@ 2018 EDIZIONI MINERVA MEDICA Online version at http://www.minervamedica.it

Minerva Endocrinologica 2019 March;44(1):70-81 DOI: 10.23736/S0391-1977.18.02860-2

REVIEW

UNILATERAL NON-ALDOSTERONE-PRODUCING ADRENOCORTICAL TUMORS

New targeted therapies for adrenocortical carcinomas

Jacopo MANSO 1, Raffaele PEZZANI 1, 2 *

1Unit of Endocrinology, Department of Medicine (DIMED), University of Padua, Padua, Italy; 2Associazione Italiana per la Ricerca Oncologica di Base (AIROB), Padua, Italy

*Corresponding author: Raffaele Pezzani, Unit of Endocrinology, Department of Medicine (DIMED), University of Padua, Via Os- pedale, 105, 35128 Padua, Italy. E-mail: raffaele.pezzani@unipd.it

ABSTRACT

Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. It has undergone in-depth clinical and labora- tory investigations, with the help of the most important research groups all over the world. Nonetheless the cure for this kind of neoplasia is not right around the corner, given its complexity and multi-faceted feature, that lead researchers to think at “one person one ACC.” Currently total resection is the most concrete option for ACC patients, whenever pos- sible. Mitotane remains the main drug for primary or adjuvant therapy, but gives partial and unsatisfactory therapeutic results, especially in metastatic ACC. This prompted the researchers to find other ways to fight against this malignancy: targeted therapy seems the most promising answer, as it is based on biomolecular and genetic cancer signature. Numer- ous specific targets were explored for the treatment of ACC, such as those involving angiogenesis, steroidogenesis, Wnt/B-catenin pathway and many others key factors. Even if large efforts have been made, no effective target therapy entered in the clinical use. This data should not be considered only as detrimental, rather it should propel scientific re- search to invest more resources into the therapeutic exploration of ACC and in particular on the most promising strategy, the targeted therapy.

(Cite this article as: Manso J, Pezzani R. New targeted therapies for adrenocortical carcinomas. Minerva Endocrinol 2019;44:70-81. DOI: 10.23736/S0391-1977.18.02860-2)

KEY WORDS: Adrenocortical carcinoma - Adrenal cortex neoplasms - Molecular targeted therapy.

A drenocortical carcinoma (ACC) is an ag- gressive malignancy with poor prognosis. It has an overall incidence of 0.5-2 cases per mil- lion per year and a 5-year survival rate of 10- 47% at 5 years.1 The rate of recurrence is very high (40-65% after two years) also in patients with radical surgery as well as the development of distant metastasis.2 Therefore, adjuvant thera- py plays an important role in this disease.3

The clinical scenario of ACC is dominated by hypersecretion of adrenal steroids in about 60% cases: predominantly hypercortisolism with or without virilization or hyperandrogenism in

women. Estrogen secreting carcinomas are less frequent (5-10% of male) but if hyperestrogen- ism is present (gynaecomastia and testicular atrophy) it is pathognomonic for ACC.4 Non- secreting ACC presents with sign and symptoms of abdominal mass. From a clinical/biochemical point of view, hormonally inactive ACC produc- es steroids or steroid-precursors in at least 95% of cases, when urinary metabolites are investi- gated with more sensitive methods such as gas chromatography/mass spectrometry.5

Unenhanced computer tomography (CT) or magnetic resonance imaging (MRI) are both val-

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ADRENOCORTICAL CARCINOMAS

id tools for the differential diagnosis between be- nign and malignant adrenal masses, even if they cannot be considered conclusive.6 In doubtful cases, enhanced CT or fluorine 18 fluorodeoxy- glucose PET (FDG-PET) may be useful for clari- fying the nature of adrenal lesions.7 Furthermore metomidate-PET, a new radiotracer that specifi- cally bind to adrenocortical tissue, seems prom- ising in differentiating ACC or adrenocortical adenomas from adrenal metastasis or pheocro- mocytomas with high sensitivity and specificity.8

The ENSAT tumor stage is a classification sys- tem proposed by the European Network for the Study of the Adrenal Tumors (ENSAT)9 which revised the original TNM classification10 with a significant improvement in the stage-specific prognosis compared to the previous TNM classi- fication by the International Union Against Can- cer. Another important cornerstone in the evalua- tion of ACC is the Weiss score, a diagnostic tool based on 9 histopathological criteria which can identify an ACC with high specificity and sen- sitivity (96% and 100% respectively) when 3 or more microscopic criteria are met.11

