arap S, Wajchenberg BL 1995 Clinical, hormonal and patho- logical findings in a comparative study of adrenocortical neoplasms in child- hood and adulthood. J Urol 154:2004-2009
13. Al-Hawary MM, Francis IR, Korobkin M 2005 Non-invasive evaluation of the incidentally detected indeterminate adrenal mass. Best Pract Res Clin Endocrinol Metab 19:277-292
14. Hamrahian AH, Ioachimescu AG, Remer EM, Motta-Ramirez G, Boga- bathina H, Levin HS, Reddy S, Gill IS, Siperstein A, Bravo EL 2005 Clinical utility of noncontrast computed tomography attenuation value (hounsfield units) to differentiate adrenal adenomas/hyperplasias from nonadenomas: Cleveland Clinic experience. J Clin Endocrinol Metab 90:871-877
15. Korobkin M, Brodeur FJ, Francis IR, Quint LE, Dunnick NR, Goodsitt M 1996 Delayed enhanced CT for differentiation of benign from malignant adrenal masses. Radiology 200:737-742
16. National Institutes of Health 2002 Management of the Clinically Inapparent Adrenal Mass (Incidentaloma) National Institutes of Health State-of-the- Science Conference Statement. Bethesda, MD: NIH
17. Gicquel C, Bertherat J, Le Bouc Y, Bertagna X 2000 Pathogenesis of adre- nocortical incidentalomas and genetic syndromes associated with adreno- cortical neoplasms. Endocrinol Metab Clin North Am 29:1-13, vii
18. Reincke M, Beuschlein F, Slawik M, Borm K 2000 Molecular adrenocortical tumourigenesis. Eur J Clin Invest 30(Suppl 3):63-68
19. Sandrini R, Ribeiro RC, DeLacerda L 1997 Childhood adrenocortical tumors. J Clin Endocrinol Metab 82:2027-2031
20. Latronico AC, Chrousos GP 1997 Extensive personal experience: adreno- cortical tumors. J Clin Endocrinol Metab 82:1317-1324
21. Koch CA, Pacak K, Chrousos GP 2002 The molecular pathogenesis of he- reditary and sporadic adrenocortical and adrenomedullary tumors. J Clin Endocrinol Metab 87:5367-5384
22. Malkin D, Jolly KW, Barbier N, Look AT, Friend SH, Gebhardt MC, Andersen TI, Borresen AL, Li FP, Garber J, Strong LC 1992 Germline mu- tations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms. N Engl J Med 326:1309-1315
23. Li FP, Fraumeni Jr JF 1969 Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med 71:747-752
24. Ribeiro RC, Sandrini F, Figueiredo B, Zambetti GP, Michalkiewicz E,
Lafferty AR, DeLacerda L, Rabin M, Cadwell C, Sampaio G, Cat I, Stratakis CA, Sandrini R 2001 An inherited p53 mutation that contributes in a tissue- specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci USA 98:9330-9335
25. DiGiammarino EL, Lee AS, Cadwell C, Zhang W, Bothner B, Ribeiro RC, Zambetti G, Kriwacki RW 2002 A novel mechanism of tumorigenesis in- volving pH-dependent destabilization of a mutant p53 tetramer. Nat Struct Biol 9:12-16
26. Wiedemann HR 1997 Frequency of Wiedemann-Beckwith syndrome in Ger- many; rate of hemihyperplasia and of tumours in affected children. Eur J Pediatr 156:251
27. Naylor EW, Gardner EJ 1981 Adrenal adenomas in a patient with Gardner’s syndrome. Clin Genet 20:67-73
28. Blaker H, Sutter C, Kadmon M, Otto HF, Von Knebel-Doeberitz M, Gebert J, Helmke BM 2004 Analysis of somatic APC mutations in rare extracolonic tumors of patients with familial adenomatous polyposis coli. Genes Chro- mosomes Cancer 41:93-98
29. Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG, Libroia A, Lips CJ, Lombardi G, Mannelli M, Pacini F, Ponder BA, Raue F, Skogseid B, Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells Jr SA, Marx SJ 2001 Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86:5658-5671
30. Skogseid B, Rastad J, Gobl A, Larsson C, Backlin K, Juhlin C, Akerstrom G, Oberg K 1995 Adrenal lesion in multiple endocrine neoplasia type 1. Surgery 118:1077-1082
31. Langer P, Cupisti K, Bartsch DK, Nies C, Goretzki PE, Rothmund M, Roher HD 2002 Adrenal involvement in multiple endocrine neoplasia type 1. World J Surg 26:891-896
32. Stratakis CA, Kirschner LS, Carney JA 2001 Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab 86:4041-4046
33. Stratakis CA, Kirschner LS 1998 Clinical and genetic analysis of primary bilateral adrenal diseases (micro- and macronodular disease) leading to Cush- ing syndrome. Horm Metab Res 30:456-463
34. Kirschner LS, Carney JA, Pack SD, Taymans SE, Giatzakis C, Cho YS, Cho-Chung YS, Stratakis CA 2000 Mutations of the gene encoding the protein kinase A type I-a regulatory subunit in patients with the Carney complex. Nat Genet 26:89-92
35. Weinstein LS, Shenker A, Gejman PV, Merino MJ, Friedman E, Spiegel AM 1991 Activating mutations of the stimulatory G protein in the McCune- Albright syndrome. N Engl J Med 325:1688-1695
36. Gicquel C, Bertagna X, Gaston V, Coste J, Louvel A, Baudin E, Bertherat J, Chapuis Y, Duclos JM, Schlumberger M, Plouin PF, Luton JP, Le Bouc Y 2001 Molecular markers and long-term recurrences in a large cohort of pa- tients with sporadic adrenocortical tumors. Cancer Res 61:6762-6767
37. Gicquel C, Bertagna X, Schneid H, Francillard-Leblond M, Luton JP, Girard F, Le Bouc Y 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
38. Gicquel C, Le Bouc Y 1997 Molecular markers for malignancy in adreno- cortical tumors. Horm Res 47:269-272
39. Gicquel C, Raffin-Sanson ML, Gaston V, Bertagna X, Plouin PF, Schlum- berger M, Louvel A, Luton JP, Le Bouc Y 1997 Structural and functional abnormalities at 11p15 are associated with the malignant phenotype in spo- radic adrenocortical tumors: study on a series of 82 tumors. J Clin Endocrinol Metab 82:2559-2565
40. Kjellman M, Kallioniemi OP, Karhu R, Hoog A, Farnebo LO, Auer G, Larsson C, Backdahl M 1996 Genetic aberrations in adrenocortical tumors detected using comparative genomic hybridization correlate with tumor size and malignancy. Cancer Res 56:4219-4223
41. Dohna M, Reincke M, Mincheva A, Allolio B, Solinas-Toldo S, Lichter P 2000 Adrenocortical carcinoma is characterized by a high frequency of chro- mosomal gains and high-level amplifications. Genes Chromosomes Cancer 28:145-152
42. Sidhu S, Marsh DJ, Theodosopoulos G, Philips J, Bambach CP, Campbell P, Magarey CJ, Russell CF, Schulte KM, Roher HD, Delbridge L, Robinson BG 2002 Comparative genomic hybridization analysis of adrenocortical tu- mors. J Clin Endocrinol Metab 87:3467-3474
43. Figueiredo BC, Stratakis CA, Sandrini R, DeLacerda L, Pianovsky MA, Giatzakis C, Young HM, Haddad BR 1999 Comparative genomic hybrid- ization analysis of adrenocortical tumors of childhood. J Clin Endocrinol Metab 84:1116-1121
44. Williamson SK, Lew D, Miller GJ, Balcerzak SP, Baker LH, Crawford ED 2000 Phase II evaluation of cisplatin and etoposide followed by mitotane at disease progression in patients with locally advanced or metastatic adreno- cortical carcinoma: a Southwest Oncology Group Study. Cancer 88:1159-1165
