Yael Mossé Laboratory

Led by Yael P. Mosse, MD, researchers in the Mossé Laboratory are studying the contribution of DNA sequence variations and activation mutations of anaplastic lymphoma kinase (ALK) genes on the development and progression of both inherited and acquired forms of neuroblastoma. The goal of the research conducted in this laboratory is to understand the underlying molecular mechanisms by which ALK gene activation contributes to development and progression of pediatric neuroblastoma, and to identify less toxic, more targeted cancer therapies to treat children with ALK-mediated disease.

Ongoing studies in the Mosse Laboratory have demonstrated that ALK gene activation plays an important role in the development and progression of inherited and acquired pediatric neuroblastoma. These findings resulted in now completed Phase 1/2 clinical studies (currently in progress) designed to evaluate the ALK inhibitor crizotinib as a treatment for children with ALK-driven treatment refractory or relapsed neuroblastoma. This work has set the stage for the next pivotal Phase 3 clinical trial for patients with high-risk neuroblastoma.

Additionally, preclinical studies using neuroblastoma cell lines and animal models of disease revealed that a more targeted, less toxic experimental ALK inhibitor, PF-06463922 (lorlatinib), inhibited neuroblastoma disease progression. Phase 1/2 clinical trials designed to assess the safety and efficacy of PF-06463922 as a single agent and in combination with chemotherapy will open Spring 2017. Both children and adults with neuroblastoma may be eligible.

Other studies in the Mossé Laboratory have found that certain ALK mutations can result in crizotinib resistance. Accordingly, researchers in this lab have determined that combinations of crizotinib and other chemotherapeutic agents typically used to treat pediatric neuroblastoma can overcome de novo resistance to crizotinib. Based on these results, crizotinib will be integrated in the treatment protocol in the next Phase III trial sponsored by the Children’s Oncology Group to evaluate treatments for ALK-mediated high-risk pediatric neuroblastoma.

The Mosse Laboratory has also implemented the Next Generation Personalized Neuroblastoma Therapy (NEPENTHE) clinical trial for pediatric neuroblastoma.  The role of the lab in this trial is to determine the DNA sequence of tumors biopsied from pediatric patients with relapsed neuroblastoma. Based on the genetic profile of individual tumors, children will be assigned to one of three treatment groups that target different genetic pathways involved in neuroblastoma tumorigenesis. The overarching goal of the NEPENTHE trial is to use molecular profiling of individual tumors to determine the best therapeutic options for children with relapsed or refractory neuroblastoma.

Simultaneously, the lab is beginning to define a broader role for ALK in pediatric cancer. Additional studies in the Mosse Laboratory have determined that ALK is differentially expressed in high levels in neuroblastoma cells and subsets of other childhood solid tumors. Based on this finding, efforts are underway to develop immunotherapeutic strategies that specifically target ALK in neuroblastoma with potential application to other pediatric solid tumors. 

Future studies in the Mosse Laboratory will continue to focus on the underlying molecular mechanisms of ALK-driven neuroblastoma and the identification of new, less toxic, targeted cancer therapies to treat high-risk and relapsed pediatric neuroblastoma.

While this work will continue to provide insights into mechanisms that underlie the development of neuroblastoma and improve therapeutic options, the Mossé Laboratory continues to search for neuroblastoma predisposition genes in families who do not have a mutation in ALK or PHOX2B, with the ultimate goal of directly impacting patient care.