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CCR Focus

Promising Therapeutic Targets in Neuroblastoma

Katherine K. Matthay, Rani E. George and Alice L. Yu
Katherine K. Matthay
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Rani E. George
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Alice L. Yu
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DOI: 10.1158/1078-0432.CCR-11-1939 Published May 2012
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Abstract

Neuroblastoma, the most common extracranial solid tumor in children, is derived from neural crest cells. Nearly half of patients present with metastatic disease and have a 5-year event-free survival of <50%. New approaches with targeted therapy may improve efficacy without increased toxicity. In this review we evaluate 3 promising targeted therapies: (i) 131I-metaiodobenzylguanidine (MIBG), a radiopharmaceutical that is taken up by human norepinephrine transporter (hNET), which is expressed in 90% of neuroblastomas; (ii) immunotherapy with monoclonal antibodies targeting the GD2 ganglioside, which is expressed on 98% of neuroblastoma cells; and (iii) inhibitors of anaplastic lymphoma kinase (ALK), a tyrosine kinase that is mutated or amplified in ∼10% of neuroblastomas and expressed on the surface of most neuroblastoma cells. Early-phase trials have confirmed the activity of 131I-MIBG in relapsed neuroblastoma, with response rates of ∼30%, but the technical aspects of administering large amounts of radioactivity in young children and limited access to this agent have hindered its incorporation into treatment of newly diagnosed patients. Anti-GD2 antibodies have also shown activity in relapsed disease, and a recent phase III randomized trial showed a significant improvement in event-free survival for patients receiving chimeric anti-GD2 (ch14.18) combined with cytokines and isotretinoin after myeloablative consolidation therapy. A recently approved small-molecule inhibitor of ALK has shown promising preclinical activity for neuroblastoma and is currently in phase I and II trials. This is the first agent directed to a specific mutation in neuroblastoma, and marks a new step toward personalized therapy for neuroblastoma. Further clinical development of targeted treatments offers new hope for children with neuroblastoma. Clin Cancer Res; 18(10); 2740–53. ©2012 AACR.

Introduction

Neuroblastoma, the most common extracranial solid tumor in children, is derived from primordial neural crest cells that ultimately inhabit the sympathetic ganglia and adrenal medulla. The clinical behavior, which ranges from spontaneous maturation to inexorable progression despite multimodal intensive therapy, is attributable to molecular differences in the tumor. The high-risk clinical prognostic factors of age >18 months and advanced stage are closely associated with unfavorable biologic risk factors, including unfavorable histopathology, tumor amplification of the MYCN oncogene, and loss of heterozygosity of 1p and 11q, or other partial chromosome deletions (1). The 5-year event-free survival (EFS) rate for high-risk neuroblastoma is <50%, including patients with metastatic neuroblastoma with ages >18 months, and patients with locoregional or metastatic neuroblastoma with tumor MYCN gene amplification (2). Until recently, the best outcome reported for high-risk neuroblastoma was achieved with intensive combination induction chemotherapy and surgery, followed by myeloablative therapy with hematopoietic stem cell rescue, and then differentiation therapy with isotretinoin (3), the first tumor-targeted therapy with demonstrated activity in neuroblastoma.

Although extensive laboratory studies and some early clinical trials have focused on small-molecule inhibitors and antibodies targeting relevant genetic pathways implicated in neuroblastoma proliferation [e.g., phosphoinositide 3-kinase (PI3K), mTOR, insulin-like growth factor I receptor (IGF-IR), among many others], in this review we will put into perspective 2 of the most successful, extremely tumor-specific agents in current use that may further improve outcome, and evaluate a third, more recent addition to the armamentarium. The first is 131I-metaiodobenzylguandine (MIBG), which targets human norepinephrine transporter (hNET, expressed in 90% of neuroblastoma tumors) for cell-specific uptake and then destroys the cell with the targeted radiation (4). The second is anti-GD2 antibody, which targets GD2 ganglioside (expressed on >98% of neuroblastomas) and mediates immune destruction of the cells. This antibody combined with cytokines improves survival for patients with high-risk disease (5). The third target is the anaplastic lymphoma kinase (ALK) gene, which encodes a receptor tyrosine kinase and has now been implicated as an oncogenic driver in neuroblastoma. ALK mutations are found in 8% to 12% of neuroblastomas at diagnosis (6, 7), and germline ALK mutations are responsible for the majority of familial cases (8, 9). Small-molecule inhibitors with proven utility in ALK-rearranged cancers (10) have shown promise in preclinical studies in neuroblastoma, and early-phase clinical trials are under way. Other targeted approaches to treat neuroblastoma and other pediatric malignancies are addressed elsewhere in the Focus section of this issue of Clinical Cancer Research (11–15).