45. Bukowski RM, Wolfe M, Levine HS, Crawford DE, Stephens RL, Gaynor E, Harker WG 1993 Phase II trial of mitotane and cisplatin in patients with adrenal carcinoma: a Southwest Oncology Group study. J Clin Oncol 11: 161-165
20 J Clin Endocrinol Metab, January 2006, 91(1):14-21
46. Wooten MD, King DK 1993 Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer 72:3145-3155
47. Flack MR, Pyle RG, Mullen NM, Lorenzo B, Wu YW, Knazek RA, Nisula BC, Reidenberg MM 1993 Oral gossypol in the treatment of metastatic adrenal cancer. J Clin Endocrinol Metab 76:1019-1024
48. Schroder LE, Glass T, Eisenberger M, Culkin D, Bukowski RM, Crawford DE Phase II evaluation of suramin in advanced adrenal carcinoma: Southwest Oncology Group (SWOG) Trial 9427. Proc 37th Annual Meeting of the Amer- ican Society of Clinical Oncology, San Francisco, CA, 2001, A2361
49. Berruti A, Terzolo M, Pia A, Angeli A, Dogliotti L 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
50. Terzolo M, Daffara F, Rossetto R, Buci L, Tagliabue M, Carbone V, Ciuti R, Ferruzzi P, Berruti A, Arvat E, Angeli A, Mannelli M 2003 Adjuvant mitotane therapy for adrenal cancer. Program of the 85th Annual Meeting of The Endocrine Society, Philadelphia, PA, 2003, p 571 (Abstract P3-412)
51. Khan TS, Imam H, Juhlin C, Skogseid B, Grondal S, Tibblin S, Wilander E, Oberg K, Eriksson B 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
52. Khan TS, Sundin A, Juhlin C, Wilander E, Oberg K, Eriksson B 2004 Vincristine, cisplatin, teniposide, and cyclophosphamide combination in the treatment of recurrent or metastatic adrenocortical cancer. Med Oncol 21: 167-177
53. Mekhail T, Hutson TE, Elson P, Budd GT, Srkalovic G, Olencki T, Peere- boom D, Pelley R, Bukowski RM 2003 Phase I trial of weekly docetaxel and gemcitabine in patients with refractory malignancies. Cancer 97:170-178
54. Dean M, Fojo T, Bates S 2005 Tumour stem cells and drug resistance. Nat Rev Cancer 5:275-284
55. Cordon-Cardo C, O’Brien JP, Boccia J, Casals D, Bertino JR, Melamed MR 1990 Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J Histochem Cytochem 38:1277-1287
56. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC 1987 Cellular localization of the multidrug-resistance gene product P- glycoprotein in normal human tissues. Proc Natl Acad Sci USA 84:7735-7738
57. Flynn SD, Murren JR, Kirby WM, Honig J, Kan L, Kinder BK 1992 P- glycoprotein expression and multidrug resistance in adrenocortical carci- noma. Surgery 112:981-986
58. Goldstein LJ, Galski H, Fojo A, Willingham M, Lai SL, Gazdar A, Pirker R, Green A, Crist W, Brodeur GM, Lieber M, Cossman J, Gottesman MM, Pastan I 1989 Expression of a multidrug resistance gene in human cancers. J Natl Cancer Inst 81:116-124
59. Fridborg H, Larsson R, Juhlin C, Rastad J, Akerstrom G, Backlin K, Nygren P 1994 P-glycoprotein expression and activity of resistance modifying agents in primary cultures of human renal and adrenocortical carcinoma cells. An- ticancer Res 14:1009-1016
60. Haak HR, van Seters AP, Moolenaar AJ, Fleuren GJ 1993 Expression of P-glycoprotein in relation to clinical manifestation, treatment and prognosis of adrenocortical cancer. Eur J Cancer 29A:1036-1038
