Abstract
Neuroblastoma (NB), comprising around 10% of all childhood neoplasms and 15% of pediatric cancer deaths is a heterogenous disease and can be divided into very low-, low-, intermediate- and high-risk NB. Treatment of very low/low-risk NB is usually based on observation, or surgery alone, whereas intermediate-risk NB is in addition to surgery treated with mild chemotherapy and roughly 80-95% of the patients are cured. In contrast, high-risk NB patients receive multimodal therapy with e.g. induction, consolidation, and maintenance therapy, which can include induction chemotherapy and surgery and in severe cases adding intensive chemotherapy and even autologous stem cell transplantation and radiotherapy. Unfortunately, however this treatment does not cure all patients and around 50% succumb to disease. For this purpose, new treatment options are urgently needed. In this review, we describe the complex molecular heterogeneity of NB, and potential new options for targeted therapy.
Neuroblastoma (NB) is the most frequently diagnosed extracranial solid childhood tumor, comprising around 10% of all childhood neoplasms and 15% of all pediatric cancer deaths (1, 2). It originates from the neural crest progenitor cells of the sympathetic nervous system and primary tumors are predominantly detected in the adrenal gland, the extraadrenal retroperitoneum, and the thorax (3, 4). NB mainly occurs in young children and notably, more than 50% of patients have metastatic NB when first diagnosed (5-7). NB has both molecular complexity and heterogeneity and can present from very low- to high-risk disease and it has been classified into different stages, which have impact on prognosis and selection of treatment strategies (4, 8-11).
In this review, we describe some clinical aspects with regard to diagnosis and treatment of NB in parallel with data on the molecular complexity and heterogeneity of NB. In addition, we present treatment options and some current advances including targeted therapy for high-risk NB. The latter, include the focus on some specific genes or pathways that drive NB tumorigenesis and present an overview on some recent clinical trials targeting these specific genes and/or pathways. In addition, we also refer to some experimental preclinical data presenting additional promising options for combating NB. Due to the complexity of NB, a major task lies on the application of newly obtained data to design novel therapeutic strategies especially for high-risk NB (11).
Epidemiology, Staging of Neuroblastoma, Symptomatology, and Diagnosis
As mentioned above, NB is the most frequent extracranial solid tumor in children and has a heterogenous presentation (1-11). More specifically, NB occurs mainly in young children under the age of 5 years, with an average age of 18-22 months at diagnosis, but it can also affect older children and in more rare cases also adults, and has an incidence of 10.2 cases per million in children below the age of 15 years (6, 12).
The etiology of NB is unknown, nonetheless there are some specific relatively frequent molecular changes (e.g., MYCN amplifications) and there are familial cases where some mutations (e.g., in ALK) have been linked to NB in some, but not in all cases (13).
According to the International Neuroblastoma Risk Group (INRG) Staging System, the extent of NB invasion can be classified into four stages such as localized disease without (L1) and with (L2) imaging-defined risk factors, extensive metastatic cancer (M) and metastatic cancer with bone marrow, liver, or skin metastases in patients under 18 months (MS) (8-10).
In addition, the INRG pre-treatment classification schema categorizes NB into very low-risk, low-risk, intermediate-risk, and high-risk groups (8-10). Before starting treatment, each NB patient is therefore stratified based on different prognostic parameters such as the stage of the disease, patient age, but also tumor histology, grade of differentiation, DNA ploidy, MYCN status, and genomic aberrations, for instance, chromosome 11q status (8-10). Very low- and low-risk NB patient cohorts have the most favorable prognosis reaching up to 95% 5-year overall survival (10, 11). Accordingly, overall 5-year survival ranges between 80 to 90% for children with intermediate-risk NB (10, 11). However, notably, around 40% of all NB patients have high-risk disease and have a very poor prognosis, with 5-year survival rates reported to be less than 50% (10, 11, 14). More details with regard to the molecular heterogeneity of NB and how this affects current and future treatment options will be presented below.