Targeting hNET with MIBG

The observation that 90% of tumors are MIBG-avid provides the rationale for using 131I-MIBG as a targeted radiopharmaceutical for high-risk neuroblastoma. MIBG is an aralkylguanidine norepinephrine analog that was originally developed to visualize tissue of sympathetic neuronal origin, and has now become an essential tool for neuroblastoma staging and response (Fig. 1; ref. 16). Early clinical trials (Table 1A) in relapsed neuroblastoma showed that 131I-MIBG was effective at producing significant response rates, and that the only severe acute toxicity was myelosuppression, which could be abrogated by hematopoietic stem cell transplant (17–21). The activity administered has varied: Set total amounts of 50 to100 mCi were given in earlier European studies regardless of patient size, and one U.K. study based the dose on the amount needed to limit whole-body radiation to 1 to 2 Gy. Studies in the United States used weight-based dosing, which correlated significantly with the whole-body radiation received (22). The maximum practical weight-based dose in a phase I trial was established as 18 mCi/kg. This dose was then tested in a large phase II study of 164 patients, 30% of whom required hematopoietic stem cell support to prevent prolonged myelosuppression. Minor acute toxicities were grade 1 or 2 nausea and vomiting, parotid pain, and (rarely) changes in blood pressure. Late toxicities included a 12% incidence of grade 2 hypothyroidism, despite the routine use of a saturated solution of potassium iodide to block thyroid uptake of free radioactive iodide (23), and the rare occurrence of ovarian failure or myelodysplastic syndrome with acute myeloid leukemia in <5% of patients (24). Of importance, almost all of these studies reported impressive response rates in relapsed disease, and in the largest phase II trial, 37% of patients had a partial response (PR) or complete response [CR (20)].

Figure 1.
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Figure 1.

MIBG uptake in neuroblastoma. A, the left panel shows the similar structures of norepinephrine and MIBG, both of which are taken up via hNET. On the right, HEK293 cells transfected with hNET show an ∼15-fold higher uptake of 123I-MIBG over the HEK-EV transfected cells. B, the CT scan (left) shows the lung metastases and retroperitoneal mass in a child with recurrent neuroblastoma at the time of 131I-MIBG therapy. The uptake of 131I-MIBG (right) in the tumors is shown at 4 days after infusion of 18 mCi/kg (total activity infused = 340 mCi). EV, empty vector.

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Table 1.

Key clinical trials of therapies for neuroblastoma targeting hNET with MIBG, GD2 ganglioside with anti-GD2 antibody, and ALK aberrations with small-molecule inhibitors

Increasing tumor radiation dose

Attempts to further improve response rates included increasing the dose and using a different iodine isotope or a higher specific activity form of the molecule (Table 1A). Because of radiation safety limitations, investigators in a recent phase I study increased the dose by administering a rapid-sequence double infusion given 2 weeks apart and supported by hematopoietic stem cell transplant (25). In this fashion, a single patient could receive as much as 42 mCi/kg over a 2-week period; however, the response rate in this small population of patients did not appear to be different from that obtained with the standard 18-mCi/kg dose. Other investigators reported a benefit from repeated MIBG infusions given 6 to 12 weeks apart, with continued improved response in some of the patients with each successive infusion (26, 27). One small phase I trial (28) used 125I-MIBG rather than the usual 131I-MIBG, based on the hypothesis that the different isotope would be more effective for microscopic tumors or single cells, because the Auger electrons travel only a few nanometers, whereas the β particles of 131I are more effective in tumors >1 mm. Myelosuppression was significant despite a lower whole-body radiation dose. Recently, a New Approaches to Neuroblastoma Therapy (NANT) phase I trial of “no-carrier-added” 131I-MIBG was conducted based on preclinical data that nonradioactive carrier MIBG molecules in the standard preparation of MIBG (specific activity: 1.2 MBq/μg) inhibit uptake of 131I-MIBG, resulting in less tumor radiation and increased risk of cardiovascular toxicity (29). In the no-carrier-added preparation of MIBG, virtually every molecule is radioactive (specific activity: 165 MBq/μg). The NANT trial showed toxicity and response profiles similar to those observed with the standard preparation, but this approach had the advantage of being able to be infused over 30 minutes instead of 90 to 120 minutes (30).