ENSAT stage at diagnosis, Weiss Score and proliferation index (evaluated by Ki-67 stain- ing), are major prognostic factors, accompanied by the feasibility of radical surgery and margin free resection.11 ACCs are variable and multifac- eted in their behavior even with the same Weiss score value or ENSAT stage. ACC are variable and multifaceted in their behavior even within the same Weiss score value or ENSAT stage. Undeniably it is difficult to deal with this rare malignancy and clinicians often observe a differ- ent drug response or a diverse progression rate in apparently similar ACC patients. The clinical heterogeneity is strictly based with biomolecular diversity, indeed different mutations and altered pathways have been described in ACC samples and deeply examined in in vitro and in vivo ex- perimental models.12 The most known alteration is the overexpression insulin-like growth factor 2 (IGF-2) occurring in >90% of ACCs which is related to IGF/mTOR pathway.13 Also vascular endothelial growth factors (VEGF) is overex- pressed14 while Wnt/ß-catenin pathway is consti- tutively activated in >50% of ACCs.15 Estrogen receptors (ER) are active in ACC16 and TP53 mu-

tations are found in a subgroup of ACCs. 17 Many other molecular aberrations, such as differential gene expression (both up- and downregulation), epigenetic modifications, chromosomal aberra- tions, and mutations have been discovered: for a full description we refer to the following re- views.12, 15, 18 In this scenario, numerous thera- peutic approaches have been attempted, and tar- geted therapy seems the most promising strategy towards cancer and specifically towards a com- plex and intricate malignancy as ACC.

Current therapeutic strategies for adrenocortical carcinoma

The majority of the recommendations in ACC therapy derived from retrospective studies or personal experience with few prospective trials, due to the rarity of this disease. At present, ACC treatment is essentially based on radical surgery eventually associated to adjuvant mitotane thera- py.19 In advanced ACC chemotherapy associated with mitotane is the standard of cure but the re- sults remain little motivating, owing to the scarce response with no impact on overall survival (OS) and the important toxicity.20 The real utility of radiotherapy and other loco-regional treatment is still somewhat debated.

Surgery

Radical surgery, when feasible, is the mainstay in ACC and the only potentially curative. Laparo- tomic approach is preferable from ENSAT stage I to III in order to achieve a disease-free resec- tion margin (RO). In fact, RO resection is consid- ered a positive prognostic factor for OS,21 while tumor seeding during the procedure is an impor- tant negative prognostic factor. To achieve radi- cal surgery, resection of neighboring organs is often necessary, therefore it is recommended that the procedure is performed by a highly special- ized team. Unfortunately, despite RO resection, recurrences occur in about 50% of patients. Ret- rospective studies demonstrate that local lymph nodes excision is significantly associated with a reduction in recurrence in localized ACC.22 However, prospective studies are needed to sub- stantiate this data.

The possible use of laparoscopic technique

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ADRENOCORTICAL CARCINOMAS

in ACC is still debated. Indeed, there are no prospective trials that define the best approach. Some recent studies showed no differences in oncological outcomes by comparing the two techniques, or even a worse outcome in laparo- scopic approach.23 Nonetheless these are retro- spective studies with multiple biases, therefore “open” approach is still the recommended one.

Mitotane

Mitotane derives from the famous insecticide dichloro-diphenyl-dichloroethane (DDT) and needs hepatic metabolization in o,p-DDA (active form) to exert its adrenolytic and cytotoxic func- tion.24

Its mechanism of action is not yet fully un- derstood, but a possible explanation has been proposed by Sbiera et al. according to which it down-regulates steroidogenesis by inhibition of sterol-O-acyl-transferase 1 determining lipid- induced endoplasmic reticulum stress with ac- cumulation of toxic lipids.25 Nevertheless, it is the most important drug in ACC therapy both in adjuvant or advanced disease setting, and it is the unique approved by the US Food and Drug Ad- ministration and European Medicine Executive Agency.26 Great emphasis on the use of mitotane as an adjuvant derived from a large retrospective case-control study by Terzolo et al., where the recurrence free survival (RFS) was significantly improved compared to the 2 control groups (42 months vs. 25 and 10 months).2 OS was 110 months in the treated group compared to 52 and 67 months in the untreated groups. Controlling mitotane blood levels in treated patients is criti- cal to verify that blood levels are between 14-20 mg/dL.27 A recent revision of retrospective data showed that blood mitotane concentrations ≥ 14 mg/dL were associated with a prolonged RFS, while levels > 20 mg/dL were associated with a higher risk of gastrointestinal and central nervous system toxicity.28 Although the benefit of using this drug in ACC is widely recognized, its clini- cal usefulness in the most localized forms (stage I and II) and undergoing radical surgery is still debated. The ESMO guidelines recommend ad- juvant mitotane therapy in ACC patients (treated with radical surgery) at high-risk for local recur- rence as defined by ENSAT stage III, Ki-67>10%