61. Abraham J, Bakke S, Rutt A, Meadows B, Merino M, Alexander R, Schrump D, Bartlett D, Choyke P, Robey R, Hung E, Steinberg SM, Bates S, Fojo T 2002 A phase II trial of combination chemotherapy and surgical resection for the treatment of metastatic adrenocortical carcinoma: continuous infusion doxorubicin, vincristine, and etoposide with daily mitotane as a P-glycop- rotein antagonist. Cancer 94:2333-2343
62. Bates S, Kang M, Meadows B, Bakke S, Choyke P, Merino M, Goldspiel B, Chico I, Smith T, Chen C, Robey R, Bergan R, Figg WD, Fojo T 2001 A Phase I study of infusional vinblastine in combination with the P-glycoprotein antagonist PSC 833 (valspodar). Cancer 92:1577-1590
63. Mistry P, Stewart AJ, Dangerfield W, Okiji S, Liddle C, Bootle D, Plumb JA, Templeton D, Charlton P 2001 In vitro and in vivo reversal of P-glyco- protein-mediated multidrug resistance by a novel potent modulator, XR9576. Cancer Res 61:749-758
64. Walker J, Martin C, Callaghan R 2004 Inhibition of P-glycoprotein function by XR9576 in a solid tumour model can restore anticancer drug efficacy. Eur J Cancer 40:594-605
65. Martin C, Berridge G, Mistry P, Higgins C, Charlton P, Callaghan R 1999 The molecular interaction of the high affinity reversal agent XR9576 with P-glycoprotein. Br J Pharmacol 128:403-411
66. Pusztai L, Wagner P, Ibrahim N, Rivera E, Theriault R, Booser D, Symmans FW, Wong F, Blumenschein G, Fleming DR, Rouzier R, Boniface G, Hor- tobagyi GN 2005 Phase II study of tariquidar, a selective P-glycoprotein inhibitor, in patients with chemotherapy-resistant, advanced breast carci- noma. Cancer 104:682-691
67. Folkman J 1975 Tumor angiogenesis: a possible control point in tumor growth. Ann Intern Med 82:96-100
68. Folkman J 2003 Angiogenesis inhibitors: a new class of drugs. Cancer Biol Ther 2:S127-S133
69. Siemann DW, Bibby MC, Dark GG, Dicker AP, Eskens FA, Horsman MR, Marme D, Lorusso PM 2005 Differentiation and definition of vascular-tar- geted therapies. Clin Cancer Res 11:416-420
70. Hicklin DJ, Ellis LM 2005 Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23:1011-1027
71. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F 2004 Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342
72. Fabian MA, Biggs III WH, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lelias JM, Mehta SA, Milanov ZV, Velasco AM, Wodicka LM, Patel HK, Zarrinkar PP, Lockhart DJ 2005 A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 23:329-336
73. Tozer GM, Kanthou C, Baguley BC 2005 Disrupting tumour blood vessels. Nat Rev Cancer 5:423-435
74. Neri D, Bicknell R 2005 Tumour vascular targeting. Nat Rev Cancer 5:436- 446
75. Nanda A, St. Croix B 2004 Tumor endothelial markers: new targets for cancer therapy. Curr Opin Oncol 16:44-49
76. Bruns CJ, Koehl GE, Guba M, Yezhelyev M, Steinbauer M, Seeliger H, Schwend A, Hoehn A, Jauch KW, Geissler EK 2004 Rapamycin-induced endothelial cell death and tumor vessel thrombosis potentiate cytotoxic ther- apy against pancreatic cancer. Clin Cancer Res 10:2109-2119
77. Guba M, Yezhelyev M, Eichhorn ME, Schmid G, Ischenko I, Papyan A, Graeb C, Seeliger H, Geissler EK, Jauch KW, Bruns CJ 2005 Rapamycin induces tumor-specific thrombosis via tissue factor in the presence of VEGF. Blood 105:4463-4469