Combining MIBG with radiosensitizers or chemotherapy

As another approach to improve efficacy, investigators have designed combination therapies by adding chemotherapy or other radiosensitizers to the MIBG (Table 1A). Exploratory studies showed the feasibility of giving 7 to 15 mCi/kg of 131I-MIBG followed 10 to 14 days later by myeloablative doses of carboplatin, etoposide, and melphalan (31–34). A phase I study of 24 patients with refractory neuroblastoma established the maximum tolerated dose (MTD) at 12 mCi/kg of 131I-MIBG, with carboplatin 1,500 mg/m2, etoposide 1,200 mg/m2, and melphalan 210 mg/m2. The dose-limiting toxicities were mucositis, vascular leak, veno-occlusive disease, and sepsis; however, only 1 toxic death occurred (35). A subsequent NANT phase II study of 50 patients reported the main toxicity as veno-occlusive disease, with 7 out of 50 responses in this highly refractory group of patients (36).

Other studies focused on using 131I-MIBG combined with chemotherapy or radiosensitizers in a nonmyeloablative regimen in refractory patients. Italian investigators treated 16 patients with relapsed or refractory neuroblastoma with 200 mCi 131I-MIBG combined with cisplatin and cyclophosphamide with or without etoposide and vincristine, and obtained 12 PRs (37). Two studies [a European study of topotecan with double infusion of MIBG (38), and a NANT phase I study of irinotecan and vincristine with MIBG (39)] combined MIBG with a camptothecin, with tolerable toxicity and measurable responses. Recent preclinical data showed additive growth inhibition from a combination of a histone deacetylase inhibitor (vorinostat) with radiation in a metastatic murine neuroblastoma model (40). In addition, vorinostat increased uptake of MIBG in neuroblastoma tumors via increased expression of hNET (41). These findings led to a NANT phase I study of vorinostat combined with 131I-MIBG, which is currently enrolling patients at dose level 5 (MIBG, 18 mCi/kg, vorinostat, 230 mg/m2), and has shown no dose-limiting toxicity to date. Other radiosensitizers are under study in preclinical testing for neuroblastoma and may prove useful in the future (42).

A few recent studies tested the incorporation of MIBG therapy into induction for newly diagnosed patients (Table 1). At a center in Amsterdam, Netherlands, a population of 41 patients who had been treated with 2 cycles of 131I-MIBG before addition of chemotherapy, had a response rate to MIBG of 66% (43). German studies evaluated the addition of MIBG therapy at the end of induction and before myeloablative therapy for patients with residual MIBG-positive disease and reported a response rate of 46% but no improvement in overall survival [OS (44)]. A Children's Oncology Group (COG) pilot trial (ANBL09P1) will test the addition of MIBG with vincristine and irinotecan prior to myeloablative therapy for all high-risk patients, regardless of residual disease, and if feasibility and tolerability are shown, a randomized trial will be undertaken.

Future perspectives for MIBG

131I-MIBG therapy is a promising strategy that now requires randomized testing in newly diagnosed high-risk patients. The practicality of this targeted radiopharmaceutical is rapidly increasing, with 9 North American and at least 7 European pediatric centers regularly administering MIBG therapy, and more centers in development. Because of the whole-body radiation that accompanies the tumor dose, it is essential to further test compounds that will increase tumor uptake and sensitivity without increasing normal organ toxicity, and to investigate different radioisotopes, such as the α emitter 211At (45). Better pretherapy tumor dosimetry using single photon emission computed tomography–computed tomography with tracer doses of 131I-MIBG (46), or positron emission tomography–computed tomography with 124I-MIBG (47) may also help to personalize the dose.