and microscopically incomplete resection (R1) or resection status unknown (Rx). For low-risk patients (stage I-II, RO and Ki-67<10%) adjuvant mitotane treatment is not mandatory.19 In order to define the usefulness of mitotane in low risk ACC patients (surgically treated), an internation- al RCT called ADIUVO is ongoing. There are no clear indications on the duration of mitotane ad- juvant therapy, but experts recommend continu- ing for at least 2 years if well tolerated.11

Radiotherapy

ACC has long been considered a radioresistant tumor, though more recently it has been shown some response to irradiation.29 In a retrospective study involving the German ACC Registry, tumor bed irradiation after surgery improved RFS at 5 years, but no difference in OS was observed.30 Even in a United States retrospective series, ad- juvant radiotherapy was able to reduce the lo- cal recurrence/progression risk by 4.7 times.31 Adjuvant radiotherapy could be an important therapeutic option, even if its impact on survival remains doubtful. So, radiotherapy in adjuvant setting should be considered for patients at high risk for local recurrence, i.e. R1 or Rx resection status or locally advance disease (stage III) and often administered concomitantly with mitotane to exploit a synergistic effect reducing the dai- ly dose of mitotane (<3 g/day).29 However, the level of evidence for these recommendations is low and future prospective trials are needed to better understand the effective potential of this treatment.

Standard pharmacological therapy in advanced ACC

Advanced ACC is characterized by poor prog- nosis, rapid progression and no effective treat- ments.4 Nevertheless, it is reported that a small number of patients are responsive to therapy and have a long survival.32 Surgery, when fea- sible, should be the first approach to metastatic or local recurrent disease. About 30% of ACCs are metastatic (stage IV) at the diagnosis:33 radi- cal surgery of primary lesion and metastasis is mandatory. In fact, metastasectomized patients (pulmonary or hepatic lesions) showed a long-

ADRENOCORTICAL CARCINOMAS

term survival and retrospective analysis demon- strated a positive influence of metastasis surgical excision with a 41% of OS.34 In some cases, the management of a large mass determining com- pression or hormonal excess requires debulking surgery to ameliorate symptoms.

Mitotane can be used alone or in combination with other chemotherapeutic agents, yet data from prospective studies on the use of mitotane in advanced ACC are lacking. Mitotane mono- therapy in advanced ACC should be used only in case of metastatic involvement of few districts, recurrence after many years (from surgery) and low Ki-67 index.35 These indications, in a pal- liative setting, were confirmed also by a very re- cent retrospective study analysis which included 127 patients with advanced ACC from German ACC Registry and ENSAT Registry treated with mitotane monotherapy.36 In this cohort 20% of patients experienced an objective response and 22% obtained disease control >12 months. Late diagnosis of advanced disease (mitotane initia- tion >360 days after primary diagnosis) and low tumor burden (<10 tumor lesions) resulted a pre- dictive factor for a better response to mitotane monotherapy.

At present, chemotherapy plays a major role in the treatment of advance metastatic ACC. Mitotane is administered in combination with chemotherapy due to its synergistic effects. In- deed, mitotane can inhibit the multidrug resis- tance protein-1 (P-glycoprotein) which is widely expressed in ACC cells and it is one of the key mechanisms of tumor escape from chemothera- py.37 Many combinations of chemotherapeutic agents have been studied in the past, but the most promising results were obtained using mitotane in association with etoposide, doxorubicin and cisplatin (EDP) or streptozotocin. The EDP-mi- totane protocol was proposed by Berruti et al., while the streptozotocin-mitotane one by Khan et al. The EDP-mitotane schedule, in the origi- nal study, obtained an overall response rate of 48.6% with 5 complete and 30 partial responses in a total of 72 ACC patients not amenable to surgery.38 The streptozotocin-mitotane schedule obtained an overall response rate of 36.4% with 1 complete and 7 partial responses.39 To evalu- ate the best treatment option in advanced ACC

between these two regimens, the First Interna- tional Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treat- ment (FIRM-ACT) was carried out and the re- sults showed the advantage of the EDP-mitotane protocol. Indeed, the EDP regimen obtained a better tumor response (23% vs. 9%) and an in- creased median progression free survival (PFS) (5 vs. 2.1 months).20 Yet, no difference in OS was achieved, again underlining the poor prognosis of advanced ACC patients. Therefore, EDP-mi- totane regimen is currently the first line therapy in advance ACC.

