Posted February 19, 2015
Mark A. Lemmon, Ph.D., University of Pennsylvania, and Yael P. Mossé, M.D., Children's Hospital of Philadelphia
The survival rate for children with neuroblastoma has not significantly improved even though the frequency and intensity of treating neuroblastoma with chemotherapy has increased in recent decades, suggesting that novel and targeted approaches to treatment of this tumor are needed. In 2008, Dr. Yael Mossé, a pediatric oncologist, identified mutations in the ALK gene as the major cause of hereditary cases of neuroblastoma. The product of the ALK gene is a receptor tyrosine kinase, suggesting that ALK signaling may be a tractable therapeutic target for neuroblastoma since other members of the receptor tyrosine kinase family have proven valuable targets in other cancers. Dr. Mossé began a collaboration with Dr. Mark Lemmon, a structural biochemist, to better understand ALK gene mutations and their role in neuroblastoma. As partnering investigators, they received a Fiscal Year 2009 (FY09) Peer Reviewed Medical Research Award (PRMRP) Investigator-Initiated Research Award to further characterize ALK alterations in neuroblastoma and to study the effects of these mutations on ALK structure and function and on tumor response to treatment.
Using nearly 1,600 neuroblastoma samples from the Children's Oncology Group, they found that approximately 8% of all patients had at least one ALK mutation and 14% of patients with the most aggressive form of the disease had ALK mutations and high-level amplification events. The presence of an ALK mutation and/or gene amplification was significantly associated with reduced event-free survival and overall survival in this cohort of patients, suggesting that ALK could represent a potential prognostic indicator for neuroblastoma. This was supported by the observation that ALK expression was higher in primary neuroblastoma tumor samples from patients with worse prognoses.
In vitro studies demonstrated that neuroblastoma cells with an ALK mutation or amplification show different sensitivities to the ALK inhibitor crizotinib, such that cells with the R1275Q mutation are sensitive to the drug while cells with the F1174L mutation are more resistant. The effect of different ALK mutations on crizotinib sensitivity is an important consideration for the treatment of patients with neuroblastoma and emphasizes the need for alternative treatment strategies that are effective with a wider range of mutations. Dr. Mossé and Dr. Lemmon showed that the ALK protein is expressed on the surface of neuroblastoma cells that contain ALK driver mutations (mutations associated with cancer transformation). Treatment with an antagonistic ALK antibody inhibited neuroblastoma cell growth, even in cells that are resistant to crizotinib. Further, the team demonstrated that targeting ALK with a combination of antibodies and small molecule inhibitors was highly effective. These findings were the basis for an FY11 PRMRP Investigator-Initiated Research Award to Dr. Mossé and Dr. Lemmon to identify potential therapeutic ALK-targeted antibodies for neuroblastoma. The team is also working to develop computational tools that will guide treatment choices for neuroblastoma patients based on patient genotype and ALK activation mechanisms.
Together, Dr. Mossé and Dr. Lemmon have taken advantage of each other's expertise to understand how ALK mutations in neuroblastoma affect cell growth, and they will continue their work toward developing novel ALK inhibition therapeutic strategies. The combination of approaches employed by these investigators will enable them to develop more rational and "smarter" treatment strategies that will significantly impact patients with the most aggressive form of neuroblastoma.
Publications:
Bresler SC, Wood AC, Haglund EA, et al. 2011. Differential inhibitor sensitivity of anaplastic lymphoma kinase variants found in neuroblastoma. Science Translational Medicine 3(108):108ra114.
Carpenter EL, Haglund EA, Mace EM, et al. 2012. Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma. Oncogene 31(46):4859-4867.
Bresler SC, Weiser DA, Huwe PJ, et al. 2014. ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. Cancer Cell 25(5):682-94.
Links:
Public and Technical Abstracts: Antibody Targeting of the ALK Oncogene in Neuroblastoma