GD2-Targeted Immunotherapy of High-Risk Neuroblastoma

Promising results have been observed with immunotherapy targeting the surface glycolipid molecule disialoganglioside (GD2), which is uniformly expressed by neuroblastomas and gliomas, some melanomas, and sarcomas (48, 49). In normal human tissues, GD2 expression is weak and restricted to neurons, melanocytes, and peripheral pain fibers (50). Thus, GD2 is an ideal antigen target for immunotherapy of neuroblastoma. Three first-generation [monoclonal antibodies (mAb) 14G2a, ch14.18, and 3F8] and 3 second-generation (Hu14.18-IL-2, hu14.18K332A, and mAb1A7) GD2-directed antibodies have been investigated for immunotherapy of neuroblastoma (Table 1B, Fig. 2).

Figure 2.
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Figure 2.

Mechanism of GD2 antibody-targeted destruction of neuroblastoma by CDC and ADCC. A, CDC: The mAb binds to the receptor and initiates the complement cascade, which results in the formation of a membrane attack complex that makes a hole within the cell membrane, causing cell lysis and death. B, ADCC: The Fc fragment of the monoclonal antibody binds the Fc receptors on monocytes, macrophages, granulocytes, and natural killer cells (NK). These cells in turn engulf the bound tumor cell and destroy it. Natural killer cells secrete cytokines that lead to cell death. GM-CSF, granulocyte macrophage colony-stimulating factor; IL, interleukin.

First-generation anti-GD2 mAbs

14G2a is an IgG 2a murine anti-GD2 mAb. In 2 phase I trials (51, 52), the dose of mAb 14G2a was escalated from 25 to 500 mg/m2/course (Table 1B). Toxicities mainly consisted of reversible pain, tachycardia, fever, changes in blood pressure, hyponatremia, and urticaria, and were more severe in adult patients. Pain is thought to occur due to binding of antibody to peripheral nerve fibers expressing GD2 (50). These 2 phase I trials included 19 neuroblastoma, 3 osteosarcoma, and 11 melanoma patients. Therapeutic activity was observed, with 1 CR and 2 PRs in neuroblastoma patients, and 6 minor responses (MR), including 3 in neuroblastoma patients (51, 52). Pharmacokinetic studies revealed a β t 1/2 of 18.3 ± 11.8 hours (53). Because antibody-dependent cellular cytotoxicity (ADCC) is the key antitumor mechanism of therapeutic antibodies, and interleukin 2 (IL-2) was shown to augment lymphocyte-mediated ADCC in vitro (54) and antitumor activity of 14G2a in vivo (55), a phase I trial of 14G2a in combination with IL-2 was conducted in 31 patients with neuroblastoma and 2 patients with osteosarcoma, with 1 PR in the former and 1 CR in the latter (56).

3F8 is a murine IgG3 anti-GD2 antibody against GD2 that was developed in the 1980s and has shown side effects and indications of antineuroblastoma activity similar to those observed with 14G2A (57). A phase II study of 3F8 showed that 13 of 34 patients with stage 4 neuroblastoma in first or subsequent response remained progression free for 40 to 130 months (57). A follow-up phase II report of 3F8 + granulocyte macrophage colony-stimulating factor (GM-CSF) in 136 patients showed an overall 5-year EFS of 38% for patients without prior relapse, and a better outcome for patients with the FCGR2A (R/R) genotype polymorphism, which favors the binding of the IgG3 antibody (58).

MAb Ch14.18 consists of the variable regions of murine IgG3 anti-GD2 mAb 14.18 and the constant regions of human IgG1-κ (59). Phase I clinical trials confirmed activity in relapsed neuroblastoma and a toxicity profile similar to that of mAb14G2a (60, 61). As expected, ch14.18 had a longer than half-life than 14G2a, with a β t 1/2 of 66.6 ± 27.4 hours (60, 62). Because GM-CSF not only raises the number of leukocytes but also enhances their anti-GD2–mediated ADCC (63), a pilot study of ch14.18 + GM-CSF showed responses in patients with recurrent/refractory neuroblastoma (64). This led to a phase II national study, which confirmed the efficacy of ch14.18 + GM-CSF, with 2 CR, 2 PR, 1 MR, and 2 with stable disease in 32 patients with recurrent/refractory neuroblastoma (65). Because most responses occurred in bone marrow or bone, it was hypothesized that this approach would be most effective in the setting of minimal residual disease. Subsequently, the feasibility of giving ch14.18 in combination with GM-CSF, IL-2, and isotretinoin during the early post-transplant period was shown in 2 pilot phase I studies (66, 67).

