Michael Hogarty Laboratory
Led by Michael Hogarty, MD, researchers in the Hogarty Laboratory are studying the cellular pathways and oncogenic mechanisms that transform normal peripheral neural cells into malignant and highly aggressive forms of pediatric neuroblastoma. The long-term goal of the research conducted in this laboratory is to identify novel targets that can be used to develop new therapies that are more effective and less toxic than current treatment regimens.
Ongoing research in the Hogarty laboratory demonstrated that broad deregulation of polyamine regulatory genes is a signature feature of highly aggressive and lethal forms of neuroblastoma with MYCN oncogene amplification. Additional experiments showed that the polyamine synthesis inhibitor difluoromethylornithine (DMFO) in combination with standard chemotherapy drugs exhibited potent anti-tumor activity in transgenic mice that develop MYCN amplified neuroblastoma and mice xenografted with human neuroblastomas with high risk genetic features such as TP53, ALK and/or MYCN alterations.
A Phase I clinical study is currently underway to evaluate the safety and effectiveness of the combination of DMFO given with celecoxib and chemotherapy drugs as a treatment for aggressive relapsed pediatric neuroblastoma.
Other research in the Hogarty laboratory used next generation DNA sequencing strategies across a large number of neuroblastomas to identify recurrent mutations in the chromatin remodeling genes, ARID1A and ARID1B, as frequently present in highly aggressive forms of neuroblastoma. Children whose tumors harbored ARID1A or ARID1B mutations were often treatment refractory and rapidly lethal. This suggests that disrupted chromatin-remodeling and epigenetic effects may play an important role in neuroblastoma tumorigenesis and aggressive disease progression.
In other studies, members of the Hogarty laboratory demonstrated by mitochondrial profiling that neuroblastomas rely on either Bcl2 or Mcl1 for their survival, but never both. Bcl2-dependent tumors are exquisitely sensitive to Bcl2 inhibitor drugs, such as venetoclax, providing a possible new treatment approach for these patients. Mcl1-dependent tumors do not respond to Bcl2 inhibitors but additional studies may reveal selective Mcl1 inhibitors in the future. Researchers also discovered that neuroblastomas studied after relapse had broadly defective mitochondrial signaling as a common feature, helping to explain their profound treatment resistance.
Future studies in the Hogarty Laboratory will continue to focus on clinical development of polyamine synthesis inhibitors, the identification of the molecular mechanisms by which ARID1A and ARID1B mutations contribute to neuroblastoma tumorigenesis and disease progression, and the use of mitochondrial profiling to identify new approaches to treat highly aggressive neuroblastomas.