Neuroblastoma Response to Therapy Trumps Age

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.

biology.arizona.edu

biology.arizona.edu

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.

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

One Response to Neuroblastoma Response to Therapy Trumps Age

  1. Heidi says:

    Excellent information. Thank you for posting.
    Independent Medical Research

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