These clinical trials led to the pivotal randomized COG phase III study (5) to determine whether immunotherapy with ch14.18 combined with GM-CSF and IL-2 on the backbone of isotretinoin would improve survival compared with isotretinoin alone for children with high-risk neuroblastoma in first response after myeloablative therapy and stem cell rescue. Eligible patients were randomized after stem cell transplantation to 6 cycles of isotretinoin (standard) or isotretinoin with 5 intercalated cycles of ch14.18 combined with GM-CSF or IL-2 in alternating cycles (immunotherapy). An analysis of 226 eligible patients showed that EFS was significantly higher for 113 patients randomized to immunotherapy, with 2-year estimated EFS from randomization of 66% ± 5% versus 46% ± 5% (P = 0.0115) for the 113 patients randomized to isotretinoin alone. The immunotherapy group also showed significantly higher OS (86% ± 4% vs. 75% ± 5% at 2 years; P = 0.0223). This approach represents a major advance and is the first effective immunotherapy for high-risk neuroblastoma as well as the first successful immunotherapy to target a nonprotein antigen.

Although ch14.18 in combination with IL-2 and GM-CSF has been shown to improve the outcome of high-risk neuroblastoma, the treatment is associated with significant toxicities, especially in cycles containing IL-2. Furthermore, the exact contribution of cytokines in vivo remains unclear. To address these issues, the Society of Pediatric Oncology European Neuroblastoma Network is conducting a study that randomizes patients with high-risk neuroblastoma to ch14.18 alone or in combination with subcutaneous infusion IL-2 to ameliorate toxicities associated with i.v. administration of IL-2.

Second-generation GD2-targeted immunotherapy and future perspectives

Building on the successful demonstration that ch14.18 + cytokines significantly improved outcome of patients with high-risk neuroblastoma, investigators are conducting a COG phase III trial to collect comprehensive toxicity data for regulatory approval of ch14.18. In addition, immunophenotypes such as FCGR3A and FCGR2A polymorphism (58, 68), and Killer-Immunoglobulin-like Receptors (KIR)-ligand mismatch (69), which may affect ADCC activity and hence clinical response to ch14.18, are under investigation. In addition, second-generation anti-GD2 antibodies and an anti-idiotype antibody vaccine have been developed and are currently in early-phase clinical trials.

Hu14.18-IL2 is a fusion protein of humanized anti-GD2 antibody (hu14.18) and IL-2. The MTD in a phase I trial was 12 mg/m2/d, ∼50% that of ch14.18. Clinical toxicities were similar to those reported with IL-2 and anti-GD2 mAbs, and antitumor activity was noted in 3 of 27 patients with neuroblastoma, although there were no measurable CR or PRs (70). A phase II study of this immunocytokine showed 5 CRs in 23 patients with neuroblastoma evaluable only by MIBG and/or bone marrow histology, but no responses for patients with measurable disease (71). In this study, patients with KIR-ligand mismatch seemed to be associated with better clinical response to immunotherapy with anti-GD2 (69). A larger phase II study adding GM-CSF is being conducted by the COG.

Hu14.18K332A is a humanized ch14.18 with a mutation to alanine at lysine 322 that limits its ability to fix complement and thereby reduces the pain associated with ch14.18 while retaining its ADCC capabilities. Preclinical studies in rats confirmed that hu14.18K322 elicited substantially less allodynia than ch14.18 (72). Preliminary findings of a phase I clinical trial of hu14.18K322 showed an MTD of 70 mg/m2/d × 4, with reduced neuropathic pain (73).