78. Kirschner LS 2002 Signaling pathways in adrenocortical cancer. Ann NY Acad Sci 968:222-239
79. Giordano TJ, Thomas DG, Kuick R, Lizyness M, Misek DE, Smith AL, Sanders D, Aljundi RT, Gauger PG, Thompson NW, Taylor JM, Hanash SM 2003 Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. Am J Pathol 162:521-531
80. de Fraipont F, El Atifi M, Cherradi N, Le Moigne G, Defaye G, Houlgatte R, Bertherat J, Bertagna X, Plouin PF, Baudin E, Berger F, Gicquel C, Chabre O, Feige JJ 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
81. Bourdeau I, Antonini SR, Lacroix A, Kirschner LS, Matyakhina L, Lorang D, Libutti SK, Stratakis CA 2004 Gene array analysis of macronodular adrenal hyperplasia confirms clinical heterogeneity and identifies several candidate genes as molecular mediators. Oncogene 23:1575-1585
82. Khanna C, Wan X, Bose S, Cassaday R, Olomu O, Mendoza A, Yeung C, Gorlick R, Hewitt SM, Helman LJ 2004 The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat Med 10:182-186
83. Yu Y, Khan J, Khanna C, Helman L, Meltzer PS, Merlino G 2004 Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators. Nat Med 10:175-181
84. Druker BJ 2004 Imatinib as a paradigm of targeted therapies. Adv Cancer Res 91:1-30
85. Druker BJ 2004 Molecularly targeted therapy: have the floodgates opened? Oncologist 9:357-360
86. Krause DS, Van Etten RA 2005 Tyrosine kinases as targets for cancer therapy. N Engl J Med 353:172-187
87. Garcia-Echeverria C, Pearson MA, Marti A, Meyer T, Mestan J, Zimmer- mann J, Gao J, Brueggen J, Capraro HG, Cozens R, Evans DB, Fabbro D, Furet P, Porta DG, Liebetanz J, Martiny-Baron G, Ruetz S, Hofmann F 2004 In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell 5:231-239
88. Warshamana-Greene GS, Litz J, Buchdunger E, Garcia-Echeverria C, Hof- mann F, Krystal GW 2005 The insulin-like growth factor-I receptor kinase inhibitor, NVP-ADW742, sensitizes small cell lung cancer cell lines to the effects of chemotherapy. Clin Cancer Res 11:1563-1571
89. Warshamana-Greene GS, Litz J, Buchdunger E, Hofmann F, Garcia-Echev- erria C, Krystal GW 2004 The insulin-like growth factor-I (IGF-I) receptor kinase inhibitor NVP-ADW742, in combination with STI571, delineates a spectrum of dependence of small cell lung cancer on IGF-I and stem cell factor signaling. Mol Cancer Ther 3:527-535
90. Cohen MH, Williams GA, Sridhara R, Chen G, Pazdur R 2003 FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist 8:303-306
91. 2005 Erlotinib (Tarceva) for advanced non-small cell lung cancer. Med Lett Drugs Ther 47:25-26
92. Edgren M, Eriksson B, Wilander E, Westlin JE, Nilsson S, Oberg K 1997 Biological characteristics of adrenocortical carcinoma: a study of p53, IGF, EGF-r, Ki-67 and PCNA in 17 adrenocortical carcinomas. Anticancer Res 17:1303-1309
93. Kamio T, Shigematsu K, Sou H, Kawai K, Tsuchiyama H 1990 Immuno- histochemical expression of epidermal growth factor receptors in human adrenocortical carcinoma. Hum Pathol 21:277-282
94. Sasano H, Suzuki T, Shizawa S, Kato K, Nagura H 1994 Transforming growth factor «, epidermal growth factor, and epidermal growth factor re-
ceptor expression in normal and diseased human adrenal cortex by immu- nohistochemistry and in situ hybridization. Mod Pathol 7:741-746