Owing to its vague symptomatology NB can develop anywhere along the sympathetic nervous system and this thereby affects the locations of primary tumors and their metastasis if present, making diagnosis difficult (5, 12). Moreover, NB frequently spreads from its primary location to other parts of the body before the appearance of any symptoms. Fever, fatigue, weight loss and joint pain are relatively common symptoms, whereas a tumor in the abdomen can cause abdominal distension and constipation and that in the chest the patient breathing problems. A primary tumor located in the spinal cord could instead cause weakness and inability to stand, crawl or walk, whereas bone lesions in the legs and hips can result in pain and limping, and tumors infiltrating the bone marrow can cause pallor from anemia. The most frequent NB primary tumor location is the adrenal glands and this is found in 40% of the cases with localized tumors and in 60% of patients with more wide spread cancer.
An early diagnosis would theoretically positively affect the patient’s outcome, but unfortunately metastases are present in more than 50% of all patients at diagnosis (5, 8, 10, 12). A physical examination, urine and blood tests (to check for increased catecholamines), and imaging tests would be included for diagnosis. Examples of the latter are: an X-ray, an ultrasound examination and computerized tomography (CT) scan, a metaiodo-benzylguanidine (MIBG) scan and magnetic resonance imaging (MRI). If a mass is found, then this can be removed by surgery or biopsied and then further scrutinized for the specific molecular characteristics of NB. These characteristics have a major impact on the biology of the disease and treatment strategies, and some are therefore presented in more detail below.
Molecular Heterogenicity of Neuroblastoma
As already postulated, NB is a heterogeneous disease and the accumulation of NB derived genomic molecular information has been used for several decades to predict the course of newly diagnosed tumors (12). Therefore, prior to initiating therapy, NB patients are stratified based on different genomic prognostic parameters in addition to age, tumor histology, grade of differentiation and stage of the disease (15).
Some genomic factors of prognostic significance are e.g., DNA ploidy, MYCN status and other aberrations, for instance, chromosome 11q status; unfortunately some of these genetic alterations and chromosomal aberrations are linked with NB aggressiveness and poor prognosis (8-10). Here some more favorable prognostic factors will be presented before some of the less favorable factors.
Aneuploidy is a common cancer trait, however having a hyper diploid to near triploid chromosome number, with no or rare structural aberrations and no MYCN amplification in young NB patients has been associated with favorable prognosis (16). Furthermore, one report studied aneuploid NBs and showed that intra-tumor diversity was a trait of most NBs, irrespective of clinical genotype (16). Using both SNP arrays and FISH analysis and various simulations, the authors concluded that the observed stochastic distribution most likely reflected a process of chromosome loss from a tetraploid state. This in turn was supported by experimental data showing frequent chromosome loss and polyploidization in NB cells (16). NB thereby exhibited prominent intra-tumor genomic diversity both with regard to numerical and structural aberrations. Taking numerical aberrations into consideration, diversity was explained by possible loss of chromosomes at mitosis, which in turn drives selection towards poly-ploidization, with even more complex scenarios of aneuploidy and clonal diversity (16).
More specific changes, however, can be associated with poor prognosis. For example, important segmental chromosomal copy number alterations are e.g., 1p loss, 17q gain, and 11q loss, which have been shown to be predictors for relapse and associated with inferior survival (17, 18).
Among other more specific genetic alterations found in NB tumors, the amplification of MYCN at chromosome band 2p24 is one of the most critical prognostic factors and is observed in 20% of NB cases and it greatly contributes to tumor development and rapid disease progression (19-21). Due to its prognostic impact, MYCN amplification is used as a prognostic biomarker for treatment stratification (12).
The anaplastic lymphoma kinase (ALK) gene is another oncogenic driver in NB, which promotes NB cell proliferation and survival (22, 23). Furthermore, it is located in close vicinity to MYCN on chromosome band 2p23 and mutations or alterations or amplifications of ALK have been suggested to be associated with familial NB cases (24). Currently, ALK mutations or amplifications have been detected in roughly up to 15% of all NB tumors and have been suggested to be independent predictors of poor prognosis (22, 23, 25).