Monoclonal antibody 1A7 is an anti-idiotype antibody that is directed against a murine anti-GD2, 14G2a, and in effect mimics the GD2 antigen. Yu and colleagues (74) conducted a clinical trial of mAb 1A7 as a surrogate GD2 vaccine in 31 patients with high-risk neuroblastoma who achieved first or subsequent responses. No systemic toxicities were seen with subcutaneous injections given periodically over 2 years, and only local reactions (transient fever in 4 patients and serum sickness in 1 patient) were observed. All patients generated anti-mAb1A7, and their immune sera displayed complement-dependent cytotoxicity (CDC) and ADCC activities. Sixteen of 21 patients who enrolled during first remission had no evidence of disease progression at a median of 6 years, whereas only 1 of 10 patients in second remission remains progression free. These findings indicate that mAb1A7 vaccine has little toxicity, is effective at inducing biologically active anti-GD2, and may be useful for controlling minimal residual disease (ref. 75; A.L. Yu and colleagues, unpublished data).

In light of the observed low toxicity profiles of mAb1A7 and hu14.18K332A, it will be desirable to replace ch14.18 with one of these products, or possibly to substitute the Hu14.18-IL2 immunocytokine for the combination of ch14.18 and exogenous IL2. Thus, it will be important to ascertain whether mAb1A7 vaccine or the mutant anti-GD2 mAb will have therapeutic efficacy similar to that of ch14.18 in future clinical trials. Given the documented synergism between chemotherapy and anticancer mAbs such as rituximab (76) and trastuzumab (77), it will be timely to assess the efficacy of anti-GD2 mAbs with chemotherapy for treatment of neuroblastoma. Recently, investigators genetically engineered human T lymphocytes to express GD2-directed chimeric antigen receptors (CAR) by grafting the specificity of 14G2a onto a T-cell receptor (78). These CAR-T cells have been used to mediate tumor regression in patients with neuroblastoma, and offer another testable strategy for GD2-directed immunotherapy (79).

ALK as a Therapeutic Target in Neuroblastoma

The least developed of the targeted therapies for neuroblastoma is that directed to the ALK tyrosine kinase receptor. This lag can be attributed to the relatively recent identification of aberrations in the ALK gene (6–9). Nonetheless, these findings have led to clinical testing of ALK targeting in a remarkably short time, largely because of the availability of crizotinib, a dual ALK/MET inhibitor that has shown efficacy in adults with ALK-rearranged cancers, such as non–small cell lung cancer (NSCLC), inflammatory myofibroblastic tumor, and anaplastic large-cell lymphoma (10, 80, 81).

ALK meets most criteria to be classed as a valid molecular target (82). Targeting mutated ALK in neuroblastoma is likely to produce a clinical benefit, for the following reasons: (i) point mutations and amplifications, which occur in ∼8% to 10% and 2%, respectively, of primary neuroblastoma tumors, are oncogenic both in vitro and in vivo, leading to constitutive phosphorylation of ALK and of downstream signaling molecules that are critical for cell proliferation and survival (6–9). Of ∼12 mutations reported in neuroblastoma, the most common affect the R1275 and F1174 residues (83). (ii) Cells expressing mutated ALK exhibit oncogene addiction with ALK inhibition leading to cell death (6). (iii) Most importantly, these aberrations are amenable to inhibition by small molecules, unlike the most unequivocal genetic marker of aggressive neuroblastoma, amplification of the MYCN oncogene (6).

Crizotinib and other ALK inhibitors

The first drug to be approved by the U.S. Food and Drug Administration (FDA) for treatment of ALK-rearranged cancers was crizotinib, an orally bioavailable ATP-competitive 2,4-pyrimidinediamine derivative [PF2341066; Pfizer Inc. (84)]. Crizotinib binds to the inactive conformation of ALK and has shown striking efficacy against ALK-rearranged tumors such as NSCLC and inflammatory myofibroblastic tumor. In early-phase clinical testing, the overall response rate was 57% in a population of 82 patients with EML4-ALK–positive NSCLC (10, 80, 81). Currently, crizotinib is being tested in an ongoing phase I/II trial for children with neuroblastoma and other solid tumors bearing ALK mutations and rearrangements (NCT00939770, ClinicalTrials.gov). Preclinical testing showed the sensitivity of neuroblastoma cell lines with ALK amplification and the R1275Q mutation to crizotinib, marked by complete and sustained regression of xenografts (85), By contrast, the F1174L mutation, which possesses a greater transforming capacity than other ALK mutations (83) and is associated with a poor response to standard therapy (83), showed only minimal response in cell lines and none at all in neuroblastoma xenografts bearing this mutation (85). ALKF1174L also mediates acquired resistance to crizotinib in adults with ALK translocation-positive cancers (86). The structural basis of this resistance is not yet understood, but it could reflect the observation that this mutation is not in direct contact with the crizotinib-binding site within the ATP-binding pocket (86), or that it has a greater affinity for ATP than crizotinib (85). In view of the lack of sensitivity of ALKF1174L to crizotinib, the pediatric phase I study has been amended to increase the recommended phase II dose based on preclinical data that suggest that the resistance can be overcome in a dose-dependent manner (85).

