Forbeck Focus Meeting 2003 - The New Biology of Enigmatic Neuroblastoma and Relevant Treatment Strategies

March 22 – 23, 2003, Westin Copley Place Hotel, Boston, MA

Organizer:
Moritz M. Zeigler, MD, Children’s Hospital, Boston


Focus:
Neuroblastoma remains the most frequent solid abdominal and thoracic malignancy of childhood, a tumor characterized by an aggressive behavior and a dismal outcome. Therapeutic strategies have historically emphasized aggressive multimodal therapy, and the marginal improved prognosis seen in the last several years has depended on the acceleration and further intensification of such treatment. Such a strategy is contradictory to the observation that the diagnosis of low stage neuroblastoma is possible by mass population screening, and low stage patients have a worse outcome in the face of more aggressive therapy. Furthermore, despite its poor prognosis, neuroblastoma is that tumor characterized by two uniquely enigmatic, yet favorable, behaviors. First, it can spontaneously or by exogenous manipulation be stimulated to change its phenotype from an aggressive and metastasizing malignancy to a mature and benign ganglioneuroma. Second, it has the potential to undergo spontaneous regression, and even frank disappearance, despite an original large and even disseminated tumor burden. As investigators have sought to understand this biological behavior, a series of specific areas of investigation have evolved that will serve as the focus for this meeting. They include a delineation of the immunobiology of neuroblastoma, a definition of signaling mediators, receptors, and their mechanisms, the study of angiogenesis, angiogenic inhibitors, and their potential linkage to signaling as well as the immune response, and the investigation of the genetic analysis of neuroblastoma as well as the putative application of gene therapy as an effector for these various treatment strategies.


Outcome Report:
Signaling Mediators and their Receptors: Fundamental mechanisms of signaling under intense study in neuroblastoma continue to explore those pathways that might contribute to our understanding of the enigmatic behavior of this tumor, where on the one hand it is characterized by aggressive growth, resistant to many conventional anticancer therapies while on the other hand it can spontaneously, or in response to therapy, undergo maturation into a benign phenotype or even undergo a regression characterized by disappearance. Michael P. LaQuaglia, MD (Memorial Sloan-Kettering Cancer Center) addressed the use of histone deactylase (HDAC) inhibitors as a potential novel anti-neuroblastoma therapy. Dai H. Chung, MD (University of Texas, Galveston) described the relationship of gastrointestinal hormones to neural crest tumors that produce vasoactive intestinal peptide (VIP), gastrin and somatostatin. In related work, Dr. Chung has also studied the antitumor activity of the benzoquinone ansamycin antibiotic geldanamycin (GA), an agent that decreases the viability of neuroblastoma cells and increases apoptotic cell death. Garrett M. Brodeur, MD (Children’s Hospital of Philadelphia) described an update of his ongoing work that has defined the regulatory role of the neurotrophins on neuroblastoma growth. Thomas H. Inge, MD, Ph.D. (Cincinnati Children’s Hospital Medical Center) described studies of the novel anthracycline antibiotic analog of doxorubicin (Dox) WP744. Jeff C. Hoehner, MD, Ph.D. (Johns Hopkins University) described the microenvironment of neuroblastomas focusing on the hypoxic tumor cell that proliferates poorly and is more prone to resistance to both chemotherapy and radiotherapy.

Gene Analysis and Therapy: Jed G. Nuchtern, MD (Baylor College of Medicine) reported on work that has focused on the helix loop helix nuclear transcription factor MYCN, a protein whose amplification is linked to the malignant neuroblastoma phenotype. Though Akita Nakagawara, MD, Ph.D. (Chiba Cancer Center Research Inst, Japan) was unable to attend, he submitted a summary of his recent application of comprehensive genomics to the study of neuroblastoma. Andrew Davidoff, MD (St. Jude Children’s Research Hosp) reported on the application of gene therapy for the antiangiogenic therapy of neuroblastoma utilizing an adeno associated virus vector. Interestingly, in an effort to further enhance anti-tumor activity, an increased dose of vector and transgene was administered, and a paradoxical acceleration of tumor growth was observed. Dr. M. Judah Folkman, (Harvard Medical School) commented that this was the classic dose-response “U-shaped curve” seen with other angiogenesis inhibitors and their anti-tumor activity, and that Dr. Davidoff has now demonstrated this phenomenon at the gene level. A. Thomas Look, MD (Harvard Medical School) described his research into the genetics of neuroblastoma using the novel zebra fish model.

Immunology and Immunotherapy: Edward M. Barksdale. Jr., MD (University of Pittsburgh) presented his ongoing work of dendritic cell therapies for advanced neuroblastoma. Anthony Sandler, MD (University of Iowa) hypothesized that an effective neuroblastoma vaccine strategy would target and directly stimulate signaling pathways that would further amplify tumor antigen-specific immune responses. James Geiger, MD (University of Michigan) reported on his efforts to translate dendritic cell therapy to the clinical realm.