95. Hacein-Bey-Abina S, Le Deist F, Carlier F, Bouneaud C, Hue C, De Villartay JP, Thrasher AJ, Wulffraat N, Sorensen R, Dupuis-Girod S, Fischer A, Davies EG, Kuis W, Leiva L, Cavazzana-Calvo M 2002 Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N Engl J Med 346:1185-1193
96. Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, Lim A, Osborne CS, Pawliuk R, Morillon E, Sorensen R, Forster A, Fraser P, Cohen JI, de Saint Basile G, Alexander I, Wintergerst U, Frebourg T, Aurias A, Stoppa-Lyonnet D, Romana S, Radford-Weiss I, Gross F, Valensi F, Delabesse E, Macintyre E, Sigaux F, Soulier J, Leiva LE, Wissler M, Prinz C, Rabbitts TH, Le Deist F, Fischer A, Cavazzana-Calvo M 2003 LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302:415-419
97. McCormack MP, Rabbitts TH 2004 Activation of the T-cell oncogene LMO2 after gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 350:913-922
98. Wolkersdorfer GW, Bornstein SR, Higginbotham JN, Hiroi N, Vaquero JJ, Green MV, Blaese RM, Aguilera G, Chrousos GP, Ramsey WJ 2002 A novel approach using transcomplementing adenoviral vectors for gene therapy of adrenocortical cancer. Horm Metab Res 34:279-287
99. Robson T, Hirst DG 2003 Transcriptional targeting in cancer gene therapy. J Biomed Biotechnol 2003:110-137
100. Chuman Y, Zhan Z, Fojo T 2000 Construction of gene therapy vectors tar- geting adrenocortical cells: enhancement of activity and specificity with agents modulating the cyclic adenosine 3’,5’-monophosphate pathway. J Clin Endocrinol Metab 85:253-262
101. Scholl SM, Michaelis S, McDermott R 2003 Gene therapy applications to cancer treatment. J Biomed Biotechnol 2003:35-47
102. Gleave ME, Monia BP 2005 Antisense therapy for cancer. Nat Rev Cancer 5:468-479
103. Rosenberg SA, Yang JC, Restifo NP 2004 Cancer immunotherapy: moving beyond current vaccines. Nat Med 10:909-915
104. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, Royal RE, Kammula U, White DE, Mavroukakis SA, Rogers LJ, Gracia GJ, Jones SA, Mangiameli DP, Pelletier MM, Gea-Banacloche J, Robinson MR, Berman DM, Filie AC, Abati A, Rosenberg SA 2005 Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 23:2346-2357
105. Laheru D, Jaffee EM 2005 Immunotherapy for pancreatic cancer - science driving clinical progress. Nat Rev Cancer 5:459-467
106. Schott M, Seissler J 2003 Dendritic cell vaccination: new hope for the treat- ment of metastasized endocrine malignancies. Trends Endocrinol Metab 14: 156-162
107. Schott M, Seissler J, Lettmann M, Fouxon V, Scherbaum WA, Feldkamp J 2001 Immunotherapy for medullary thyroid carcinoma by dendritic cell vac- cination. J Clin Endocrinol Metab 86:4965-4969
108. Stift A, Sachet M, Yagubian R, Bittermann C, Dubsky P, Brostjan C, Pfrag- ner R, Niederle B, Jakesz R, Gnant M, Friedl J 2004 Dendritic cell vaccination in medullary thyroid carcinoma. Clin Cancer Res 10:2944-2953
109. Ortmann D, Hausmann J, Beuschlein F, Schmenger K, Stahl M, Geissler M, Reincke M 2004 Steroidogenic acute regulatory (StAR)-directed immuno- therapy protects against tumor growth of StAR-expressing Sp2-0 cells in a rodent adrenocortical carcinoma model. Endocrinology 145:1760-1766
110. Lake RA, Robinson BW 2005 Immunotherapy and chemotherapy-a prac- tical partnership. Nat Rev Cancer 5:397-405
