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The Hogarty Laboratory is a translational research lab focused on improving the understanding of what drives the aggressive behavior of the childhood cancer, neuroblastoma. The lab discovered mutations in ARID1A and ARID1B as neuroblastoma driver genes, and led the preclinical development of polyamine- depleting drugs that are now being tested in the clinic against MYC-dependent neuroblastomas.The lab also has a longstanding focus on Bcl2-family signaling in neuroblastoma and are among the few labs worldwide to optimize mitochondrial profiling to functionally define apoptotic dependencies. The Hogarty Lab posited that cancers are likely to have more restricted survival dependency heterogeneity, and that these dependencies can be exploited using Bcl2 family inhibitors. This provides an opportunity to apply precision medicine principles to targeting a tumor’s survival mechanisms.
- Profiling solid tumor survival dependencies: The Hogarty Lab pioneered functional mitochondrial profiling to define solid tumor survival dependencies. It was the first to adopt mitochondrial profiling to interrogate stress signaling in solid tumors. In collaboration with Anthony Letai, MD, PhD at Dana-Farber Cancer Institute, Boston, whose group developed this assay, the lab optimized the platform for solid tumors. Mitochondrial profiling, along with protein-protein interaction assays, are being used to identify solid tumor dependencies that can then be exploited.
- Multidrug resistance in cancer: Using mitochondrial profiling approaches, the lab discovered that multidrug resistant neuroblastoma mitochondria resist transducing bona fide death stimuli due to reduced inter-organelle contacts between mitochondria and endoplasmic reticulum. This provides a new paradigm for understanding, and possibly restoring, cancer therapy resistance.
- The requirement for polyamines in MYC-dependent cancer progression: Neuroblastomas have activating mutations in MYC and the Hogarty Lab identified polyamine sufficiency as a MYC dependency and drug target. The lab team was inspired by the work of John Cleveland, PhD’s group studying MYC-driven lymphoma, and have subsequently discovered that the ODC1 oncogene is co-amplified with MYCN in 6 percent of all neuroblastomas, a biomarker of poor prognosis, and that the entire polyamine pathway is coordinately deregulated by MYC. Drugs like difluoromethylornithine (an ornithine decarboxylase inhibitor) can deplete polyamines, block tumor initiation, and potently cooperate with chemotherapy in complementary tumor models.