Standard of Care Therapies According to Risk Stratification of NB
Treatment for childhood NB is, as mentioned above, risk-based and children are individually assigned to low-, intermediate- or high-risk NB according to the Children’s Oncology Group for Canada and the US (COG) (26). The corresponding European body is The International Society of Paediatric Oncology Europe Neuroblastoma Group (SIOPEN). Notably, both use the International Neuroblastoma Staging System (INSS), for assessing e.g., stage and age, and the International Neuroblastoma Pathology Classification (INPC), for distinguishing between neuroblastoma with favorable histology (FH) and unfavorable histology (UH) (26-28). Therapy can consist of a complex of possibilities from observation to very intensive multimodal treatment (26-28).
Surgery, as mentioned above, is often applied to remove the NB mass that has not spread to other parts of the body, as well as adjacent lymph nodes. In some cases, it is difficult to remove the tumor, but then a biopsy can be taken in order to get more information regarding the characteristics of the tumor.
For patients with low-risk NB, treatment can range from observation or tumor resection by surgery in order to remove the NB mass and adjacent lymph nodes, with chemotherapy restricted to those with low-risk biology, and today 5-year overall survival (OS) is roughly 98% (26-28).
For patients with intermediate-risk NB, chemotherapy is often given before definitive resection. This is given in a multiagent mode and can consist of doxorubicin, cyclophosphamide, a platinum drug, and etoposide (26-28). The numbers of cycles given depends on the biology of the tumor and its response to therapy and with a goal to obtain a partial response with a reduction of the primary tumor and metastasis (at least a 50% reduction of tumor mass). Radiation is reserved only for NB intermediate-risk patients with progressive or unresectable disease after chemotherapy. For intermediate-risk patients 5-year OS is approximately 95% (26-28). Attempts to decrease the duration and intensity of therapy have been made to diminish side effects and this has been shown to be possible in several studies (26-28).
For patients with high-risk NB, therapy is intensified and is generally given in three phases (26-28). The induction phase includes chemotherapy e.g. with dose intensive cycles of cisplatin and etoposide alternating with vincristine, cyclophosphamide and doxorubicin followed by surgery. The consolidation phase includes tandem cycles of lethal doses of myeloablative therapy rescued by autologous stem cell transplantation (SCT) (collected during the induction chemotherapy) and radiation therapy to the site of the primary tumor (26-28).
Following the consolidation phase, a maintenance/post consolidation phase may follow which is used with the aim to ablate potential minimal residual disease (MRD) after SCT. For high-risk NB patients after SCT, dinutuximab can be given together with granulocyte-macrophage colony stimulating factor (GM-CSF) and when given together with isotretinoin event free survival (EFS) has been improved (26, 29, 30). With the above strategies, 5-year OS for high-risk NB can reach up to 56-60% (26-28).
Therapies Upon Resilient NB or NB Recurrence
Unfortunately, a proportion of high-risk NB is resistant to current treatment strategies and likewise recurrent NB is problematic and presents a clinical challenge (26). Symptoms of relapsed NB can vary immensely similar to newly diagnosed NB, depending on tumor size, location and if the tumor has spread. Such symptoms may include an abdominal mass, enlarged lymph nodes in the neck, swelling and bruising around the eyes, unexplained fevers, bone pain, limping, weakness or paralysis, weight loss or poor appetite.
Treatment of resilient or recurrent NB will therefore vary with regard to the specific recurrence and also depends on the initial risk staging of the disease including the molecular characteristics of the disease (26). However, when attempts to use surgery, chemotherapy, or radiotherapy fail other options are necessary. Moreover, due to poor outcomes and insufficient targeted specificity of the standard NB treatment, preclinical and clinical studies suggest that targeted NB therapy might play a key role in fighting high tumor heterogeneity (26).