Given the unsatisfactory results with first-line chemotherapy, many patients require salvage therapy: gemcitabine plus metronomic 5-fluoro- uracil or capecitabine have been proposed as the second and third-line regimens, however achiev- ing very modest results.40

Other local therapies

Minimally invasive procedures are getting in- creasing interest in management of metastatic lesions. Radiofrequency thermal ablation (RFA) may have a role in local control of ACC repeti- tive lesions. Wood et al. performed RFA in liver, kidney, lymph nodes and lung ACC metastasis obtaining 53% of growth arrest in 8 of 15 lesions at 6 months.41 Another interventional radiology technique is the transarterial chemoemboliza- tion (TACE) and it has been used in 29 advanced ACC patients with liver metastasis achieving a median survival of 11 months.42

These minimally invasive techniques may be considered for local control of disease and com- pared to surgery show a safer and less expansive profile; nevertheless, prospective trials are lack- ing and are necessary to evaluate the results in term of local disease control in comparison with surgery.

Targeted therapy

Conventional therapies in metastatic and unre- sponsive ACC have failed in the treatment of ACC. This result has led clinicians to look at novel approaches to manage ACC patients and indeed recent works on new oncosuppressors or oncogenes involved in the pathogenesis of ACC

MANSO ADRENOCORTICAL CARCINOMAS TABLE I .- Clinical trials on targeted therapy for ACC and their status. *Terminated: interrupted before the deadline for poor results. provided the knowledge to extend the molecu- lar tools to fight against this malignancy (Table I, Figure 1). bined with capecitabine in 10 patients, but no stable disease or partial response have been re- ported.45 Sorafenib, a multi-targeted tyrosine kinase in- Angiogenesis in targeted therapy hibitor that can bind to VEGFR, platelet-derived growth factor (PDGFR) and RAF-1, has been evaluated in 25 patients (a multicenter phase II study) in association with metronomic pacli- taxel did not give any clinical recovery,46 even if preclinical data advised good expectations for sorafenib.47 Of note as a previous phase I study reported sorafenib combined with tipifarnib, a farnesyltransferase inhibitor, to induce a positive response in 2 ACC patients.48 Similarly a case report suggested as sorafenib could be clinically useful: one patient with metastatic ACC showed regression.49 Unfortunately these exceptional re- sults were rather anecdotal than a rule. Angiogenesis is the physiological process of new blood vessels formation, which starts from pre- existing blood vessels. Blocking angiogenesis by targeting pro-angiogenic factors such as vascu- lar endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and angiopoietin-1 (Ang-1) is a current and a promising strategy for the differ- ent solid tumors.43 VEGF and VEGF receptor 2 (VEGFR2) are frequently altered in cancer and also ACC showed an increase in VEGF expres- sion.44 Consequently different clinical trials have been attempted without the expected results. For Similar to sorafenib, sunitinib, a multi-tar- geted tyrosine kinase inhibitor that can bind to VEGFR2, platelet-derived growth factor recep- example bevacizumab, a monoclonal antibody successfully used for other diseases, was com- cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher. CAT1: acyl coenzyme A cholesterol acyltransferase; AXL: GAS6 receptor; c-kit: stem cell ligand receptor; c-MET: hepatocyte growth factor receptor protein; CTLA-4: cytotoxic T lymphocyte-associated antigen 4; EGF: epidermal growth factor; EGFR, epidermal growth factor receptor; ER: endoplasmic reticulum; FGFR: fibroblast growth factor receptor; IGF1R: insulin-like growth factor 1 receptor; IR: insulin receptor; mTOR: mammalian target of rapamycin; PD-1: programmed cell death protein 1; PDGF: platelet-derived growth factor; PDGFR: platelet-derived growth factor receptor; PD-L1: programmed death-ligand 1; TGF-beta: transforming growth factor beta; VEGF-A: vascular endothelial growth factor A; VEGFR: vascular endothelial growth factor receptor. 74 MINERVA ENDOCRINOLOGICA

