August 13, 2013 1 Comment
In April of 2013, we received a tissue sample from investigators in Victoria, Espirito Santo, Brazil. The pediatric oncologist involved requested assistance in the management of a four-year-old child with Stage IV (metastatic) neuroblastoma.
The patient was originally diagnosed in February with abdominal pain and a tumor. The tumor was identified by ultrasound as a large left-sided retroperitoneal mass. The patient was treated with the combination of doxorubicin plus cyclophosphamide. Within a month, it was evident that his “high risk neuroblastoma” would require stronger chemotherapy. Doses were adjusted upward and cisplatin was added. As the patient’s tumor infiltrated his bone marrow, his tolerance of chemotherapy became limited. By early June, after recovering from severe infectious complications, with no evidence of response to treatment, he was taken to surgery.
For background, neuroblastoma is the third most common malignancy of childhood. It arises from sympathetic ganglia (nerve cells) and presents in different forms. It has long been recognized that these tumors can be driven by an up-regulation of the oncogene MYCN. Children above the age of 1.5 years and those with wide dissemination are at highest risk.
We received this patient’s tissue and immediately isolated the malignant populations. As the tumor is only identified in children, it was a somewhat unusual occurrence for our laboratory. In addition, the patient had already received extremely aggressive treatment without benefit. We chose among the drugs that we considered potentially active for study and proceeded with our analysis.
The EVA-PCD assay results were highly instructive. First, those drugs that the patient had already received (platins, alkylating agents) were clearly inactive. Second, the signal transduction inhibitors like imatinib, and everolimus were also inactive. What was striking however, was the extraordinary degree of sensitivity to taxol that placed this patient among the most sensitive patients we have ever tested. The profile for taxol also extended to two taxol-based combinations: taxol plus platinum and taxol plus gemcitabine. However neither combination revealed significant synergy, suggesting that taxol was the principally active agent.
As I considered our laboratory findings in the context of the contemporary pediatric neuroblastoma literature, several interesting threads emerged. The first, was that investigators in Leiden, Netherlands had described a microtubule associated protein (MAP) encoded double cortin-like kinase gene (DCLK1) in neuroblastoma patients. The second was the very early but promising work using aurora kinase inhibitors in this disease. It became evident that these observations had their nexus at microtubule function. In keeping with the adult literature this would clearly support classes of drugs that induce G2-M arrest in the cell cycle. I reasoned that the taxanes were highly appropriate for this child based both on our findings and these related molecular correlates.
We contacted the physician in Brazil, and recommended a taxol-based treatment program. It became evident that neither taxol, nor the related carboplatin plus taxol or taxol plus gemcitabine regimens, were in this pediatric oncologist’s lexicon for neuroblastoma. Our report included references to clinical trials in adult tumors where these combinations have been broadly applied. However, it was going to require a certain amount of creative thinking for this well-trained pediatric oncologist to cross walk our “adult” recommendations to this child in need. Fortunately, with the assistance from our collaborators in Sao Paolo, the physician agreed to use our combination in this child who was failing standard treatment.
The results were prompt and dramatic. Within a single cycle of therapy, virtually all symptoms resolved. The child began to eat well and gain weight and despite chemotherapy, the bone marrow function rapidly recovered and the blood counts normalized. With completion of two cycles, a repeat CT scan revealed complete resolution of measurable disease.
I have corresponded with the pediatric oncologist and expressed our delight with the outcome and of her willingness to work with us. This case represents not only a transnational collaboration (the subject of a recent ASCO presentation) but also the successful cross-fertilization between the pediatric and adult oncology specialties. We are deeply gratified on both accounts.