Currently, the only targeted therapy, which has been approved by the Food and Drug Administration (FDA) for high-risk NB patients, is the anti-GD2 monoclonal antibody therapy (e.g., Dinutoximab – unituxin) (27-29). The use of dinutoximab together with autologous SCT has increased survival for high-risk NB from 46% to 66% (29). Likewise, combining anti-GD2 with GM-CSF and 13-cis retinoic acid in high-risk NB patients showed promising results (30). However, despite the fact that anti-GD2 therapy has improved survival rates, all NB patients are still not cured, furthermore, the latter comes with severe neuropathic and other side effects (26, 27). Nonetheless, to improve survival, dinutuximab beta was combined with IL-2 but it was associated with greater toxicity, and unfortunately did not improve outcome (31).
Some clinical attempts have also been made to use check point inhibitors (ICI) in childhood cancers, but the responses were not optimal (32-34). For this purpose, an analysis was performed to investigate the possible contribution of neoantigens and tumor infiltrating lymphocytes in NB and Wilms tumor (35). The report showed that the number of neoantigens varied, however, the authors reported that NB had high numbers of CD8+ infiltrating lymphocytes and concluded that these issues should be considered when designing clinical trials with ICI (35).
Nonetheless, numerous genetic alterations are present in NB and some are being investigated as potential druggable targets and clinical trials are in parallel ongoing to improve survival and quality of life of patients with NB. Moreover, additional experimental studies are pursued to explore the effects of various targeted therapies and their combinations. Some of these aspects are presented below.
ALK inhibitors. ALK is a receptor tyrosine kinase, which is involved in cell proliferation and neuronal differentiation (36). Accordingly, an activating ALK mutation induces over-proliferation of cells and aberrant differentiation in NB tumors (23, 37). To date, ALK is therefore one of the most extensively investigated druggable targets against NB.
One of the ALK-targeted drugs is crizotinib, a tyrosine kinase inhibitor, which has been demonstrated to exhibit anticancer activity, especially when combined with chemotherapy, in NB cell lines harboring ALK alterations and NB murine xenografts (38-40). However, several clinical studies have shown that the response rate to therapy with crizotinib in relapsed/refractory NB patients is insignificant and it has thereby not shown any marked clinical activity (41, 42).
Another ALK inhibitor, ceritinib, in combination therapy with the CDK4/6 inhibitor ribociclib, has been found to promote cell death and inhibit growth of ALK mutated NB cell lines and more importantly, to induce complete tumor regression in ALK-driven NB xenografts (43).
The efficiency of ceritinib has been also tested in clinical trials, particularly in pediatric patients with ALK-positive tumors, where response has been observed in 20% of NB patients (44). In addition, treatment with lorlatinib (PF-6463922), an ALK/ROS1 inhibitor, has resulted in complete tumor regression in mouse xenograft models of NB with or without crizotinib resistance (45).
Consequently, a phase I study of lorlatinib has been initiated to test its clinical activity alone or in combination with chemotherapy in patients with relapsed/refractory NB (NCT03107988). In addition, a second generation ALK inhibitor, ensartinib, is also being investigated in patients with relapsed/refractory NB with ALK alterations in a phase II Pediatric MATCH trial studies (NCT03213652).
Finally, in the clinical trial ‘’NEPENTHE’’, a combination of ceritinib and ribociclib, is currently under investigation in relapsed NB patients (NCT02780128).
MYCN pathway inhibitors. MYCN, also mentioned above, is often amplified in NB and this correlates with worse prognosis, so MYCN has therefore been indirectly targeted in many ways (19, 20).
One of the strategies to control MYCN transcription is through the inhibition of the epigenetic regulator BET, especially BRD4 (46). Among a number of BET inhibitors, including JQ1, OTX-015 and GSK1324726A (I-BET726) have been shown to exert inhibitory effects on NB cell growth in vitro, on tumor growth in NB xenograft models in vitro and, also, to down-regulate MYCN expression (47-49). Recently, a novel BET inhibitor, MZ1, has been reported to suppress NB cell proliferation, induce G1/S cell cycle arrest, and reduce NB xenograft tumor volume (50). Moreover, currently, a phase I clinical trial is evaluating the efficacy of two BET inhibitors, BMS-986158 and BMS-, in young patients with NB (NCT03936465).