Target therapy	Molecular target or pathway	Status
Axitinib	Inhibition VEGFR-1, VEGFR -2, VEGFR -3	Completed
Bevacizumab + capecitabine	Inhibition VEGF-A + chemotherapy	Terminated
Cabozantinib	Inhibition c-MET, VEGFR2, RET, AXL	Recruiting
Sorafenib + metronomic paclitaxel	Inhibition VEGFR, PDGFR, RAF-1 + chemotherapy	Terminated
Sorafenib + tipifarnib	Inhibition VEGFR, PDGFR, RAF-1 + inhibition arnesyltransferase	Completed
Sunitinib	Inhibition VEGFR-2, PDGFR-b, c-kit	Completed
Sunitinib + sirolimus	Inhibition VEGFR-2, PDGFR-b, c-kit + inhibition mTOR	Completed
Suramin	Inhibition EGF, PDGF, TGF-beta	Terminated
Erlotinib + gemcitabine	Inhibition EGFR + chemotherapy	Completed
Gefitinib	Inhibition EGFR	Terminated*
Imatinib	Inhibition ABL, PDGFR, c-kit	Unknown
Imatinib + dacarbazine + capecitabine	Inhibition ABL, PDGFR, c-kit + chemotherapy	Unknown
Dovitinib	Inhibition FGFR	Completed
Linsitinib (OSI-906)	Inhibition IGF1R, IR	Completed
Cixutumumab	Inhibition IGF1R	Completed
Cixutumumab + mitotane	Inhibition IGF1R + ER stress	Completed
Cixutumumab + temsirolimus	Inhibition IGF1R + inhibition mTOR	Unknown
Temsirolimus + lenalidomide	Inhibition mTOR + immunomodulatory and antiangiogenic	Unknown
ATR-101	Inhibition ACAT1	Completed
IL-13 pseudomonas exotoxin	immunotherapy	Unknown
Avelumab	Binds to PD-L1 with Inhibition PD-1	Recruiting
Nivolumab	Inhibition PD-1 (immunotherapy)	Active, not recruiting
Nivolumab + ipilimumab	Inhibition PD-1 + inhibition CTLA-4 (immunotherapy)	Recruiting
Pembrolizumab	Inhibition PD-1 (immunotherapy)	Recruiting

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Figure 1 .- Conventional chemotherapy and targeted therapy.

Conventional chemotherapy Cytotoxic drugs can interact with DNA to avoid cell replication without specificity to cancer cells

Paradigmatic shift for cancer treatment

Targeted therapy

Specific mechanism of action induces increase in therapeutic index

Depending on identifying specific target for cancer treatment

Targeted therapy for ACC

Angiogenesis c-MET

Epidermal growth factor receptor (EGFR) Fibroblast growth factor receptors (FGFR) Insulin-like growth factor (IGF) Mammalian target of rapamycin (mTOR) Steroidogenesis inhibition Wnt/B-catenin pathway Immunotherapy

tor b (PDGFRb) and stem cell ligand receptor (c-kit), have been tried in 38 patients (a single arm phase II study) with unresponsive ACC.50 The study reported a median PFS of 2.8 months and a stable disease for 5 patients which had an increased PSF (between 5.6 and 11.2 months). Interestingly the work found a negative cor- relation between the serum concentrations of sunitinib and mitotane. Mitotane is an inducer of CYP3A4 activity, thereby can potentially at- tenuates antitumor activity of sunitinib if used in combination. Again a case report experienced a partial response (7.5 months) for a patient treated with sunitinib after failure of mitotane.51 More recently sunitinib was associated with sirolimus, an mTOR inhibitor, in one ACC patient with par- tial response.52

Axitinib, a selective inhibitor of VEGFR1, -2, and -3, was evaluated in 13 metastatic pa- tients treated or not with chemotherapeutics or mitotane. The authors described a reduced PFS of 5.5 months and a stable disease of 3 months

in 8 patients, suggesting as axitinib had limited effectiveness in ACC and therefore other targets should be explored.53

Suramin, a polysulfonated polyaromatic sym- metrical urea used in the treatment of trypano- somiasis and onchocerciasis, was tested in 13 patients with advanced ACC, however no result was posted.54

c-MET in targeted therapy

c-MET, a tyrosine-protein kinase with a fun- damental role for embryonic development, or- ganogenesis and wound healing, has been found dysregulated in many cancer types triggering metastasis and invasion.55 A recent work ana- lyzed MET gene amplification in patients with advanced cancers in phase I study, among which 13 had ACC.56 Only 2 presented MET amplifi- cation status, nonetheless treatment with c-MET inhibitor gave no response or clinical benefit.