111. Betz MJ, Shapiro I, Fassnacht M, Hahner S, Reincke M, Beuschlein F 2005 Peroxisome proliferator-activated receptor-y agonists suppress adrenocorti- cal tumor cell proliferation and induce differentiation. J Clin Endocrinol Metab 90:3886-3896
112. Ferruzzi P, Ceni E, Tarocchi M, Grappone C, Milani S, Galli A, Fiorelli G, Serio M, Mannelli M 2005 Thiazolidinediones inhibit growth and invasive- ness of the human adrenocortical cancer cell line H295R. J Clin Endocrinol Metab 90:1332-1339
113. Heaney AP, Fernando M, Melmed S 2003 PPAR-y receptor ligands: novel therapy for pituitary adenomas. J Clin Invest 111:1381-1388
114. Huang JW, Shiau CW, Yang YT, Kulp SK, Chen KF, Brueggemeier RW, Shapiro CL, Chen CS 2005 Peroxisome proliferator-activated receptor y-in- dependent ablation of cyclin D1 by thiazolidinediones and their derivatives in breast cancer cells. Mol Pharmacol 67:1342-1348
115. Shiau CW, Yang CC, Kulp SK, Chen KF, Chen CS, Huang JW, Chen CS 2005 Thiazolidenediones mediate apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 functions independently of PPARy. Cancer Res 65:1561-1569
116. Liu J, Li XD, Ora A, Heikkila P, Vaheri A, Voutilainen R 2004 cAMP- dependent protein kinase activation inhibits proliferation and enhances ap- optotic effect of tumor necrosis factor-a in NCI-H295R adrenocortical cells. J Mol Endocrinol 33:511-522
117. Fassnacht M, Hahner S, Beuschlein F, Klink A, Reincke M, Allolio B 2000 New mechanisms of adrenostatic compounds in a human adrenocortical cancer cell line. Eur J Clin Invest 30(Suppl 3):76-82
118. Rossi R, Zatelli MC, Valentini A, Cavazzini P, Fallo F, del Senno L, degli Uberti EC 1998 Evidence for androgen receptor gene expression and growth inhibitory effect of dihydrotestosterone on human adrenocortical cells. J En- docrinol 159:373-380
119. Zatelli MC, Rossi R, degli Uberti EC 2000 Androgen influences transforming growth factor-ß1 gene expression in human adrenocortical cells. J Clin En- docrinol Metab 85:847-852
120. Zatelli MC, Rossi R, del Senno L, degli Uberti EC 1998 Role of transforming growth factor ß1 (TGFß1) in mediating androgen-induced growth inhibition in human adrenal cortex in vitro. Steroids 63:243-245
121. Beuschlein F, Looyenga BD, Bleasdale SE, Mutch C, Bavers DL, Parlow AF, Nilson JH, Hammer GD 2003 Activin induces x-zone apoptosis that inhibits luteinizing hormone-dependent adrenocortical tumor formation in inhibin- deficient mice. Mol Cell Biol 23:3951-3964
122. Fassnacht M, Franke A, Dettling A, Hahner S, Zink M, Wudy S, Allolio B 2002 Clodronate inhibits adrenocortical cell proliferation and P450c21 activ- ity. J Endocrinol 174:509-516
123. Brown JW, Cappell S, Perez-Stable C, Fishman LM 2004 Extracts from two marine sponges lower cyclin B1 levels, cause a G2/M cell cycle block and trigger apoptosis in SW-13 human adrenal carcinoma cells. Toxicon 43:841- 846
124. Green S 1992 “Antineoplastons.” An unproved cancer therapy. JAMA 267: 2924-2928
125. 1998 The antineoplaston anomaly: how a drug was used for decades in thousands of patients, with no safety, efficacy data. The Cancer Letter, Vol 24, September 25, 1998
126. Burzynski SR 2004 The present state of antineoplaston research (1). Integr Cancer Ther 3:47-58
127. Arora A, Scholar EM 2005 Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther 315:971-979
JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community.