Aggressive efforts to develop new ALK inhibitors are under way. An example is CH5424802 [Chugai Pharmaceuticals Ltd. (87)], an orally available benzo[b]carbazole derivative that was shown to potently inhibit the growth of neuroblastoma cells expressing amplified ALK. This agent also displayed in vitro inhibitory activity against neuroblastoma cells expressing ALKF1174L, which was shown to be comparable to that achieved in cells with wild-type (WT) ALK. Whether CH5424802 will show efficacy for in vivo models of neuroblastoma with mutated ALK remains to be seen. Additionally, LDK378 (Novartis Pharmaceuticals), an orally active inhibitor of the ALK kinase, is currently being tested in phase I trials in adult patients (NCT01283516, ClinicalTrials.gov), and may hold promise for the treatment of neuroblastoma patients with mutated ALK.

As observed with other kinase inhibitors, eventual resistance to crizotinib and other ALK inhibitors will likely develop, either through mutations within the ALK kinase domain or by upregulation of an alternative signaling pathway (86, 88). This phenomenon has already been described in adult patients and will undoubtedly emerge in children who initially respond to crizotinib. Preclinical models of resistance are needed to enable prediction of resistance mechanisms and aid in the design of drug combinations to delay or circumvent resistance. Effective targeting of resistance mutations would be aided by resolution of the crystal structure of ALK in its active confirmation, and of the F1174L mutant in particular.

Future prospects for clinical application of ALK targeting

Although the number of patients whose tumors have ALK aberrations is approximately half that associated with MYCN oncogene amplification, there are several reasons why inhibition of ALK would be a feasible therapeutic option in neuroblastoma. First, ALK is expressed on the surface of most neuroblastoma tumor cells (89) and is restricted to the brain following development. Thus, ALK, like GD2, would be an ideal tumor-associated antigen to target with immune-based therapies (Fig. 3). Anti-ALK antibodies may be beneficial not only for patients with aberrant ALK in their tumors, alone or in combination with small-molecule inhibitors (90), but also for the larger number of patients whose tumors express WT ALK.

Figure 3.
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Figure 3.

Current and future prospects for targeting ALK in neuroblastoma. Mutated ALK could be targeted by small-molecule inhibitors alone or in combination with inhibitors of downstream signaling pathways. ALK-directed immunotherapy such as anti-ALK antibodies could induce cytotoxicity by directly inhibiting the mutated receptor or by provoking a cytotoxic immune response. Nanoparticles carrying ALK siRNA could result in inhibition of ALK activity, leading to cell death. ERK, extracellular signal-regulated kinase; JAK, Janus-activated kinase; MAPK, mitogen-activated protein kinase; STAT, signal transducers and activators of transcription.

Second, a proportion of neuroblastoma cells that overexpress phosphorylated ALK that is neither mutated nor amplified respond to ALK depletion by undergoing apoptosis. Such tumor cells are also responsive to ALK inhibition by small molecules (91) and may even be amenable to RNA interference-based therapeutic strategies (92). Thus, ALK is apparently activated in such cells by alternative mechanisms, suggesting that ALK inhibition may be a useful therapeutic strategy for a larger subset of patients than previously projected.