Similarly, a phase I trial of a selective non- adenosine triphosphate competitive c-MET in- hibitor tivantinib (ARQ 197) was tested in 51 pa- tients with solid tumors, of which only one had ACC. For this patient no specific information is available, however in general stable disease ≥4 months was observed in 14 patients with c-MET signaling blockade.57

Epidermal growth factor receptor in targeted therapy

Epidermal growth factor receptor (EGFR) is a member of the ErbB family of receptor tyrosine kinases, upregulated in many cancer cell types including ACC.58-62 EGFR can mediate prolifer- ation and survival signaling and is implicated in migration, invasion and resistance to cell death- inducing signals.

Erlotinib is an EGFR tyrosine kinase inhibi- tor the effects of which were also evaluated in ACC.62 Erlotinib was combined with gemcitabi- ne as a salvage chemotherapy in 10 patients af- fected by very advanced ACC and only one ex- perienced a minor response (median PFS of 8 months). The authors established that erlotinib plus gemcitabine had no benefit, at least for pa- tients with metastatic or locally advanced or re- current ACC.

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On the same line, gefitinib, another EGFR ty- rosine kinase inhibitor, was preliminarily stud- ied in 18 patients (a multicenter phase II trial) with unresectable ACC.63 No responders, partial responders or patients with stable disease was reported, suggesting again as this drug had no clinical activity in ACC patients. This work can be identified with the Clinical Trial code identi- fier NCT00215202, even if no result was posted.

Only one work analyzed the effects of ima- tinib mesilate, a selective inhibitor of the ABL, PDGF receptor (PDGFR) and c-kit tyrosine ki- nases. The phase II study was approved for en- docrine malignancies, of which 4 were ACC. No objective response was observed, with disease progression for 3 and 1 discontinuation for ad- verse effects.64 Moreover imatinib, associated with dacarbazine and capecitabine, was evalu- ated in 6 ACC patients, one with partial response and another with minor response, with a PFS of 8.8 and 6.4 months, respectively.65

Fibroblast growth factor receptors in targeted therapy

Fibroblast growth factor receptors (FGFR) are a class of receptors involved in multiple devel- opmental processes, tissue repair, angiogenesis and inflammation.66 A phase 1/2 study tested derazantinib (ARQ 087), an oral pan-FGFR in- hibitor, in a cohort of patients with solid cancer, of which 4 had ACC. Only one ACC patient showed FGFRI amplification and stable disease, at least for the at ≥16 weeks of observation with tumor reduction.67

Moreover dovitinib, a tyrosine kinase inhibitor of FGFR, was tested in 17 patients with unresect- able ACC (a phase II trial) resulting in one partial response. The median PFS was 1.8 months and no improvement of overall survival was shown even if about 23% of patients had stable disease (>6 month).68

Insulin-like growth factor in targeted therapy

Insulin-like growth factor (IGF) system plays a key role in normal cell and in tumor cell biol- ogy. IGF system is comprised 2 ligands (IGF1 and IGF2), which are structurally similar to in- sulin, and 2 tyrosine kinase receptors (IGF1R

and IGF2R). Importantly IGF1R signaling as a therapeutic target has been broadly studied and clinically explored.69 In ACC IGF2, IGFR1 and insulin receptor (IR) have been found overex- pressed suggesting a pivotal role for this path- way in adrenocortical tumorigenesis.70, 71

OSI-906 (linsitinib), a dual inhibitor of IG- FIR and IR, was first evaluated in 72 patients (of which 15 ACCs) with advanced solid tumors in a multicenter phase I study.70 It was reported that 2 ACC patients had partial response, there- fore a double-blind randomized phase III trial of 139 patients with locally advanced or metastatic ACC was successively performed.72 Despite the high expectations for the study, the drug did not show a statistical difference in PFS (44 vs. 46 days, P=0.30) or OS (323 vs. 356 days, P=0.77) in ACC patients when compared to placebo and consequently the study was prematurely stopped. Given the importance of IGF pathway in ACC, different hypothesis emerged for linsitinib fail- ure. One potential detrimental interaction might reside in mitotane treatment: it is known that this drug can interact with CYP3A4, as linsitinib.73 Indeed >90% of patients of the clinical trial was exposed to short mitotane wash out period. Furthermore, whether linsitinib reached its mo- lecular targets is still questioned. And it should not be forgotten that, even if IGF system plays a key role in ACC, this neoplasia is the result of numerous drivers alterations.12 Only multiple or combined targeting could potentially induce a curative effect, as suggested in other malignan- cies.74

