An extensive literature and efforts by many groups have been directed toward the development of new drugs to treat high-risk neuroblastoma. There has been a move away from the empirical testing of agents that may or may not have activity against adult human cancers to a more pragmatic approach, in which only those compounds for which there is a strong preclinical rationale are being tested in patients. This section highlights some, but certainly not all, recent advances in therapies for patients with neuroblastoma.
The successful use of treatment with the anti-GD2 monoclonal antibody to prevent relapse in patients with neuroblastoma is an example of an immunotherapeutic approach to the eradication of residual neuroblastoma cells at the completion of cytotoxic therapy.56
Future efforts will be focused on improving antibody-based approaches, as well as on developing synergistic combination therapies. There are plans to study the humanized anti-GD2 immunocytokine that is engineered to target the delivery of interleukin-2 (hu14.18–interleukin-2) to the tumor microenvironment. This treatment appears to have substantial but manageable toxicity,61
and in a recent phase 2 study, it showed antitumor activity in patients with a relatively small disease burden.62
In addition, the previously described regimen reported by Yu and colleagues also includes isotretinoin (13-cis
and there is interest in the possibility of improving the retinoid component of therapy for patients with minimal residual disease. Fenretinide, a synthetic retinoid that exerts antitumor activity in neuroblastoma models primarily through the induction of programmed cell death, has been proposed as an alternative or additional retinoid to be used to target rare residual neuroblastoma cells that survive after intensive chemoradiotherapy.63,64
Finally, since the immunotherapeutic approaches currently used by the COG have significant immediate toxicity, efforts in Europe to combine anti-GD2 antibody therapy with lower doses of interleukin-2 could possibly lead to the development of safer methods for eradicating minimal residual disease.
Because neuroblastomas arise from the developing sympathetic nervous system, the majority of these tumors express the norepinephrine transporter on their cell surface. This fact was exploited decades ago when radiolabeling of the norepinephrine analogue metaiodobenzylguanidine (131
I-labeled or 123
I-labeled MIBG) was used to develop a scintigraphic localization method for detecting tumors that express these transporters, such as neuroblastomas. Investigators have subsequently taken advantage of this molecular target to deliver high levels of radiation to neuroblastoma cells, despite the fact that norepinephrine transporters are not actively involved in the oncogenic process. 131
I-labeled MIBG has been extensively investigated as a potential therapeutic agent65
and has the highest objective response rate of any drug studied in patients with relapse.66
Current efforts are focused on integrating targeted radiotherapy with 131
I-labeled MIBG into the consolidation phase of therapy, an approach that appears to be feasible in light of the results of a phase 1 study in which this agent showed promising antitumor activity in patients with primary refractory disease.67
One of the potential theoretical problems with 131
I-based therapy is that the DNA damage occurs at a relatively long path length from the β
-particle emission of the compound. Thus, a cell that takes up 131
I-labeled MIBG is not killed; to achieve sufficient overall cytotoxicity, the DNA-damaging energy must travel to adjacent cells. Since isolated residual tumor cells exist primarily in the marrow compartment, drugs radiolabeled with α
-emitting radionuclides, which have much greater energy and shorter path lengths than do β
-emitting radionuclides, might have superior efficacy.68
Two large collaborative research efforts are now focused on discovering additional therapeutic targets for neuroblastoma and other pediatric cancers. The Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program (http://target.cancer.gov
) is being conducted in close alignment with the Cancer Genome Atlas project. As the acronym suggests, the genomic profiling and resequencing efforts are focused not only on discovering the mechanisms that drive oncogenesis, but also on identifying compounds that will be likely to work specifically on the identified pathways. In addition, the Pediatric Preclinical Testing Program (PPTP) is using murine models of pediatric cancers to screen drugs that are in the early stages of clinical development for use in the treatment of more common adult cancers for possible activity against pediatric diseases. So far this program has screened almost three dozen anticancer agents; for neuroblastoma, one of the most compelling results to date was the broad activity of an inhibitor against aurora kinase A, the key regulator of the cell-cycle G2–M checkpoint.69
This drug was fast-tracked to a pediatric phase 1 trial on the basis of these results; if anti-neuroblastoma activity is confirmed in the clinical setting, the power of this screening approach will be confirmed, since there were no a priori data recommending aurora kinase A as a potential molecular target. The TARGET and PPTP approaches are complementary, and both can inform and provide prioritization for the critical experiments that are in the early phase of clinical testing in patients with refractory neuroblastoma.
The discovery of ALK
as the major neuroblastoma-predisposition gene was immediately extended to show that ALK
somatic mutation or gene amplification occurs in up to 15% of newly diagnosed neuroblastomas.9–12
The fact that neuroblastoma-derived cell lines show a much higher frequency of mutation (30%) suggests that mutations may be acquired or selected for, since the majority of cell lines are derived from patients at the time of relapse. Accumulating preclinical data show that targeted inhibition of ALK in cell models that harbor ALK
mutation or amplification is highly effective, and these observations are providing the basis for early-phase clinical trials.70
If ALK inhibition is restricted to tumors with aberrant ALK signaling, ethical methods of obtaining access to tumor cells will need to be developed so that patients can be appropriately selected for ALK-inhibition–based therapies.
The future holds promise for making considerable advances in our understanding and treatment of neuroblastoma. From the basic-science perspective, it is likely that the majority of critical mutations that cause neuroblastoma or influence its natural history will be discovered. This work should identify the key molecular targets for rational drug development. The rich history of international collaboration in studying this disease will afford the opportunity to test these new approaches in carefully controlled clinical trials that should result in more precise and effective therapeutic strategies. In the meantime, survivors of high-risk neuroblastoma require ongoing multi-disciplinary follow-up to reduce the long-term morbidity that often accompanies cure with the therapy currently provided.