Another strategy is to promote N-Myc degradation, and this is done by inhibition of the Aurora A kinase (AURKA), a serine/threonine-protein kinase 6, which prevents N-Myc degradation by stabilizing it (51). Data from a recent study has indicated that the AURKA inhibitor MLN8237 (alisertib) impairs cell growth and promotes G2/M cell cycle arrest in both the NB cell line IMR32 in vitro and in a mouse xenograft model (52).
Clinically, MLN8237 has been examined in combination with chemotherapeutic agents, irinotecan and temozolomide, in NB patients in phase I and II clinical trials (NCT01601535, NCT02444884) (53).
The AURKA inhibitor LY3295668 (erbumine) has also entered a phase I clinical trial with reported manageable toxicity profile and therapeutic activity in some relapsed/refractory NB patients (NCT04106219) (54).
A final strategy to target N-Myc is through the inhibition of the ornithine decarboxylase 1 (ODC1), the rate limiting enzyme in polyamine synthesis (55). Earlier, a preclinical study in an NB-prone transgenic mouse model demonstrated suppressed tumor initiation and prolonged survival upon treatment with the ODC1 inhibitor difluoromethylornithine (DFMO) (56). Furthermore, a marked synergistic antitumor effect was observed when combining DFMO and celecoxib, an anti-inflammatory drug, in transgenic and xenograft-bearing NB mouse models (57). In clinical studies, a phase I trial has confirmed well tolerability of DMFO in children with relapsed NB (58). Currently, multiple ongoing clinical studies are therefore evaluating the antitumor activity of DMFO alone, and in combination with various agents in patients with recurrent/refractory NB as well as NB that is in remission (NCT02030964, NCT02139397, NCT02395666, NCT02679144).
Tropomyosin receptor kinase (Trk) inhibitors. Trk receptors, mainly TrkA and TrkB, belong to the family of neurotrophin factor receptors, which are involved in the development of the nervous system (59). Notably, high levels of TrkA are associated with favorable prognosis, since they stimulate the differentiation of NB tumors leading to spontaneous regression of cancer (60, 61). Conversely, high expression of TrkB is linked with poor prognosis and high-risk NB (62, 63).
Previous studies observed impaired NB tumor growth after treatment with the pan-Trk inhibitor GNF-4256 alone as well as when combined with chemotherapy in a xenograft mouse model (64). Similarly, the combination of the pan-Trk inhibitor AZD6918 and the topoisomerase II inhibitor etoposide was also demonstrated to inhibit NB growth in mice (65).
Furthermore, prior reports showed significant antitumor growth effects of entrectinib (RXDX-101), a pan-Trk, ALK and ROS1 inhibitor, as a single agent as well as when used in combination with chemotherapeutic drugs in NB cells in vitro and in xenograft models (66). Of note, in the recent phase1/2 (STARTRK-NG) clinical trial, treatment with entrectinib (RXDX-101) showed a strong and lasting therapeutic response in children with relapsed/refractory NB (NCT02650401) (67, 68).
In addition, a significantly suppressed growth of TrkB-over-expressing NB xeno-grafts was observed upon treatment with the pan-Trk inhibitor lestaurtinib (CEP-701) (62). Furthermore, in an analogous phase I clinical study, a durable clinical benefit of lestaurtinib (CEP-701) therapy was observed in around half of pediatric patients with recurrent/refractory NB (NCT00084422) (69).
Mitogen-activated protein kinase (MEK) inhibitors. The mitogen-activated protein kinase (MAPK, or RAS–RAF–MEK–ERK) signal-ing pathway plays a major role in mediating cell proliferation, growth, differentiation, apoptosis, and cellular communication (70). Notably, MEK is a critical component and regulator of the MAPK pathway and is mutated in around 80% of relapsed NB cases, and could thereby be an important target (71).