Similarly cixutumumab, a human monoclonal antibody that targets IGF1R, was associated with mitotane as a first-line treatment in unresectable recurrent/metastatic 20 ACC patients (multi- center, randomized double-arm phase II trial).75 Therapeutic effects were present in 8 patients, (1 partial response and 7 stable diseases) with a me- dian PFS of 6 weeks. Again the authors conclud- ed that the combination regimen demonstrated low therapeutic efficacy.

Furthermore, cixutumumab was associated with temsirolimus (an mTOR inhibitor) in 10 advanced ACC patients (a phase I dose escala- tion study) and 4 of them had stable disease (>7 months).76 Given the promising results, the study

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proponents enlarged ACC cohort and studied 26 patient, 11 of which (42%) demonstrated stable disease >6 months (23412108). The authors sug- gested as cixutumumab and temsirolimus were well tolerated, but exhibited modest activity in refractory ACC. The rationale of double target- ing key factors such as IGF1R and mTOR should be also considered in future enlarged studies.

Mammalian target of rapamycin in targeted therapy

Mammalian target of rapamycin (mTOR) is a serine-threonine kinase known to sense cell en- ergy status and the environmental and cell nu- trition. It has pivotal role in cell growth, prolif- eration, development, longevity and many other aspects of cell life and is frequently dysregulated in cancer.77

Temsirolimus is an mTOR inhibitor was eval- uated in 3 advanced ACC patients (a phase I tri- al) in association with lenalidomide, an immuno- modulatory and antiangiogenic drug.78 Only one patient showed stable disease (>6 months) and the median PFS was 2.2 months, while median overall survival was 7.8 months.

A role for mTOR in adrenocortical tumors has been demonstrated by some preclinical stud- ies,47, 79 while only one work explored prelimi- narily everolimus, another mTOR inhibitor, in 4 advanced ACC patients.80 Of note that two pa- tients associated everolimus to mitotane, though no patients had beneficial response (all had pro- gressive disease).

Steroidogenesis inhibition in targeted therapy

ATR-101, a selective inhibitor of acyl coen- zyme A cholesterol acyltransferase (ACAT1), is now being studied in a phase I clinical trial (NCT01898715) in 63 participants enrolled for determining safety and tolerability of the drug.81 Indeed ACAT1 is located in the endoplasmic re- ticulum (ER) where it drives the esterification of free cholesterol into cholesterol esters.82 Its inhibition leads to adrenal toxicity, mediated by ER stress and calcium release which in turn in- duces to cell death.83 These are the premises that directed the clinicians to the above mentioned clinical trial.

Alongside ATR-101, steroidogenic factor-1 (SF-1), a nuclear transcription factor involved in the steroidogenic tissue, has been associated with poor prognosis, being amplified and over- expressed in ACC.84 Different preclinical works analyzed the effectiveness in reducing prolifera- tion of ACC cell lines using inverse agonists of SF1, nonetheless no clinical trials have been yet endeavored.85

Wnt/B-catenin pathway in targeted therapy

Wnt/ß-catenin pathway is involved in embryonic development, controlling cell proliferation and migration, and has a pivotal role in the develop- ment of many different tumors.86 It is well known that the pathway is altered in ACC, indeed more than 50% of ACCs has been shown to have con- stitutive activation of this pathway, especially through -catenin mutations. 15, 87 A phase I study with CWP232291, a small molecule that inhib- ited Wnt-mediated transcriptional activity, was tested in acute myeloid leukemia patients and other hematological tumors, but yet no results are available.88 Numerous compounds are in clini- cal development (most in phase I clinical trial), unfortunately none specific for ACC.89 It should be noted that also adrenocortical tumors possess B-catenin mutations and this fact needs to be in depth considered in the future development of a Wnt/B-catenin targeted therapy for ACC.