Third, ALK inhibition may provide an effective targeting strategy against MYCN-amplified tumors, which account for nearly half of all high-risk neuroblastomas. ALKF1174L cosegregates with MYCN amplification in patients, and this combination is associated with a particularly poor prognosis, as shown by the fatal outcome of 9 of 10 children with ALKF1174L/MYCN amplified tumors (83). ALKF1174L also has been shown to potentiate the oncogenic activity of MYCN in vivo, although by itself, ALKF1174L appears to be insufficient to cause the malignant transformation of neural crest–derived stem cells (93, 94). The latter observation may in part explain the occurrence of ALK mutations in low-stage neuroblastomas. Both WT and F1174L ALK upregulate MYCN expression in vitro (95), and in vivo (R. George, unpublished data). Moreover, these 2 genes signal through a common signaling pathway, PI3K/AKT/mTOR, and targeting ALK with short hairpin RNAs has been shown to inhibit cell growth in tumor lines with concomitant MYCN amplification (6). Together, these observations suggest that inhibition of ALK, whether WT or mutant, could be a means of inducing the death of MYCN-amplified tumor cells, either alone or in combination with emerging strategies that target MYC, such as BET bromodomain inhibition (96).

Neuroblastoma has been at the forefront of pediatric cancers in terms of stratification of patients based on molecular aberrations, the prototypical example of which is MYCN amplification. More recently, the discovery of ALK mutations has bolstered the prospects of effective molecularly targeted therapy for high-risk tumors, although considerable work needs to be done before ALK inhibition can occupy the same high-priority ground as hNET-MIBG and anti-GD2 antibody therapy.

Conclusions

The targeted approaches to high-risk neuroblastoma discussed above will provide new ammunition to fight both measurable and microscopic disease in patients. The remaining challenges will be to determine how to combine these agents with standard cytotoxic agents and when to introduce them during therapy, whether in the neoadjuvant setting, during consolidation, or to treat minimal residual disease. Perhaps the greatest challenge for investigators of this orphan disease is to achieve worldwide access to and commercialization of these therapies. MIBG and anti-GD2 antibodies have both been under investigational testing with proven activity in neuroblastoma since the 1980s, yet because of the very small market, neither has been developed commercially. It is hoped that the impressive activity of MIBG in phase II studies, and the recent success in a randomized trial of the ch14.18 mAb, will prompt the acceptance of new drug applications by the FDA. Paradoxically, an ALK small-molecule inhibitor has already been approved based on activity in the more-common adult cancers, although it is still in early clinical trials for neuroblastoma. Anti-GD2 antibodies and MIBG both provide targeting for most neuroblastomas, but the acute toxicity of the former and the radiation isolation and possible late effects of the latter limit their utility to pediatric centers with expertise. Although oral ALK inhibitors are currently limited to a subset of tumors, they offer a truly personalized approach to treatment.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Authors' Contributions

Conception and design: K.K. Matthay, R.E. George, A.L. Yu

Development of methodology: A.L. Yu

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): A.L. Yu

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): K.K. Matthay, A.L. Yu

Writing, review, and/or revision of the manuscript: K.K. Matthay, R.E. George, A.L. Yu

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): A.L. Yu

Study supervision: A.L. Yu

Grant Support

Edwin Conner Fund, Alex's Lemonade Stand Foundation, Frank A. Campini Foundation, Dougherty Foundation, National Institutes of Health (PO1 CA81403 and R01 CA148688), and Sidney Kimmel Translational Scholar Award.

  • Received November 9, 2011.
  • Revision received March 15, 2012.
  • Accepted March 18, 2012.
  • ©2012 American Association for Cancer Research.

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Clinical Cancer Research: 18 (10)
May 2012
Volume 18, Issue 10
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Promising Therapeutic Targets in Neuroblastoma
Katherine K. Matthay, Rani E. George and Alice L. Yu
Clin Cancer Res May 15 2012 (18) (10) 2740-2753; DOI: 10.1158/1078-0432.CCR-11-1939

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Promising Therapeutic Targets in Neuroblastoma
Katherine K. Matthay, Rani E. George and Alice L. Yu
Clin Cancer Res May 15 2012 (18) (10) 2740-2753; DOI: 10.1158/1078-0432.CCR-11-1939
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    • Abstract
    • Introduction
    • Targeting hNET with MIBG
    • GD2-Targeted Immunotherapy of High-Risk Neuroblastoma
    • ALK as a Therapeutic Target in Neuroblastoma
    • Conclusions
    • Disclosure of Potential Conflicts of Interest
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