Experimentally, it was previously shown that binimetinib, a MEK1/2 inhibitor, could reduce viability in NB tumor cells (72). Moreover, combining binimetinib and ribociclib (a cyclin D dependent kinase -CKD1, CDK4, and CDK6) inhibitor induced an additive inhibition of tumor growth in NB xenografts models (73). In contrast, in xenografts models of ALK-addicted NB, trametinib, another MEK1/2 inhibitor when used alone failed to suppress tumor growth (74). However, the combination of trametinib and CA3, a yes-associated protein inhibitor, successfully abrogated tumor growth and resulted in a 100% survival rate in xenograft mice (75).
In addition, data from an expansion cohort in a phase I/II study (NCT02124772) suggested that trametinib alone or combined with the BRAF inhibitor dabrafenib could be clinically effective and well tolerated in patients with refractory or relapsed NB (76).
Other inhibitors or drugs. The inhibitors targeting the phosphoinositide 3-kinase (PI3K) pathway, the Cyclin D dependent kinase (CDK) inhibitor pathway, the poly-ADP-ribose polymerase (PARP), fibroblast growth factor receptors (FGFR) and WEE1 or rigosertib have in many cases special specificity towards NB. However, there are other pathways or molecules (PI3K, CDK4/6, FGFR, PARP, WEE1) that can be manipulated in a similar context. Clinical trials and experimental data targeting these pathways are described below.
The PI3K pathway. Alterations in the PI3K pathway are known to play an important role in many cancers, since they regulate cellular growth, proliferation and cell survival (77). The PI3K pathway, activated by growth receptor tyrosine kinases, recruits and activates AKT, resulting in further downstream activation of other kinases, e.g., the mammalian target of rapamycin (mTOR) (77). This in turn enhances tumor growth by promoting intravasation and invasion, making the abrogation of this pathway favorable for tumor therapy (78). PI3K is also frequently mutated in cancer and likewise in NB, so agents targeting PI3K could be of interest for NB treatment (79).
Clinical trials with PI3K inhibitors have therefore been initiated also for NB and one such example is the phase I trial NCT02337309 with the SF1126 (PI3K/mTOR inhibitor) for relapsed/refractory NB that has been conducted by the NANT consortium.
The CDK pathway. CDK4 and CDK6, enzymes in the CDK pathway, are often activated in many cancers, and they stimulate progression of the cell cycle from G1 to S-phase (80, 81). When the CDK4/6 pathway is dysregulated, it can induce a surge in proliferation, and this can be observed in many cancers and targeting them could be beneficial (82, 83). Inhibition of CDK4/6 could thereby potentially arrest the cell cycle, and would then present a favorable target for cancer treatment in NB (84).
CDK4/6 inhibitors palbociclib, ribociclib and abemaciclib have been FDA-approved for estrogen receptor (ER) positive metastatic breast cancer (85) and moreover these were shown to exert synergistic effects with PI3K inhibitors (86-89). This has likely enhanced the initiation of some clinical trials for refractory or recurrent NB. There are ongoing phase I clinical trials with PI3K or PI3K/mTOR inhibitors and a multi-sub-study phase II trial with the CDK4/6 inhibitor palbociclib for recurrent NB e.g., NCT02337309, NCT03213678, and NCT03526250. In addition, in the Pediatric MATCH treatment trial NCT03526250 the use of palbociclib is investigated for refractory or recurrent NB.
FGFR inhibitors. FGFR mutations are not common in NB but they do exist (90). In recurrent/relapsed NB/medulloblastoma (MB) with FGFR mutations, the FGFR inhibitor Erdafitinib is included in the pediatric MATCH phase II trials NCT03210714 and NCT03155620. Experimentally, we have recently shown dose dependent responses of several NB MB cell lines to PI3K and FGFR inhibitors (77, 79, 91, 92). In addition, when combining PI3K and CDK4/6 inhibitors or PI3K and FGFR inhibitors, additive and synergistic effects were observed (91, 92). Moreover, preclinical studies by others and us have shown that PI3K and FGFR inhibitors combined with chemotherapy could also have synergistic effects (79).