Immunotherapy in targeted therapy

Immunotherapy is a promising strategy devel- oped in the last decades which tries to sustain and instruct immune system to eliminate cancer cells. It is essentially based on immune check- point inhibitors, molecules that act by inhibiting the mechanisms of immune escape.90 Given the stimulating effects of these compounds in several tumors, there is now the urgent need to test them also in ACC patients. In this sense programmed cell death protein ligand 1 (PD-L1) has been pre- liminarily studied. PD-L1 is a part of the PD-1/ PD-L1 axis, fundamental for accurate regulation of the T-cell response, implicated in many im- mune processes including inflammation and au- toimmunity.91 Indeed a prospective case-control phase 0 study has been started in 2007 and is still

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MANSO

ongoing (NCT00457587), while another work studied PD-L1 expression by IHC in 28 ACC pa- tients in both tumor cell membrane and tumor in- filtrating mononuclear cells without association with clinico-pathologic parameters or survival.

Another phase I clinical trial explored the use of interleukin-13-Pseudomonas exotoxin in 5 patients with metastatic ACC.92 The drug is a recombinant cytotoxin consisting of human in- terleukin-13 (IL-13) with a truncated form of Pseudomonas exotoxin A. While one patient had stable disease (about 5 months) the others pro- gressed within 1-2 months. The rationale of the work was based on the higher expression of in- terleukin 13 in ACC compared to normal adrenal tissue.

So far the use of targeted therapy shows little impact on ACC therapy. Different targets are po- tentially available to impact on ACC treatment and many drugs combination can be explored. Some encouraging results arose from preclinical data, but translating these effects into a true phar- macological therapy is still a great challenge.

Future perspectives and conclusions

Limited data are available for targeted therapy in ACC, especially if we consider clinical trial ap- proach12 (Table I). Nonetheless interesting bio- molecular data continuously emerge from pre- clinical experimentations. A recent work reported that novel key factors could have potential thera- peutic impact for patients with advanced ACC.93 Indeed De Martino et al. showed that, in addition to the above mentioned druggable targets, DNA- damage response and G1 cell cycle progression are fundamental pathways in ACC. For example ATM serine/threonine kinase, STK11, and GNAS are altered in a subset of ACC patients, similarly to cyclin dependent kinase 4 (CDK4) amplifica- tion and CDKN2A and CDKN2B deletion. The authors suggested that no simple molecular-driv- en targeted approach could be decisive, as ACC lacks of a single druggable molecular altera- tion. Likewise, these data were confirmed and expanded by next-generation sequencing based genomic profiling reporting numerous genomic alterations.94 The authors suggested the impor- tance of targeting Hedgehog pathway and RAS

signaling (in addition to the other common altera- tions in mTOR, EGFR and CDK pathways) with specific inhibitors for a future targeted therapy. Furthermore Costa et al. hinted that DNA meth- ylation could be a potential therapeutic target, as provided by cytosine methylation inhibitor in in vitro results.12 The authors proposed that also mi- croRNAs (mainly used for distinguishing adeno- mas from ACC or other tumors) could be thera- peutically attractive, being involved in apoptotic pathway at least in cell models.12 These works stress as ACC is a complex and multifaceted malignancy with numerous alterations identified and with resistance to conventional therapies. No clear or univocal target seems to have a pivotal therapeutic role in ACC. Nonetheless researchers all over the world, including the ENSAT group, are joining and have joined their resources and strength to fight against this rare malignancy. In particular fundamental works recently emerged, which analyzed the “omics” of patient samples affected by ACC.18,95-97 These data give potential insights into a targeted therapy and a personal- ized medicine approach to ACC. A recent work based on a small cohort of ACC patients suggest that targeted therapy might not be always use- ful, mostly due to complexity and variability of genetic and epigenetic ACC background.98 How- ever, we should not dismiss the potential of tar- geted therapy, but we need to approach it with a multidisciplinary and personalized approach. Our hope is that these strategies will walk togeth- er in a clinical setting to ameliorate the prognosis and to achieve effective cure for ACC patients.

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Conflicts of interest .- The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.

Article first published online: May 28, 2018. - Manuscript accepted: May 9, 2018. - Manuscript received: April 21, 2018.

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New targeted therapies for adrenocortical carcinomas

ABSTRACT

Current therapeutic strategies for adrenocortical carcinoma

Surgery

Radiotherapy

Other local therapies

Targeted therapy

c-MET in targeted therapy

Insulin-like growth factor in targeted therapy

Steroidogenesis inhibition in targeted therapy

Wnt/B-catenin pathway in targeted therapy

Immunotherapy in targeted therapy

Future perspectives and conclusions

References

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