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.

Do We Already Have the Tools We Need to Cure Cancer?

The rapid-fire sequence of the annual American Association of Cancer Research (AACR) meeting, held in May, followed by the annual American Society of Cllinical Oncology (ASCO) meeting, held in June, provides the opportunity to put scientific discoveries into perspective as they find their way from theoretical to practical.

Members of AACR, the basic science organization, ponder deep biological questions. Their spin-offs arrive in the hands of members of ASCO as Phase I and Phase II trials, some of which are then reported at ASCO meetings.

Many of the small molecules my laboratory has studied over the years are now slowly making their way from “Gee Whiz” to clinical therapy. At the ASCO meeting I attended many of the Phase I sessions, where alphabet soup compounds had their first “in-human” trials. As most of these compounds are familiar to me, I was very interested in these early, though highly preliminary, results.

Departing from one Developmental Therapy (Phase I) session, with visions of signal transduction pathways in my head, I attended a poster discussion on triple negative breast cancer. For those of you unfamiliar with the term, it refers to an increasingly common form of breast cancer that doesn’t mark for the usual estrogen, progesterone, or HER-2 features. Often occurring in younger patients, this form of breast cancer can be aggressive and unresponsive to some forms of therapy. Much work has gone into defining sub-types of this disease and slow progress is being made.

As I examined the posters, one caught my eye, “Clinical Characteristics and Chemotherapy Options of Triple Negative Breast Cancer: Role of Classic CMF regimen. (Herr, MH et al, abstract #1053, ASCO 2012.) What these investigators showed in a series of 826 breast cancer patients was that those treated with the oldest drug combination for breast cancer (CMF) did better than those who received the more modern and more intensive anthracycline or taxane-based regimens. CMF, originally developed by Italian investigators in the 1970s, was the principal therapy for this disease for two decades before it was replaced, first by anthracycline and later by taxane-based treatments. What struck me was the unexpected superiority of this old regimen over its more modern, toxic and expensive brethren.

I began to wonder about other modern therapies and their real impact upon cancer outcomes. One study in HER-2 positive patients revealed relative equivalency between weekly taxol, every three-week Taxotere and Abraxane-based therapy. Once again, the cheaper, older, less toxic Taxol regimen proved superior. While most of the attendees at the ASCO meeting were considering how the newest VEGF inhibitor Regorafenib, or the addition of aflibercept, might impact their practices, I was somewhat underwhelmed by the results of these statistically significant, but clinically marginal survival advantages, all associated with great expense.

As I pondered the implications of the CMF results in triple negatives and those of the taxol results in HER-2 positives, I considered other old-fashioned therapies with newfound potential. Among them, losartan, the angiotensin antagonist that influences tumor stroma or the results of an earlier published study that identified intraconazole (a widely available anti-fungal therapy), as an inhibitor of the hedgehog pathway. While the pharmaceutical industry promotes the use of vismodegib, a hedgehog inhibitor for basal cell skin cancer, and dozens of trials examine VEGF and FGF inhibitors, I wondered whether losartan or intraconazole or other simple compounds and combinations might not already provide many of the tools we need. Is it possible that effective treatments for cancer are at hand?

Lacking the tools to decipher the signals and combine the agents to greatest effect, are we destined to continue to blindly administer increasingly expensive, toxic, yet arguably no more effective therapies? With the myriad of drugs and combinations available today, might it be that we “can’t see the forest for the trees.”