PARP and WEE1 inhibitors. Experimentally, the PARP inhibitor Olaparib and the WEE1 inhibitor were shown to have dose-dependent effects on MB cell lines and when combining PARP with WEE1 inhibitors synergy was disclosed, and synergistic effects between the two have likewise been shown by others (93, 94). We anticipate that this could be the case for NB. Moreover, WEE1 is useful for targeting cell lines with non-functional p53 and could therefore be useful for some NBs, which in fact have such mutations (95, 96). Nonetheless, the efficacy of WEE1 is not dependent on the presence of P53 mutations (97). Clearly there are many so far not extensively investigated options that could be of potential use also for NB patients.
Rigosertib. Finally, a short note on rigosertib. An investigation was initiated to examine the effects of rigosertib in preclinical models and the authors disclosed that NB grown as monolayers or spheroids and xenografts with MYCN amplifications were the most sensitive cell lines (98). Furthermore, combining rigosertib with vincristine was a particularly favorable combination (98).
Summary and Conclusion
The past decades, recent clinical advances as well as those in cancer genomics have allowed NB classification into very low-, low-, intermediate-, and high-risk stages disclosing a high degree of clinical and genetic diversity. Nevertheless, standard of care for NB still generally consists of observation or surgery alone for very low- and low-risk NB, surgery together with chemotherapy for intermediate-risk NB, or induction, consolidation, and post-consolidation chemotherapy for high-risk disease.
For novel therapeutic options, huge efforts have focused on identifying specific gene mutations or amplifications as potential targets for specific treatments with some relatively novel NB specific approaches already included in clinical trials.
Currently, there are, however, also other more general pathway inhibitors, that are FDA-approved for the treatment of other types of tumors, that could potentially be of interest also for NB. Inhibitors targeting PI3K, including CDK4/6, FGFR, PARP and WEE1 alone or combined with each other, or with chemotherapy or radiotherapy could be highly interesting for future tailored treatments, and their use is already initiated in several trials for other cancers. Nevertheless, resistance to these pathway inhibitors may also emerge, and this could potentially be overcome by combining inhibitors of different pathways or combining pathway inhibitors with chemotherapy.
Another strategy is to treat NB using immunotherapy, where the major challenge lies in the identification of neoantigens to engineer therapies with more than one target at a time. Moreover, possible immunosuppression could in some cases probably be counteracted by immune check point inhibitors.
Finally, efforts should also be continuously focused on the molecular characterization of NB at diagnosis, thereby allowing early identification and application of specific targeted therapy. As experimental research continuously expands the knowledge in the field and large international trials are being initiated, the biology of individual treatment responses will eventually be better understood. Using this broader information combining targeted therapies with conventional current therapies may have the potential to improve the overall survival in NB.
To conclude, NB is a heterogeneous disease and can be staged as very low-, low-, intermediate- to high-risk disease. Its treatment also spans from observation, to surgery, to multimodal treatments, including consolidation and post-consolidation treatments. While low-risk to intermediate-risk NB has an overall cure rate of 90-95%, high-risk NB has a cure rate of 50-60% making it imperative to develop additional therapeutic options. Some of these new alternatives are based on molecular profiles frequently and preferentially observed in NB, while others are based on more general cancer characteristics. Combining all options may increase survival.
Acknowledgements
This research was supported by the Stockholm Cancer Society, the Swedish Cancer Foundation, the Lindhés Advokatbyrå, the Åke Wiberg Foundation, SLS (Svenska Läkaresällskapet). SH was supported by the Swedish Childhood Foundation.
Footnotes
Authors’ Contributions
ML, TD, ONK: literature research, article writing; ML, TD, SH: literature research, article writing, edits; All Authors: Article idea, outline, article writing, edits.
Conflicts of Interest
The Authors declare that they have no conflicts of interest in relation to this study.
- Received June 7, 2023.
- Revision received July 3, 2023.
- Accepted July 5, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
